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Angioedema

Author(s): Vanessa Ngan, Staff Writer, 2006 Updated: Dr Georgia Morley, NHS, England. Copy edited by Gus Mitchell. April 2022


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What is angioedema?

Angioedema is a skin reaction similar to urticaria. It is characterised by an abrupt, temporary, localised swelling of the deep dermal layer, subcutaneous tissue, and mucous membranes. Although it can affect any part of the body, it most often occurs around the eyes and lips and genitals. Swelling may occur in other organs, including the intestines and upper airway. 

There are multiple types of angioedema, including allergic, drug-induced, idiopathic, and hereditary angioedema (HAE). 

Urticaria is the development of transient localised oedema in the dermis, characterised by wheals and often co-exists with angioedema. Wheals are usually superficial skin-coloured or pale swellings, surrounded by erythema

Angioedema

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Who gets angioedema?

Urticaria is a common skin presentation, affecting up to 20% of people; an estimated 40% of patients with chronic urticaria (lasting over 6 weeks) have associated angioedema. The prevalence of hereditary angioedema is estimated to be 1 in 500,000.

ACE-inhibitor induced angioedema is rare, however, it is the sub-type most likely to result in hospitalisation and is more common in African-Americans. 

What causes angioedema?

Angioedema is caused by an increase in local capillary permeability and plasma extravasation, usually mediated by mast cells, histamine, or bradykinin release.

Angioedema is most commonly histamine-mediated; mast cell and basophil stimulation results in histamine release. Angioedema with urticaria tends to suggest a histaminergic form, which includes acute allergic angioedema and histaminergic idiopathic angioedema. The exact cause depends on the type of angioedema a patient has.

Angioedema type Causes
Acute allergic angioedema
(almost always occurs with urticaria within 1-2 hours of exposure to the allergen)
Non-allergic drug reaction
(onset may be days to months after first taking the medication)
  • Angiotensin-converting enzyme (ACE) inhibitors
  • Cascade of effects via kinin production, arachidonic acid metabolism and nitric oxide generation
Idiopathic angioedema
(frequently chronic and relapsing and usually occurs with urticaria)
  • In most cases the cause of angioedema is unknown
  • Can be histaminergic or non-histaminergic — will not respond to antihistamines
  • Recent research indicates that 30–50% of this type of angioedema may be associated with some types of autoimmune disorders including systemic lupus erythematosus (SLE)
Hereditary angioedema
(very rare autosomal dominant inherited disease)
  • Inherited abnormal gene that causes a deficiency of a normal blood protein
  • 3 types: Type 1 and II mutations of C1NH (SERPING1) gene on chromosome 11, encoding C1 inhibitor protein; Type III mutation in F12 gene on chromosome 12, encoding coagulation factor XII.
  • Type 1 results in low levels and function of circulating C1 inhibitor; Type II has normal levels of C1 inhibitor protein but a reduction in function
  • Occurs in 1 in 50,000 males and females; Type III is more severe in women (associated with oestrogen). 
  • Can occur spontaneously but may also be triggered by emotional stress, minor trauma such as dental procedures, and hormonal factors e.g. oestrogen derived medicines.
  • Decreased C1 inhibitor activity leads to excessive kallikrein, which in turn produces bradykinin, a potent vasodilator.
Acquired C1 inhibitor deficiency
  • Acquired during life rather than inherited
  • May be due to B-cell lymphoma or antibodies against C1 inhibitor
  • Associated with lymphoproliferative and autoimmune disease e.g. SLE
  • Age of onset is usually over 40 years
  • No family history of angioedema
Inducible angioedema

What are the clinical features of angioedema? 

General features include: 

  • Localised oedema
  • Usually affecting eyelids or lips
  • Skin-coloured or slightly red in colour
  • Associated with burning sensation
  • Not itchy
  • Non-pitting
  • Swelling usually resolve within 24-48 hrs
  • Lesions do not weep or blister and resolve without scaling (in contrast to acute eczema)
  • May affect other organs such as:
    • Intestines — causing abdominal pain
    • Upper airway — producing difficulty in breathing and swallowing.
Angioedema type Clinical features
Acute allergic angioedema
  • Almost always occurs with urticaria
  • Angioedema and urticaria both usually occur within 1-2 hours of exposure to an allergen (exception is ACE inhibitor-induced angioedema that usually occurs within the first week of treatment but can occur weeks to months later)
  • Reactions are usually self-limiting and subside within 1-3 days
  • Reactions will recur with repetitive exposures or exposure to cross-reactive substances
Non-allergic drug reaction
  • ACE inhibitor-induced angioedema occurs without urticaria
  • Likely to affect the face, lips, and tongue
  • Can be severe and require hospitalisation
Idiopathic/chronic angioedema
  • Similar to acute allergic but angioedema keeps on recurring and often no known cause is found
Hereditary angioedema
  • Patients often experience no symptoms until they reach puberty
  • Swellings can occur without any provocation or induced by precipitating factors, including local trauma, vigorous exercise, emotional stress, alcohol, and hormonal factors (menstruation, pregnancy, oestrogen)
  • Some patients may get a transitory prodromal non-itchy rash, headache, visual disturbance or anxiety
  • Face, hands, arms, legs, genitals, digestive tract and airway may be affected; swellings spread slowly and may last for 3-4 days
  • Abdominal cramps, nausea, vomiting, difficulty breathing and rarely urinary retention from swelling of internal tracts
  • Urticaria (wealing) does not occur
  • The tendency to angioedema is less pronounced in adults

Angioedema features

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How do clinical features vary in differing types of skin?

When angioedema is associated with urticaria, erythematous skin may appear purplish on darker skin tones.

What are the complications of angioedema? 

  • Tongue or throat swelling — difficulty breathing.
  • Can be life-threatening if the airway is involved. 

How is angioedema diagnosed?

Angioedema is usually diagnosed following clinical examination and detailed history taking. Important features include:

  • Time of onset
  • Exposure to potential allergens
  • Drug history e.g. ACE inhibitors
  • Family history of allergies, skin rashes, or angioedema.

Examination of the patient is important for assessing severity and determining the likely cause.

  • Airway should be assessed and secured first
  • Signs of upper airway involvement
    • Including stridor, difficulty in breathing talking and swallowing
  • Urticaria present or not
  • Areas involved
    • Face, lips, genitals, tongue
  • Abdominal pain and swelling
    • Can be a sign of HAE, important to rule out other causes
  • Signs of anaphylaxis
    • i.e. rule out anaphylaxis as a life-threatening differential – sudden onset of symptoms, airway, breathing or circulation problems, signs of shock.

If hereditary angioedema is suspected, testing can find low C4 and C1-INH levels (part of the complement system). However, cases of HAE with normal C4 levels have been reported.

Skin prick testing or RAST testing may be used when allergic angioedema is suspected. 

What is the differential diagnosis for angioedema?

What is the treatment for angioedema?

Treatment is dependent on the subtype of angioedema. Angioedema is usually treated in the same way as acute urticaria when mild.

General measures

  • Aim to identify potential triggers
  • Avoidance or removal of causative agents e.g. allergens, drugs
  • Adequate observation time in a hospital environment if angioedema has continued to progress despite treatments.

Specific measures

Allergic and Idiopathic Histaminergic Angioedema

  • For very mild symptoms, treatment may not be required
  • Antihistamines in the acute phase
    • Non-sedating second-generation antihistamines tend to be used first-line e.g. cetirizine, loratadine
    • Higher than usual (four times the standard) doses may be necessary 
    • Prophylactic antihistamines may be used
  • Depending on the severity or with impending airway jeopardy, a short course of oral steroids e.g. prednisolone and adrenaline may be required.
  • Tranexamic acid can be offered for refractory recurrent angioedema
  • Omalizumab may be reserved as prophylaxis for refractory recurrent angioedema
  • Adrenaline autoinjectors are seldom required for angioedema with weals 

Hereditary and Acquired Angioedema due to C1INH deficiency

Treatment for HAE aims to decrease morbidity and mortality, and reduce the need for hospitalisation. 

Acute presentations

  • C1-INH replacement - human plasma-derived treatments administered via Intravenous injection e.g. complement C1 esterase inhibitors (Berinert, Cinryze)
  • Bradykinin antagonists e.g. Icatibant

Prophylaxis

  • Androgen therapy e.g. Danazol
    • Side effects should be considered including weight gain, menstrual irregularities, and hirsutism.
  • Tranexamic acid

For more information, see Hereditary angioedema

What is the outcome for angioedema?

The prognosis of angioedema is dependent on the presentation severity and the initiation of, and response to appropriate treatment.

Mild symptoms often self-resolve within 72 hours. However, angioedema can be life-threatening, particularly after insect bites and stings, and in hereditary and ACE-inhibitor induced angioedema if there is airway involvement. This requires emergency assessment and intervention.

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Bibliography

  • Cicardi M, Aberer W, Banerji A. Classification, diagnosis and approach to treatment for angioedema: consensus report for the Hereditary Angioedema International Working Group. Eur J Allergy Clin Immunol. 2014; 69:602–16. DOI: 10.1111/all.12380. Journal
  • Depetri F, Tedeschi A, Cugno M.  Angioedema and emergency medicine: from pathophysiology to diagnosis and treatment. Eur J Intern Med. 2019; 59: 8–13. DOI: 10.1016/j.ejim.2018.09.004. Journal
  • Kaplan AP. Angioedema. World Allergy Organ J. 2008;1(6):103–13. doi:10.1097/WOX.0b013e31817aecbe. PubMed
  • Misra L, Khurmi N, Trentman T. Angioedema: Classification, management and emerging therapies for the perioperative physician. Indian J Anaesth. 2016;60(8): 534–41. doi: 10.4103/0019-5049.187776. Journal
  • Powell R, Leech S, Till S, Huber P, Nasser S, Clark A. BSACI guideline for the management of chronic urticaria and angioedema. Clin Exp Allergy. 2015; 45: 547–65. Guideline
  • Radonjic-Hoesli S, Hofmeier K, Micaleto S, Schmid-Grendelmeier P, Bircher A, Simon D. Urticaria and Angioedema: an Update on Classification and Pathogenesis. Clin Rev Allergy Immunol. 2018; 54(1): 88–101. DOI: 10.1007/s12016-017-8628-1. Journal

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