PatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.
Angio-oedema results from a similar pathological process to that involved in urticaria, with fluid leakage and oedema occurring after inflammation of postcapillary venules. However, angio-oedema results from this process occurring in deeper layers of the skin below the dermis (urticaria affecting skin above the dermis). The table under 'Pathophysiology', below, illustrates the differences between angio-oedema and urticaria.
Angio-oedema can occur with or without urticaria. Like urticaria, it can be acute or chronic (more than six weeks' duration) as well as allergic, hereditary or idiopathic. Although rarely life-threatening, chronic urticaria and angio-oedema are very troublesome and have a detrimental effect on individuals affected, comparable with severe coronary artery disease.
Angio-oedema and urticaria involve the same pathological process. Urticaria may occur alone in about 50% of cases. Urticaria occurs with angio-oedema in between 40% and 85% of cases, and angio-oedema without urticaria in only 10% of cases.
- Urticaria is characterised by well-defined areas of temporary, pruritic oedema of the dermis. These wheals have raised erythematous borders with central pallor or blanching.
- Angio-oedema is non-pitting, subdermal oedema mainly seen around easily distensible structures (such as the periorbital area, lips, tongue, oropharynx and genitals). It can cause rapid pharyngeal obstruction as the swelling increases. Unlike urticaria, there is typically no itching of the affected skin.
|Tissues involved||Subcutaneous and submucosal surfaces.||Epidermis and dermis.|
|Organs affected||Skin and mucosa, particularly the eyelids, lips and oropharynx.||Skin only.|
|Duration||Transitory (between 24-96 hours).||Transitory (usually <24 hours).|
|Symptoms||Pruritus may or may not be present. Often accompanied by pain and tenderness.||Pruritus is usually present. Pain and tenderness are uncommon.|
|Physical signs||Erythematous or skin-coloured swellings occurring below the surface of the skin.||Erythematous patches and wheals on the surface of the skin.|
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What causes the oedema?
Angio-oedema results from vascular leakage in the layers of skin below the dermis and in the subcutis. The mast cells in dermis or mucosa are central to the various mechanisms involved. On degranulation the mast cell releases vasoactive mediators such as:
- Bradykinin and other kinins
Membrane-derived mediators such as leukotrienes and prostaglandins are subsequently released and this contributes to both the early- and late-phase responses with extravasation of fluid into the superficial tissues.
These various mediators act on arterioles to cause dilatation and this, in turn, causes leakage of fluid from venules because of their looser cell junctions. The triggers and mechanisms for release of these vasoactive mediators are what define the different types of angio-oedema.
What are the triggers and trigger mechanisms?
There are several different triggers or causes; some mechanisms are better understood than others and some are very rare. The following classification (which breaks types down into histaminergic, bradykinin-mediated, with C1 esterase inhibitor (C1-INH) deficiency or without and non-histaminergic, idiopathic angio-oedema) may help to determine effective treatment options.
Histaminergic or mast cell-mediated angio-oedema
- Immunoglobulin E (IgE)-mediated angio-oedema (and urticaria): this is an allergic reaction and may result from specific antigen ingestion or exposure to drugs (such as certain beta-lactam antibiotics), non-steroidal anti-inflammatory drugs (NSAIDs), latex, radiocontrast media, food (for example, nuts and strawberries), alcohol, insect stings (for example, Hymenoptera (wasps, bees, ants, etc)), autoimmune diseases such as thyroiditis and systemic lupus erythematosus (SLE).
- Direct mast cell mediator release: this is a pseudo-allergic reaction with triggers such as stress, heat, and cold; drugs and infection trigger the release of histamine from mast cells. Typical examples of drugs are radiocontrast media, dextran, muscle relaxants, opiates and cyclo-oxygenase inhibitors. Patients may have combined IgE- and non-IgE-mediated angio-oedema in response to these drugs.
- Histaminergic idiopathic angio-oedema: this is a pseudo-allergy for which no pathophysiological trigger has yet been found. 86% respond to antihistamines. Food additives, preservatives and dyes may fall into this group.
