Angioedema

Introduction

Localized and self‐limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive mediator(s).

• Urticaria and/or angioedema has been reported in up to 20% of the general population. In addition, 40-50% of patients with chronic urticaria have angioedema.

History:

Although urticaria was first reported approximately 200 BC, angioedema itself was not described until the 1500’s. The term ‘angioedema’ was first coined in 1586. In the 19^th century, a case of HAE was reported in a family where the common cause of death was ‘fatal suffocation’. Angioedema received further recognition in the 1960’s after cases were reported dating to the 17^th century from Swedish church records, where it was common to register cause of death. In 1963, it was discovered that patients with HAE possessed low levels of C1 INH. First described in 1972, acquired angioedema was initially characterised by angioedema symptoms, C1-INH deficiency and hyperactivation of the complement pathway.

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Aetiology

Angioedema is caused by a rapid increase in permeability of submucosal or subcutaneous capillaries and post-capillary venules with localized plasma extravasation. Most causes of angioedema are dependent upon the release of either histamine or bradykinin; other vasoactive substances may be contributory.

Histamine-mediated angioedema:

Mast-cell mediated angioedema results from IgE-mediated degranulation of mast cells. The majority of cases are associated with urticaria and/or pruritus. Anaphylaxis is a severe example of this type of angioedema, which is preceded by exposure to an allergen. Allergic reactions without anaphylaxis can also give rise to angioedema.

• IgE-mediated allergic reactions (such as to food, drug, or environmental triggers)
• Nonsteroidal anti-inflammatory drug (NSAID) use (including aspirin)
• Chemically-induced histamine release (most commonly opiates, highly cationic antibiotics, and muscle relaxants)

Bradykinin-mediated angioedema:

Mechanistically, activated factor XII cleaves prekallikrein to produce kallikrein
Plasma kallikrein then cleaves kininogen to release bradykinin, which binds to B2 receptors on endothelial cells. To modulate bradykinin production, C1 INH inhibits plasma kallikrein and activated factor XII. If C1 INH is deficient in quantity or quality, an uninhibited contact system will produce excess bradykinin.

• Hereditary angioedema (HAE): Rare genetic disorder caused by deficiency of C1 esterase inhibitor (C1-INH) and characterized by recurrent episodes of severe swelling that affect the limbs, face, intestinal tract and airway.
• Acquired C1-inhibitor deficiency (AAE)
• ACE inhibitor-associated angioedema (M/C cause)

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Clinical features

Angioedema has multiple subtypes, but at their core is a temporary increase in endothelial permeability which in turn leads to plasma extravasation in the deeper layers of the dermis and submucosa.

Prodromal symptoms (87–95% cases):

• Tingling sensation in affected area 1-2 hours before episode

Hallmark manifestation:

• Abrupt nonpitting swelling of the skin, mucous membranes, or both, including the upper respiratory and gastrointestinal tracts, which typically lasts from many hours to 3 days. The involved tissues then return to normal.
• Sites of predilection: Face, hands, feet, and genitalia. Lip and eye (periorbital) swelling are the most common.
• Swelling of the tongue, pharynx, and larynx is particularly problematic. Fatalities can occur because of laryngeal edema, but pharyngeal edema and tongue swelling can be similarly disastrous if they are massive.

Other manifestations:

Histamine vs bradykinin-mediated angioedema:

A distinguishing feature of histaminic/allergic angioedema is its ‘temporal’ relationship to a trigger. The onset of symptoms is typically rapid – minutes to a few hours after exposure. Typically, mast cells are not involved in bradykinin-induced angioedema thus, pruritus and urticaria are noticeably absent. Increased vascular permeability is caused by bradykinin, resulting in contraction of non-vascular smooth muscle, vasodilation and oedema formation. In addition to the typical locations of swelling, bradykinin-induced angioedema affects the gastrointestinal mucosa.

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Diagnosis

In order to determine the etiology of angioedema, a detailed medical history must be taken with particular attention to identifying possible triggers, as well as the medication history and family history.

Lab studies:

• Type I HAE (85% cases): Quantitative C1INH deficiency (which is functionally abnormal as well)
• Type II HAE (15% cases): Functionally abnormal C1INH
• Type III HAE (rare): Resembles Type I & Type II HAE but complement levels, including C1 inhibitor, are normal
• Acquired C1 inhibitor deficiency (ACID): Low C1q levels. In contrast, patients with ACE-induced, idiopathic, and allergic AE have normal complement profiles.3,6
• Type I & II HAE and ACID: C4 & C2 levels are low during and between attacks.

Differential diagnosis:

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Management

Acute episodes of allergic angioedema are exquisitely responsive to therapy with anti-histamines, oral corticosteroids, and epinephrine; while other forms are refractory to this conventional therapy and may take hours to days to resolve. In all instances, particular attention must be paid to airway maintenance if the patient is experiencing tongue or laryngeal involvement. Supportive care should also include pain management and hydration if abdominal symptoms are predominant. Prompt removal of any suspected triggers is warranted.

Medication management focuses on three aspects: acute episode management, short-term prophylaxis, and long-term prophylaxis, with ED management focusing on the acute episode.

Histamine-mediated angioedema:

histamine-mediated angioedema i

• Epinephrine
• Steroids
• Antihistamines
• IV fluids

Bradykinin-mediated angioedema:

Treatment is unique from angioedema associated with histamine since antihistamines, corticosteroids, and epinephrine have little effect on the swelling. Instead, medications that either inhibitor production of bradykinin or compete with the receptor are utilized.

• C1-INH concentrates: Provide plasma protein that regulates kallikrein and Factor XII activity, reducing bradykinin production.
  • Plasma-derived: Berinert, Cinryze
  • Recombinant: Ruconest
• Kallikrein inhibitor: Ecallantide (Kalbitor), berotralstat
  • Reduces bradykinin synthesis by preventing the cleavage of kininogen
• Bradykinin-2-receptor antagonist: Icatibant acetate (Firazyr)
  • Selective and competitive bradykinin B2 receptor antagonist
  • Fresh frozen plasma (FFP): Contains varying amounts of C1-INH.

Short-term prophylaxis of bradykinin-mediated angioedema:

Induce production of C1-inhibitor and are very effective in preventing attacks, but have no benefit in treating an attack.

• Androgens: Danocrine
• Antifibrinolytics: Tranexamic acid and aminocaproic acid

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Summary: