Angio-oedema results from a similar pathological process to that involved in urticaria, with fluid leakage and oedema occurring after inflammation of post-capillary venules. However, angio-oedema results from this process occurring in deeper layers of the skin below the dermis (urticaria affecting skin above the dermis).

Angio-oedema can occur with or without urticaria. Like urticaria, it can be acute or chronic (more than 6 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.¹

Pathophysiology

What are the clinical manifestations?

Angio-oedema and urticaria involve the same pathological process. They can occur together. Urticaria may occur alone in about 50% of cases.¹ Urticaria occurs with angio-oedema in between 40% and 85% of cases, and angio-oedema without urticaria in only 10% of cases.¹

• 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.

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:

• Histamine
• Serotonin
• 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.¹

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 depending in part on the particular immunological mechanism. Some mechanisms are better understood than others and some are very rare. There are different classifications and these can be confusing as they are often inconsistent (for example, in whether they differentiate between causes of angio-oedema alone or with urticaria) and there is often overlap between different types described. The following attempts to put a clinically informative and useful perspective on the mechanisms involved:

• Allergic angio-oedema:
  • immunoglobulin E (IgE)-mediated angio-oedema (and urticaria). It may result from specific antigen ingestion or exposure. For example:
    • Drugs
    • Latex
    • Food such as, for example, nuts and strawberries
    • Insect stings, for example Hymenoptera (wasps, bees, ants, etc.)
      Note that food additives, preservatives and dyes do not cause angio-oedema (or chronic urticaria) by an IgE-mediated mechanism.¹
  • It may result from a reaction to environmental factors such as cold and heat.
• Idiopathic angio-oedema:
  • This appears to result from a direct effect on mast cells.
  • Triggers such as stress, drugs and infection can trigger release of histamine from mast cells. Typical examples of drugs are:
    • Radiocontrast media
    • Dextran
    • Opiates
  • Thyroid dysfunction should be considered as there is an association with autoimmune conditions such as thyroiditis.
• Hereditary angio-oedema (HAE):²
  • This only accounts for about 0.5 % of cases of angio-oedema.
  • Although rare it is important to identify, as treatments are available and it has a high mortality rate.
  • They typically present in childhood (median age about 5 years, worsening at puberty) with self-limiting attacks of facial or mouth swelling after local trauma. Typically it may be noticed after dental treatment or local trauma to the mouth.
  • They are broadly autosomal dominant disorders (on chromosome 11). There may be a family history (only about 25%), but an individual case may be caused by a new mutation. The possible genetic abnormalities responsible are varied with over 150 different mutations responsible.
  • There are 2 types and they both involve plasma enzyme C1 esterase inhibitor (C1-INH) deficiency (part of the complement pathway):
    • Type 1 HAE. This accounts for 80 to 85% of HAE. There are low plasma levels of a normal C1-INH protein (30% of normal).
    • Type 2 HAE has normal or elevated levels of a dysfunctional C1-INH. Ineffective levels of C1-INH allow an abnormal increase in the activity of the total complement pathway and the production of vasoactive substances (for example, histamine, serotonin, and kinins).
• 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 2 types:
    • Type 1 (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 2 (AAE-II) is more common and is associated with presence of autoantibodies 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 and steroids in an acute attack (unlike patients with the acute allergic form).
• Angiotensin-converting enzyme (ACE) inhibitor-induced angio-oedema:
  • This is responsible for between 4% and 8% of cases of angio-oedema.
  • 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.¹
  • The episodes of angio-oedema may persist for months after stopping the ACE inhibitor.¹
  • Individuals of Afro-Caribbean origin are at increased risk of ACE inhibitor-induced angio-oedema.
  • ACE inhibitors trigger attacks by a potentiation of bradykinin.
  • Antihistamines, corticosteroids and adrenaline are often used to treat these individuals but their efficacy is unclear.¹
• Non-histaminergic angio-oedema:
  • This may occur in 1 in every 20 cases of angio-oedema.
  • There is angio-oedema without urticaria in such cases.
  • Parasites, infections and autoimmune disease are not associated.
  • Patients do not respond to antihistamines.
• Other types:
  • Other drugs may precipitate attacks by effects on arachidonic acid metabolism. Examples include:
    • Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs)
    • Cyclooxygenase inhibitors

Epidemiology

• Angio-oedema is common and affects between 2% and 15% of the population.
• 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 30 and 50% of chronic urticaria. It may be associated with other autoimmune conditions such as thyroiditis.¹

Presentation

History

• 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?¹

    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.¹ This should include specific exclusion of drugs associated with angio-oedema and urticaria:
    • ACE inhibitors
    • Aspirin
    • Opiates
    • Radiocontrast substances
    • Dextran
    • NSAIDs
    • Statins
    • Antipsychotic drugs
    • Oestrogens
  • Other possible triggers should be identified. For example:
    • Hymenoptera stings
    • Food allergies:
      • Shellfish
      • Nuts
      • Tomatoes and fresh berries
      • Eggs
      • Dairy products
      • Chocolate
      • Additives and preservatives
    • 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
    • Chronic urticaria (has often been associated with Helicobacter pylori infection)
  • 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. If any associated urticarial lesions are tender and painful rather than itchy. If there is evidence of residual petechial haemorrhage, purpura or bruising in the skin. When the patient has any symptoms or signs of underlying disease (such as fever, significant malaise and arthralgia).