This responds suboptimally to treatment with antihistamines, adrenaline (epinephrine) and corticosteroids. It may be divided into those with or without C1-INH deficiency.
With C1-INH deficiency
- Hereditary angio-oedema (HAE).
- Acquired angio-oedema (AAE): these are relatively rare and start usually in adult life. There is, of course, no family history of angio-oedema. There are two types:
- Type I (AAE-I) is associated with other diseases, most commonly B-cell lymphoproliferative disorders, and involves immune complex formation. It can produce a serum sickness-like illness with angio-oedema, arthralgia, urticaria and a palpable purpura. The purpura is produced by a necrotising venulitis.The disease process impairs or disrupts normal C1-INH function. The angio-oedema may precede development of other symptoms, making it important to look for underlying malignancy in AAE-I.
- Type II (AAE-II) is more common and is associated with presence of auto-antibodies to C1-INH. There is no underlying malignancy.
There is a high mortality with 25-30% of patients dying from asphyxia. Unfortunately, they do not respond well to adrenaline (epinephrine) and steroids in an acute attack (unlike patients with the acute allergic form).
Without C1-INH deficiency
- Angiotensin-converting enzyme (ACE) inhibitor-induced angio-oedema: this is responsible for between 4% and 8% of cases of angio-oedema. ACE inhibitors trigger attacks by a potentiation of bradykinin. Most cases were initially thought to occur in the first week of treatment but it is now known that later-onset angio-oedema, sometimes after many years of uneventful drug use, is common. The episodes of angio-oedema may persist for months after stopping the ACE inhibitor. Individuals of Afro-Caribbean origin are at increased risk of ACE inhibitor-induced angio-oedema. Antihistamines, corticosteroids and adrenaline (epinephrine) are often used to treat these individuals, with poor efficacy.
- Oestrogen-related hereditary angio-oedema - HAE type lll: this is an oestrogen-sensitive condition. Women become symptomatic during pregnancy or after oestrogen therapy. Symptoms usually appear later in life and attacks are less severe. Men are rarely symptomatic.
- Autoimmune angio-oedema: in some cases, autoimmune angio-oedema is resistant to antihistamine and corticosteroids and so mechanisms other than histamine release are being sought.
Non-histaminergic idiopathic angio-oedema
14% of patients with idiopathic angio-oedema do not respond to antihistamines. There is angio-oedema without urticaria in such cases. Parasites, infections and autoimmune disease are not associated. Full or partial relief of symptoms may be achieved with tranexamic acid.
- Angio-oedema is common, but varies with the population investigated. Lifetime prevalence rates of 8.8% have been reported.
- The most common variety is recurrent idiopathic angio-oedema.
- The inherited (autosomal dominant) forms are rare and prevalence is only about 1/100,000 of the population.
- Autoimmune urticaria/angio-oedema accounts for between 40-45% of chronic urticaria. It may be associated with other autoimmune conditions such as thyroiditis.
- Detail of the current episode should be recorded. Is there associated urticaria? What is the duration of the attack?
- Is there any family history or history of recurrent episodes with particular triggers? Hereditary types often present in childhood with swelling of the face and mouth following local trauma (such as dental extraction).
- What is the trigger? Patients with angio-oedema or urticaria should be questioned in detail to identify the offending antigen in cases of allergic angio-oedema. Initial questions include:
- Is allergy likely?Allergy is more likely if the urticaria or angio-oedema occurs:
- Only and reproducibly within 60 minutes (usually within 20 minutes) of eating a particular food.
- If a particular food has been eaten followed by exercise.
- After exposure to latex.
- After any drugs the patient has taken (aspirin, NSAIDs and ACE inhibitors in particular).
- A full medication history is mandatory. This should include specific exclusion of drugs associated with angio-oedema and urticaria. Other possible triggers should be identified. For example Hymenoptera stings or food allergies, local trauma (particularly dental procedures or following tonsillectomy), physical factors (for example, sunlight, cold, and heat), animal dander, emotional stress, postinfective illness, thyroid disease associated with autoimmunity, leukaemia or Helicobacter pylori infection.
- Is allergy likely?
