Angioedema

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

For reading more on patient information, click here

Overview

Angioedema can be classified into the following types: Allergic angioedema, bradykinin mediated angioedema, drug induced angioedema, hereditary angioedema, and acquired angioedema. Angioedema should be differentiated from: Acute urticaria, anaphylaxis, food Allergy, and drug allergy. Abdominal attacks have also been known to cause a significant increase in the patient's white blood cell count, usually in the vicinity of 13-30,000. As the symptoms begin to diminish, the white count slowly begins to decrease, returning to normal when the attack subsides. Possible complications include: Anaphylactic reaction and life-threatening airway blockage (if swelling occurs in the throat). Angioedema that does not affect the breathing may be uncomfortable, but is usually harmless and goes away in a few days. Predicting where and when the next episode of edema will occur is impossible. Most patients have an average of one episode per month, but there are also patients who have weekly episodes or only one or two episodes per year. The triggers can vary and include infections, minor injuries, mechanical irritation, operations or stress. In most cases, edema develops over a period of 12-36 hours and then subsides within 2-5 days. The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue are swollen up. Urticaria (hives) may develop simultaneously. Rash may be present. To prevent recurrent attacks of angioedema: Avoiding irritating the affected area, staying away from known allergens, and never taking medications that are not prescribed for the patient.

Historical Perspective

• Dr Heinrich Quincke first described the clinical symptoms of angioedema in 1882.
• Sir William Osler explained in 1888 that some cases may have a hereditary etiology. He coined the term hereditary angio-neurotic edema.

Classification

Angioedema can be classified into the following types:

• Allergic angioedema
• Bradykinin mediated angioedema
  • Drug induced angioedema
  • Hereditary angioedema
    • Type 1 - decreased levels of C1INH (85%);
    • Type 2 - normal levels but decreased function of C1INH (15%);
    • Type 3 - no detectable abnormality in C1INH, occurs in an X-linked dominant fashion and therefore mainly affects women; it can be exacerbated by pregnancy and use of hormonal contraception (originally described by Bork et al in 2000, exact frequency uncertain).It has been linked with mutations in the factor XII gene.
• Acquired angioedema

Pathophysiology

Allergic reaction is a life-threatening cause of angioedema. Allergic reaction involves detection of a foreign substance by the immune system that results in histamine release into the bloodstream. The cause of angioedema cannot be identified in many cases. The following may cause angioedema:

• Hypersensitivity to: Animal dander (scales of shed skin), exposure to sunlight, cold or heat, foods such as berries, shellfish, fish, nuts, eggs, milk, and others
• Insect bites
• Estogen
• Drug allergies: Reaction to medications such as antibiotics (aztreonam, atovaquone and proguanil hydrochloride, penicillin, meropenem, and sulfa drugs), cexamethasone, ceftazidime, clobazam, cromolyn, cytomegalovirus immune globulin, niacin, nonsteroidal anti-inflammatory drugs (NSAIDs, blood pressure medicines (ACE inhibitors), pregabalin, prednisolone, rabeprazole, ritonavir, ustekinumab.
• Side Effect to Medications like: Aminohippurate, amobarbital sodium, boceprevir, caspofungin acetate, cefoxitin sodium, chloramphenicol sodium succinate, doxycycline, eslicarbazepine acetate, estramustine, hepatitis B immunoglobulin,hydroxyprogesterone caproate, imipenem-cilastatin,lacosamide, lincomycin hydrochloride, lisinopril and hydrochlorothiazide, meropenem, naratriptan, oxaprozin, oxytetracycline, polidocanol, potassium iodide, phenobarbital, quazepam, sodium aurothiomalate, sorafenib, streptomycin, sulfasalazine, trovafloxacin mesylate, zopiclone, sirolimus, cefadroxil, cefaclor, taliglucerase alfa, trichophyton mentagrophytes and trichophyton rubrum, trospium
• Pollen
• Infections or autoimmune diseases

Hives and angioedema may also occur after infections or with other illnesses (including autoimmune disorders such as lupus, leukemia and lymphoma). A form of angioedema runs in families and has different triggers, complications, and treatments. This is called hereditary angioedema.