Examination

• Assess airway:
  • 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.
• General examination:
  • 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 hereditary angio-oedema, massive abdominal oedema may present with colicky abdominal pain, abdominal distention and signs suggestive of bowel obstruction.

Differential diagnosis

• Anaphylaxis
• Asthma
• Other skin conditions:
  • Bullous pemphigoid
  • Cellulitis
  • Contact dermatitis
  • Erysipelas
  • Erythema multiforme
  • Morbilliform drug eruptions
  • Systemic lupus erythematosus
  • Urticaria pigmentosa
• Other causes of facial swelling or airway obstruction:
  • Epiglottitis (can occur in adults)
  • Peritonsillar abscess
  • Retropharyngeal abscess

Investigations

Investigations are determined by the clinical history and presentation, but may not be necessary.¹ Possible investigations include:

• A full blood count (FBC) and differential white count, which are useful. 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.¹
• Erythrocyte sedimentation rate (ESR). If elevated this suggests an underlying systemic condition such as chronic infection, vasculitis and paraproteinaemia.¹
• Urinalysis looking for haematuria and proteinuria will help to detect the presence of urinary tract infection and renal involvement in vasculitis.¹
• Skin testing and/or radioallergosorbent test (RAST) on blood to confirm sensitivity to allergens (such as nuts, fish,drugs, envenomation and latex).
• Plasma levels of various components of the complement pathway (complement profile) can be useful, particularly where hereditary angio-oedema (HAE) is suspected. Levels of the enzyme C1-INH deficiency 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.
• Thyroid function and antibody testing when there is a history of thyroid disease. In about one-fifth of patients with chronic urticaria there are antithyroid antibodies compared with a figure of 6% in the general population.¹
• Stool tests for ova, cysts and parasites when there is chronic urticaria associated with the angio-oedema and a history of poor sanitation or travel to such areas.
• Investigations for collagen vascular disease should be performed with arthralgia, photosensitivity or other suggestive symptoms.
• Abdominal ultrasound may be useful when HAE causes acute abdominal symptoms (to exclude some surgical pathologies).

Management^1,3

• Prevention:
  • Management must include the identification as well as the exclusion of possible triggers.¹
  • Patient education and a personalised management plan are essential to management.¹ This may involve avoidance of certain drugs (for example, aspirin, NSAIDs and ACE inhibitors).
• Treatment of acute attacks of angio-oedema:
  

  Acute angio-oedema attacks: 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 for acute anaphylaxis (including adrenalin, antihistamines and steroids). Aerosolised adrenalin 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.

• Chronic urticarias and angio-oedema:
  • Autoimmune urticarias triggered by physical factors are more resistant to treatment and often follow a protracted course.¹
  • A standard dose of a non-sedating H1 antihistamine should be started.¹
  • 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.¹
  • 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.¹
• Other treatments for angio-oedema:
  • C1NH concentrates have been used in hereditary angio-oedema (HAE) types 1 and 2..
  • In acquired angio-oedema type 1 (AAE-I), treatment of any underlying lymphoproliferative disease can eliminate the cause of the angio-oedema. In AAE-I and acquired angio-oedema type 2 (AAE-II), antifibrinolytics and androgens can also be helpful.
  • Immunosuppressive drugs may be useful in AAE-II to reduce autoantibody production (for example, cyclophosphamide).
  • In allergic angio-oedema avoidance, antihistamines and adrenaline are used. It may be useful to carry an adrenaline pen-injector for use when there is airway involvement (under Management heading above, see Treatment of acute attacks of angio-oedema).
  • New drugs are being developed for HAE.

Prevention

• A management plan which takes account of triggers will allow for attacks to be prevented. For example, ACE inhibitors can cause angio-oedema without urticaria, resulting in airway compromise, and should be withdrawn in subjects with a history of angio-oedema.¹
• Antiandrogens (such as danazol) can often prevent attacks in hereditary angio-oedema (HAE) by raising C1 esterase inhibitor (C1-INH) levels. In acquired angio-oedema type 1 (AAE-I), danazol may be useful but not in acquired angio-oedema type 2 (AAE-II).
• In AAE, severe attacks may be aborted with C1-INH concentrates (needs very large doses) or fresh frozen plasma. It is worth considering prophylactic treatment with antifibrinolytic agents and C1-INH before surgery.
• It may be appropriate to avoid trauma and contact sports.

Complications

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.

Document references

1. Management of chronic urticaria and angio-oedema, British Society for Allergy and Clinical Immunology (2007); Clin Exp Allergy. 2007 May; 37(5):631-50.
2. WR Heymann. Angioedema, Hereditary. eMedicine. October 2009
3. Grattan C, Powell S, Humphreys F; Management and diagnostic guidelines for urticaria and angio-oedema. Br J Dermatol. 2001 Apr;144(4):708-14. [abstract]

Internet and further reading

• Angio-oedema and anaphylaxis, Clinical Knowledge Summaries (2007)
• Dodds N, Sinert R; Angioedema. eMedicine. (2010)

Acknowledgements