- However, remember that very often angio-oedema can occur without identifiable cause or warning.Vasculitis is more likely if:
- The angio-oedema is relentless rather than evanescent and self-limiting.
- Individual lesions last for more than 24 hours.
- Any associated urticarial lesions are tender and painful rather than itchy.
- There is evidence of residual petechial haemorrhage, purpura or bruising in the skin.
- The patient has any symptoms or signs of underlying disease (such as fever, significant malaise and arthralgia).
- Ensure patency and identify any obstructive symptoms (with, for example, stridor, dysphonia).
- Severe attacks can indicate the onset of systemic anaphylaxis and are characterised initially by dyspnoea or throat symptoms.
- Temperature, pulse and blood pressure.
- Distribution of the oedema:
- Usually well demarcated and in easily distensible tissues.
- Face (especially the lips, tongue, ears, eyes and uvula), limbs and genitalia are the most common sites.
More unusual manifestations:
- In HAE, massive abdominal oedema may present with colicky abdominal pain, abdominal distention and signs suggestive of bowel obstruction.
- Other skin conditions - eg, bullous pemphigoid, cellulitis and erysipelas, contact dermatitis, erythema multiforme, morbilliform drug eruptions, SLE or urticaria pigmentosa.
- Other causes of facial swelling or airway obstruction - eg, epiglottitis (can occur in adults), peritonsillar abscess or retropharyngeal abscess.
Investigations are determined by the clinical history and presentation, but may not be necessary in the acute phase. Possible investigations include:
- FBC and differential white count; the eosinophil count may be elevated in parasitic infections and in some drug-induced reactions. There may also be an elevated neutrophil count in urticarial vasculitis.
- ESR; if elevated, this suggests an underlying systemic condition such as chronic infection, vasculitis and paraproteinaemia.
- Urinalysis; haematuria and proteinuria may indicate the presence of urinary tract infection and renal involvement in vasculitis.
- Skin testing and/or radioallergosorbent test (RAST) blood test; confirms sensitivity to allergens (such as nuts, fish, drugs, envenomation and latex).
- Plasma levels of various components of the complement pathway (complement profile); levels of the enzyme C1-INH can be measured. Initially the serum C4 level is measured and, if low, quantitative and functional C1 assays are performed.
- Investigate for underlying malignancy in acquired angio-oedema (AAE).
- Thyroid function and antibody testing; about 20% of patients with chronic urticaria have thyroid antibodies compared with a figure of 6% in the general population.
- Stool tests for ova, cysts and parasites; if there is a history of travel to areas with poor sanitation.
- Investigations for collagen vascular disease; if there is arthralgia, photosensitivity or other suggestive symptoms.
- Abdominal ultrasound may be useful when HAE causes acute abdominal symptoms (to exclude some surgical pathologies).
In general, the management of angio-oedema depends on whether it is acute or chronic; on the severity and frequency of attacks, and on its mechanism. Non-histamine-mediated angio-oedema tends to respond poorly to adrenaline (epinephrine), corticosteroids and antihistamines, and often requires alternative treatments.
Histamine or mast cell-mediated angio-oedema
Treatment of acute attacks of angio-oedema
- These often need no treatment.
- However, when there is oedema around the head and neck, observation to detect airway involvement is required (for example, hoarseness).
- Airway involvement requires a regimen similar to that for acute anaphylaxis (including adrenaline (epinephrine), antihistamines and steroids).
- It is advisable for patients to carry an adrenaline (epinephrine) pen injector for when there has been airway involvement during previous episodes.
- Aerosolised adrenaline (epinephrine) has been used in a conventional nebuliser. Airway interventions can be difficult because there may be a massive degree of oral obstruction (a nasal approach may be easier) and some patients may need cricothyrotomy.
- Patients with mild, limited symptoms can be reassured that symptoms are self-limiting and typically disappear within hours to days, on steroids and antihistamines.
- Management must include the identification, as well as the exclusion, of possible triggers.
- Patient education and a personalised management plan are essential to management. This may involve avoidance of certain drugs (for example, aspirin) known to trigger attacks.
Chronic urticarias and angio-oedema
- Autoimmune urticarias triggered by physical factors are more resistant to treatment and often follow a protracted course.