• The progression to angioedema usually involves the pathway leading to activation of bradykinin.
• Bradykinin is a molecular peptide that causes vasodilation. Bradykinin mediated vasodilation results in rapid fluid accumulation in the interstitial space resulting in edema of the underlying tissue. Bradykinin is a known pain mediator and in addition to pain can be released in response to various different stimuli.
• Angioedema can also be mediated by mechanisms that interfere with bradykinin production or metabolism. ACE is one of the enzymes that degrades bradykinin and is blocked by ACE inhibitors, can result in angioedema as a medication side effect.
• A hereditary deficiency of C1-esterase inhibitor (C1INH) results in continuous activation of complement system resulting in excess production of bradykinin and kallikrein. C1-esterase inhibitor (C1INH) inhibits the conversion of C1 to C1r and C1s, which in turn activates other proteins of the complement system.
• Angioedema can also be due to an autoimmune disorder that results in antibody formation against C1INH. This is a type of acquired angioedema and is associated with the development of lymphoma.
• An episode of angioedema can be triggered in susceptible individuals as a result of consumption of foods that are vasodilators like alcohol and cinnamon. Medication like ibuprofen, acetaminophen and aspirin can increase the probability of an episode in some patients.

Differentiating [disease name] from other Diseases

• The following table outlines the differential diagnosis of various types of angioedema:

	Concentration of C1-esterase inhibitor	Function of C1-esterase inhibitor	C4	Tryptase
Hereditary angioedema type I	↓	↓	↓	Normal
Hereditary angioedema type II	N/↑	↓	↓	Normal
Hereditary angioedema type III	Normal	Normal	Normal	Normal
Acquired Angioedema	↓	↓	↓	Normal
ACE inhibitor induced Angioedema	Normal	Normal	Normal	Normal
Anaphylaxis	Normal	Normal	Normal	N/↑

Angioedema should be differentiated from:

• Acute urticaria
• Anaphylaxis
• Food Allergy
• Drug allergy

Risk Factors

• Common risk factors in the development of angioedema are previous history of allergic reactions, family history of allergic reactions, and other autoimmune disorders (atopia, eczema, etc).

Natural History, Complications and Prognosis

• The stomach attacks in angioedema can last anywhere from 1-5 days on average, and can require hospitalization for aggressive pain management and hydration. Abdominal attacks have also been known to cause a significant increase in the patient's white blood cell count, usually in the vicinity of 13-30,000. As the symptoms begin to diminish, the white count slowly begins to decrease, returning to normal when the attack subsides.
• Possible complications include:
  • Anaphylactic reaction.
  • Life-threatening airway blockage (if swelling occurs in the throat).
• Angioedema that does not affect the breathing may be uncomfortable, but is usually harmless and goes away in a few days.
• Predicting where and when the next episode of edema will occur is impossible. Most patients have an average of one episode per month, but there are also patients who have weekly episodes or only one or two episodes per year. The triggers can vary and include infections, minor injuries, mechanical irritation, operations or stress. In most cases, edema develops over a period of 12-36 hours and then subsides within 2-5 days.

Diagnosis

Symptoms

• History of recent exposure to an allergen (e.g. peanuts) should be inquired.
• Common Symptoms:
  • Swelling of face - the skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue, swell up over the period of minutes to several hours. The swelling can also occur elsewhere, typically in the hands.
  • Difficulty breathing
  • Pain - the pain associated with the swellings varies from mildly uncomfortable to agonizing pain, depending on its location and severity.
  • Itching - the swelling can be itchy
  • Abdominal pain
  • Vomiting
  • Weakness
  • Abdominal cramping.
  • Swollen lining of the eyes (chemosis).

• In Hereditary angioedema (HAE) there is usually no associated itch or urticaria, as it's not an allergic response. Patients with HAE can also have recurrent* episodes (often called "attacks") of abdominal pain, usually accompanied by intense vomiting, weakness, and in some cases, watery diarrhea, and an unraised, non-itchy splotchy/swirly rash.

Physical Examination

• The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue are swollen up. Urticaria (hives) may develop simultaneously. Rash may be present.
• Swollen neck may be present.
• Stridor and wheeze may be heard in lung fields.
• Swollen genitals may be seen.
• Swollen extremities may be present.
• Slightly decreased sensations may be present in the affected areas due to compression of the nerves.

Laboratory Findings

• The diagnosis is made on the clinical picture. Routine blood tests (complete blood count, electrolytes, renal function, liver enzymes) are typically performed. Mast cell tryptase levels may be elevated if the attack was due to an acute allergic (anaphylactic) reaction. When the patient has been stabilized, particular investigations may clarify the exact cause; complement levels, especially depletion of complement factors 2 and 4, may indicate deficiency of C1-inhibitor.

