Angio-oedema

What is angio-oedema?¹

Angio-oedema is swelling of deep dermis, subcutaneous, or submucosal tissue, often affecting the face (lips, tongue, and eyelids), genitalia, hands, or feet. Less commonly, submucosal swelling affects the bowel and airway. It is a result of increased leakage of plasma from the capillaries located in the deep layers of the skin and the mucosae.²

Angio-oedema involves a similar pathological process to that in urticaria, with fluid leakage and oedema, and frequently co-exists. Angio-oedema most commonly occurs with urticaria but may occur in isolation.

Angio-oedema can be classified:

• According to duration:

  • Acute: symptoms last for less than six weeks.

  • Chronic: symptoms persist for six weeks or longer.

• According to cause:

  • Allergic angio-oedema.

  • Non-allergic drug reaction.

  • Idiopathic angio-oedema.

  • Hereditary C1 esterase inhibitor deficiency (or hereditary angio-oedema).

  • Acquired C1-INH deficiency (or acquired angio-oedema).

Pathophysiology^{1 3}

Angio-oedema and urticaria involve the same pathological process. Urticaria may occur alone in about 50% of cases. Urticaria occurs with angio-oedema in around 40-85% of cases; angio-oedema without urticaria occurs in only 10% of cases.

• Urticaria is characterised by well-defined areas of temporary, pruritic oedema of the dermis. These weals 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.

Facial angio-oedema

Boussetta N1*, Ghedira H2, Hamdi MS1, Ariba BY1, Metoui L1, Ghasallah I1, Zriba S2, Louzir B1, Msaddak F2, Ajili F1 and Othmani S11 - Department of Internal Medicine, Military Hospital of Tunis, Tunisia2 - Department of Hematology, Military Hospital of Tunis, Tunisia, CC BY 4.0, via Wikimedia Commons

The oedema is caused by increased vascular permeability and leakage of plasma into the deeper skin layers. This is due to a weakening of the endothelial cell barrier and is mediated by mast cell-derived mediators, particularly histamine, or by bradykinin. Where histamine mediates, superficial tissue is more often affected, thus causing urticarial weals in association with angio-oedema. Where bradykinin mediates, the dermis is usually spared and it is less likely that there will be weals and itching.

Types of angio-oedema

There are a number of causes of angio-oedema and this affects clinical presentation, investigation and subsequent management.

• Allergic. Usually an acute reaction. Urticaria is commonly associated. Causes include:

  • Food: nuts, shellfish, milk, eggs.

  • Medication: non-steroidal anti-inflammatory drugs (NSAIDs), penicillin, vaccines.

  • Insect bites.

  • Latex.

  • Contrast media for radiological investigations.

• Non-allergic drug reaction. Most commonly angiotensin-converting enzyme (ACE) inhibitors . This is usually a delayed reaction which may occur days to weeks after starting medication. It is more common in those of Afro-Caribbean origin. This is bradykinin-mediated and not accompanied by urticaria.

• Idiopathic. This is usually a chronic and relapsing angio-oedema. The cause is unknown. Many are thought to be autoimmune in nature and are associated with other autoimmune conditions.

• Hereditary angio-oedema (HAE).⁴ This is a rare inherited gene abnormality, with three types. Two types cause C1 esterase inhibitor (C1-INH) deficiency, which results in excessive bradykinin. The other rare type affects coagulation factor XII. See the separate Hereditary Angio-oedema article for more information.

• Acquired C1-INH deficiency. This is usually secondary to lymphoma or to a connective tissue disorder such as systemic lupus erythematosus (SLE).

Attacks of angio-oedema in chronic or recurring types may be triggered by factors such as viral infections or stress.

Some authorities classify angio-oedema as urticaria when it occurs with weals.⁵ UK guidelines, however, consider angio-oedema with and without weals.³

How common is angio-oedema?

• Angio-oedema is common, but varies with the population investigated. Lifetime prevalence rates of 8.8% have been reported.⁶

• The most common variety is recurrent idiopathic angio-oedema.

• The inherited (autosomal dominant) forms are rare and prevalence is only about 1 in 30,000-80,000 of the population.⁴ HAE usually presents after puberty.

Symptoms of angio-oedema

Presentation depends on the cause/type of angio-oedema as above. In all cases there is marked swelling, usually of the eyes and mouth. The pharynx, tongue, hands, feet and genitals may be affected. There may be difficulty breathing if swelling is severe. Skin may appear normal or may have associated weals. Swelling may be burning or painful, or there may be itching if there is associated urticaria. There may be abdominal pain if gastrointestinal mucosa is affected. Those with C1-INH deficiency are more likely to have angio-oedema of internal tracts, causing abdominal symptoms.

Clinical assessment^{1 4}

Careful assessment will help determine the type, the cause and thereby the treatment.

History

• Detail of the current episode should be recorded:

  • Is there associated urticaria? (If so, allergy, idiopathic or autoimmune cause is more likely).

  • Is swelling itchy or is it painful?

  • What is the duration of the attack?

  • Is there a history of angio-oedema occurring within 20-60 minutes of eating a particular food, or exposure to a specific allergen?