- A standard dose of a non-sedating H1 antihistamine should be started.
- The treatment regime should be modified according to treatment response and development of side-effects. Higher-than-normal doses of antihistamines may be needed for severe urticaria or angio-oedema.
- If an antihistamine is required in pregnancy, the lowest dose of chlorpheniramine or loratadine should be used. Similarly, If an antihistamine is needed with breast-feeding, it is recommended that either loratadine or cetirizine be taken at the lowest dose.
Non-histamine- or bradykinin-mediated angio-oedema
- It is important to distinguish these from histamine-mediated angio-oedemas, as there may be no urticaria, and they respond poorly to adrenaline (epinephrine), corticosteroids and antihistamines.
- Airway compromise requires prompt life-saving procedures such as intubation and ventilation.
- Severe abdominal pain also requires emergency treatment.
- Acute attacks may be treated with C1-INH concentrates derived from fresh frozen plasma.
- Icatibant - a bradykinin receptor antagonist - and ecallantide - a kallikrein antagonist - provide subcutaneous alternatives to C1-INH.
- Individualised management plans which take into account triggers are required for prevention and prophylaxis of these conditions
- Patients should be encouraged to carry management cards that briefly explain the patient's diagnosis, outline the indicated treatment for acute attacks, and provide contact information for the supervising clinician.
Acquired angio-oedema (AAE)
- Severe attacks may be aborted with C1-INH concentrates (needs very large doses) or fresh frozen plasma.
- Antifibrinolytics such as tranexamic acid and aminocaproic acid may be useful in mild attacks. Anti-androgens may also be used but are less effective.
- In acquired angio-oedema type 1 (AAE-I), danazol may also help to prevent attacks.
- In AAE-I, treatment of any underlying lymphoproliferative disease can eliminate the cause of the angio-oedema.
- Immunosuppressive drugs may be useful in AAE-II to reduce auto-antibody production (for example, cyclophosphamide).
- Case reports and limited data support the use of C1-INH, fresh frozen plasma and icatibant to treat attacks associated with laryngeal oedema.
- ACE inhibitors are contra-indicated once angio-oedema has occurred.
- Discontinuation of the drug results in resolution of symptoms in most but not all cases.
- Although angiotensin-II receptor antagonists have been reported to cause angio-oedema, switching to this drug type is usually successful.
The most severe complication is asphyxia and death from life-threatening airway obstruction. However, quality of life can be affected where there are chronic, lesser manifestations of the disease.
Further reading & references
- Angio-oedema and anaphylaxis; NICE CKS, January 2012
- Anaphylaxis; NICE Clinical Guideline (December 2011)
- Clinical Practice Guideline: Initial Evaluation and Management of Patients Presenting with Acute Urticaria or Angioedema; American Academy of Emergency Medicine (2006)
- Management of chronic urticaria and angio-oedema; British Society for Allergy and Clinical Immunology (2007)
- Grigoriadou S, Longhurst HJ; Clinical Immunology Review Series: An approach to the patient with angio-oedema. Clin Exp Immunol. 2009 Mar;155(3):367-77.
- Zingale LC, Beltrami L, Zanichelli A, et al; Angioedema without urticaria: a large clinical survey. CMAJ. 2006 Oct 24;175(9):1065-70.
- Sanchez-Borges M, Asero R, Ansotegui IJ, et al; Diagnosis and treatment of urticaria and angioedema: a worldwide perspective. World Allergy Organ J. 2012 Nov;5(11):125-47. doi: 10.1097/WOX.0b013e3182758d6c.
- Evaluation and management of urticaria in adults and children; British Association of Dermatologists (2007)
- Colas C, Montoiro R, Fraj J, et al; Nonhistaminergic idiopathic angioedema: clinical response to icatibant. J Investig Allergol Clin Immunol. 2012;22(7):520-1.
- Vasekar M, Craig TJ; ACE inhibitor-induced angioedema. Curr Allergy Asthma Rep. 2012 Feb;12(1):72-8. doi: 10.1007/s11882-011-0238-z.
Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.
Dr Richard Draper
Dr Hayley Willacy
Dr John Cox