• The hereditary form (HAE) often goes undetected for a long time, as its symptoms resemble those of more common disorders, such as allergy or intestinal colic. An important clue is the failure of angioedema to respond to antihistamines or steroids, a characteristic that distinguishes it from allergic reactions. It is particularly difficult to diagnose HAE in patients whose episodes are confined to the gastrointestinal tract. Besides a family history of the disease, only a laboratory analysis can provide final confirmation. In this analysis, it is usually a reduced complement factor C4, rather than the C1-INH deficiency itself, that is detected. The former is used during the reaction cascade in the complement system of immune defense, which is permanently overactive due to the lack of regulation by C1-INH.

Imaging Findings

• There are no specific imaging findings associated with angioedema, although in case of severe allergic reaction may show pleural effusion.

Treatment

Allergic Angioedema

In allergic angioedema, avoidance of the allergen and use of antihistamines may prevent future attacks. Cetirizine, marketed as Zyrtec, is a commonly prescribed antihistamine for angioedema. Some patients have reported success with the combination of a nightly low dose of cetirizine to moderate the frequency and severity of attacks, followed by a much higher dose when an attack does appear. Severe angioedema cases may require desensitization to the putative allergen, as mortality can occur. Chronic cases require steroid therapy, which generally leads to a good response.

Bradykinin Mediated Angioedema

Drug Induced Angioedema

In ACE inhibitor use, the medication needs to be discontinued, and all similar drugs need to be avoided. There is a certain degree of controversy whether angiotensin II receptor antagonists are safe in patients with a previous attack of angioedema.

Hereditary Angioedema

In hereditary angioedema, specific stimuli that have previously luxated attacks may need to be avoided in the future.

Acute Treatment

The aim of acute treatment is to halt progression of the edema as quickly as possible, which can be life-saving, particularly if the swelling is in the larynx. In Germany, most acute treatment consists of C1-INH concentrate from donor blood, which must be administered intravenously. In an emergency, fresh frozen blood plasma, which also contains C1-INH, can also be used. However, in most European countries, C1-INH concentrate is only available to patients who are participating in special programmes. Fresh Frozen Plasma (FFP) can be used as an alternative to C1-INH concentrate.

In severe cases, stridor of the airway occurs, with gasping or wheezy inspiratory breath sounds and decreasing oxygen levels. Intubation is required in these situations to prevent respiratory arrest and risk of death.

Long-term Prophylaxis

Patients in whom episodes occur at least once a month or who are at high risk of developing laryngeal edema require long-term prophylaxis. This often involves male sex hormones (androgens), which increase production of C1-INH in the liver through an as yet unknown mechanism. The dose should be kept as low as possible because of its frequent adverse effects. The use of androgens is particularly problematic in children and they must not be taken during pregnancy. Several cases in which patients developed benign liver tumours during treatment with the androgen danazol resulted in the substance being taken off the market in Germany at the beginning of 2005.

As an alternative, drugs known as fibrinolysis inhibitors, such as tranexamic acid, are used, although their effect is comparatively weak and their potential for side effects is questionable.

Short-term Prophylaxis

Short-term prophylaxis is normally administered before surgery or dental treatment. In Germany, C1-INH concentrate is used for this and given 1-1.5 hours before the procedure. In countries where C1-inhibitor concentrate is not available or only available in an emergency (laryngeal edema), high-dose androgen treatment is administered for 5-7 days.

Acquired Angioedema

In acquired angioedema types I and II and non-histaminergic angioedema, antifibrinolytics such as tranexamic acid or ε-aminocaproic acid may be effective. Cinnarizine may also be useful because it blocks the activation of C4 and can be used in patients with liver disease while androgens cannot.

Prevention

To prevent recurrent attacks of angioedema:

• Avoiding irritating the affected area.
• Staying away from known allergens.
• Never taking medications that are not prescribed for the patient.

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  Angioedema. Adapted from Dermatology Atlas.

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  Angioedema. Adapted from Dermatology Atlas.

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  Angioedema. Adapted from Dermatology Atlas.

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  Angioedema. Adapted from Dermatology Atlas.

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  Angioedema. Adapted from Dermatology Atlas.

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  Angioedema. Adapted from Dermatology Atlas.

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  Angioedema. Adapted from Dermatology Atlas.

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  Angioedema. Adapted from Dermatology Atlas.