  • Is there history of other triggers? (For example, insect stings, local trauma such as dental procedures or surgery, stress, infection.)

• Past episodes. Recurrent episodes with no obvious trigger with associated urticaria suggest idiopathic type.

• Family history. HAE is an autosomal dominant condition so suspect if a parent is known to have this.

• Medication - specifically exclude medication associated with angio-oedema, particularly ACE inhibitors, NSAIDs and antibiotics. After withdrawal of an ACE inhibitor it may take up to three months for recurrences to cease.

• Past medical history (autoimmune conditions, lymphoma).

• Features of anaphylaxis past or present.

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.

• Skin: weals, petechiae, bruising or purpura.

• 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.

Investigations⁴

Investigations are determined by the clinical history and presentation as well as by response to anti-histamines, 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/CRP. 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 prick testing and in some cases radioallergosorbent test (RAST) blood test may confirm sensitivity to certain allergens.

• 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.

• Thyroid function and auto-antibody testing.

• Stool tests for ova, cysts and parasites, if there is a history of travel to areas with poor sanitation.

• Investigate for underlying malignancy in acquired angio-oedema (AAE).

• Skin biopsy may be required to exclude vasculitis.

Differential diagnosis

• Anaphylaxis.

• Asthma.

• Other skin conditions - eg, bullous pemphigoid, cellulitis and erysipelas, contact dermatitis, erythema multiforme, lymphoedema, 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.

• Other causes of an acute abdomen.

Angio-oedema treatment^{1 2 3}

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; it often requires alternative treatments.

Angio-oedema with weals

This is usually histamine or mast cell-mediated angio-oedema and responds well to antihistamines, steroids and adrenaline (epinephrine).

Acute attacks

• Mild attacks may not need 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 if there has been airway involvement during previous episodes.

• People with mild, limited symptoms can be reassured that symptoms are self-limiting and typically disappear within hours to days, on antihistamines with or without a short course of oral steroids.

Prevention of acute attacks

• Management must include the identification, as well as the avoidance, 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

• Allergen avoidance. if applicable, stop ACE inhibitors and avoid starting one in future.

• 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. The first-line antihistamine can be doubled (in some cases four times the standard dose may be required) or a second one added.

• Antihistamines should be avoided if possible in pregnancy. If an antihistamine is required in pregnancy, cetirizine 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.

• Tranexamic acid may be considered (anecdotal evidence).

• Other second-line options which may be used in secondary care include:

  • Leukotriene receptor antagonists (montelukast, zafirlukast).

  • Omalizumab.

  • Immunomodulators (ciclosporin, mycophenolate mofetil).

Angio-oedema without weals

• Airway compromise requires prompt life-saving procedures such as intubation and ventilation.

• Stop ACE inhibitors and avoid starting one in future.

• Use a long-acting, non-sedating antihistamine and increase doses if necessary unless known to be non-histamine-mediated. Consider tranexamic acid if these antihistamines are ineffective.

• Exclude C1-INH deficiency. Where this is present, there is poor response to antihistamines, steroids and adrenaline (epinephrine). People diagnosed with C1-INH deficiency should be under the care of a specialist centre.

• Where there is C1-INH deficiency, the following are treatment options:⁷

  • C1-INH concentrates derived from fresh frozen plasma or the recombinant C1-INH conestat alfa.

  • Icatibant - a bradykinin receptor antagonist, blocks bradykinin. Can be used subcutaneously and therefore has potential for self-administration.

  • Ecallantide - antagonist of kallikrein (involved in the production of bradykinin). There is a risk of anaphylaxis and it cannot be self-administered.⁸

  • Prophylactic regular doses of C1-INH may be required.

  • Long-term prophylaxis with androgens (danazol).

• 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.

ACE inhibitor-induced angio-oedema^{9 10}

• Symptoms usually resolve when the ACE inhibitor is withdrawn but can take some months to do so. In some cases symptoms persist in the long term.⁵ ACE inhibitors are contra-indicated once angio-oedema has occurred.

• It is bradykinin-mediated and antihistamines, steroids and adrenaline (epinephrine) are not effective or recommended.

• Airway protection management may be required.

• Case reports and limited data support the use of C1-INH and icatibant to treat attacks associated with laryngeal oedema.

• Angiotensin-II receptor antagonists may be used instead where benefit is perceived as crucial; however, a small percentage also develop angio-oedema with this alternative.¹¹

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.

Prognosis¹

The prognosis of angio-oedema depends on the type:

• Acute allergic angio-oedema is self-limiting in most cases and will resolve in 1-3 days, but relapses are common and unpredictable. If the cause/trigger can be identified and avoided, angio-oedema can be prevented (or the risk of an attack reduced).

• Idiopathic angio-oedema often has a chronic and relapsing course.

• ACE inhibitor-related angio-oedema can become more severe if the drug is not discontinued, and can be life-threatening in 20% of cases.

• Hereditary angio-oedema usually requires lifelong treatment, and the prognosis of acquired angio-oedema depends on the treatment of the underlying disorder.