Angioedema – Causes and Treatment

Angioedema is the rapid swelling (edema) of the dermis, subcutaneous tissue, submucosal tissues, or mucous membranes as a result of vascular leakage.

It is also known by the terms giant urticaria, Quincke edema, and angioneurotic edema.

It is a nonpitting and nonpruritic edema. There is no color change on the involved skin.

The lips and periorbital edema are the most common manifestations. Face, hands, feet, and genitalia are other common sites.

Swelling that involves the tongue and upper airways are life-threatening and are medical emergencies.

Angioedema can affect people of all ages.

Approximately 10-20% of the population may experience at least 1 episode of angioedema during their lifetime.

Pathophysiology 

Angioedema is a result of a sudden increase in local vascular permeability in subcutaneous or submucosal tissue often mediated by histamine and bradykinin.

Mast cells and basophils are the primary sources of histamine. The activation of mast cells or basophils with subsequent histamine release may be either mediated or unmediated by immunoglobulin E (IgE). IgE-mediated mast cell activation and degranulation, key elements of an allergic reaction, often manifest as urticaria and angioedema.

Hereditary angioedema (HAE), angiotensin-converting enzyme (ACE) inhibitor-induced angioedema, and certain idiopathic angioedemas are examples of bradykinin-mediated angioedema; bradykinin levels are elevated during an episode of angioedema.

Leukotriene may play an important role in the NSAIDs induced angioedema.

Urticaria and Angioedema

The two conditions are remarkably similar but angioedema differs from urticaria in several respects. Angioedema usually involves the deeper layer of skin (reticular dermis) whereas urticaria affects the more superficial layer of skin (papillary dermis and mid-dermis).

Read more about Skin Anatomy and Physiology

Mucosal involvement is observed only in angioedema but not in urticaria.

Itching is the most prominent complaint in urticaria, but it is less troublesome or absent in angioedema. Pain or tenderness is not common in urticaria but frequent or even severe in angioedema.

Classification of Angioedema

Angioedema with urticaria

• Acute (< 6 weeks) or chronic (>6 weeks)
• Allergic
  • Food
  • Insect sting
  • Latex
• Pseudoallergic
  • NSAIDs [aspirin most common]
  • IV contrast material
•  Physical
  • Cold
  • Vibration
  • Pressure
  • Physical exercise
• Autoimmune disease
• Idiopathic

Angioedema without urticaria

Acquired Angioedema (AAE)

• Idiopathic (no identifiable causes)
  • Idiopathic histaminergic – Responds to antihistamines
  • Idiopathic nonhistaminergic – No response to antihistamines
• Acquired angioedema related to ACE Inhibitors
  • Seen on On ACE inhibitor therapy
  • Interfere with the degradation of bradykinin
  • No other identifiable causes
• C1 INH deficiency
  • No family history of angioedema
  • Onset > 40 years of age
  • Low C1q levels
  • No genetic mutation in C1 INH gene
  • Secondary reduction of C1 INH function.

Hereditary Angioedema

• Hereditary angioedema with C1 INH deficiency
  • Impaired normal C1 INH production and/or function
  • Mutation in 25% of cases
  • Family history in others
• Normal C1 INH
  • Hereditary angioedema with FXII mutations
  • Hereditary angioedema of unknown origin

Causes 

• Idiopathic [40%]
  • Nonspecific triggers present
    • Trauma
    • Surgical procedures
    • Stress
• Hypersensitivity
  • Food
  • Drugs
  • Insect stings
  • Preservatives
  • Food colorants

• Physical stimuli
  • Cold
  • Vibrations
• Autoimmune disease
• Infection
• ACE inhibitors
• NSAIDs
• C1-INH deficiency

Angioedema has also been associated with certain conditions

• Cytokine-associated angioedema syndrome
  • Gleich syndrome or episodic angioedema with eosinophilia
• Well syndrome or eosinophilic cellulitis (ie, granulomatous dermatitis with eosinophilia
• Helicobacter pylori infection
• Systemic viral, bacterial, or parasitic infections
• Thyroid autoantibodies

Clinical Presentation

When a patient presents with angioedema, the presence or absence of urticaria should be looked into. Those with urticaria are further evaluated and treated on the line of urticaria. Otherwise, the following approach is used.

The patient presents with subcutaneous swelling. Face, tongue, hands, feet, genitalia can be affected, and rarely, edema of the soft palate may occur.

Abdominal pain occurs from intestinal involvement. Nausea, vomiting, and ascites could be seen and sometimes be the presenting symptom of angioedema. Throat tightness, voice changes, and breathing problems may suggest airway involvement.

Angioedema can be acute or chronic, and each episode may last a few hours to a few days. Burning sensation and pain can be present.

In hereditary acquired edema, idiopathic angioedema, and drug-induced angioedema, there would be of relapsing, self-limiting edema lasting for 1-7 days and are followed by a disease-free interval.

The history may reveal triggers of the attack [such as local trauma or surgery]

On examination, the affected areas show edema of distensible tissues, often with ill-defined margins.

In severe abdominal involvement, abdominal distention and signs consistent with bowel obstruction may be present.

Patients may have only changes in bowel sounds and diffuse or localized tenderness.

The oral cavity can be visualized directly for tongue or uvula but laryngoscopy is indicated to assess laryngeal or vocal cord involvement. Family history and history about possible triggers like food, medicine, etc [see causes] should be asked.

Angioedema can be life-threatening when it involves the larynx and upper airway. Throat pain or discomfort, dysphonia, and dysphasia may indicate laryngeal involvement. In severe attacks, dyspnea can indicate the onset of systemic anaphylaxis.

Differential Diagnoses

• Acute Urticaria
• Anaphylaxis
• Cellulitis
• Delayed Hypersensitivity Reactions
• Allergies

Lab Studies

Mild cases of angioedema do not require any laboratory tests.

For recurrent angioedema without a clear trigger, the following tests may be considered

• Complete blood count
• Erythrocyte sedimentation rate
• C-reactive protein (CRP) levels
• D-dimer level
• Urinalysis
• Metabolic profile
• Antinuclear antibody testing
• Complement activity [CH50 level]
  • If low consider C1-INH function and C1q levels
• Thyroid function tests
  • Thyroid-stimulating hormone
  • Free T4
• Thyroid autoantibody
• Tests for allergy
  • Food
  • Stinging insects
  • Latex
  • Antibiotics

Read more about Allergy Skin Tests – Indications, Procedure, and Interpretation

Other studies

Further tests are based on the initial laboratory results or to probe a specific medical condition

These include

• Stool analysis for ova and parasites
• H pylori workup
• Hepatitis B and C workup
• Rheumatoid factor
• Cryoglobulin levels

In patients  with recurrent angioedema without urticaria, the following tests should be performed to establish or rule out C1-INH deficiency–associated angioedema

• C1 INH levels to know the deficiency
• C4 level
• C1 esterase inhibitor measurements
• C1q level

Imaging

Most angioedema patients do not need any imaging studies.

Abdominal imaging [x-rays or CT] reveals findings consistent with small bowel wall edema during angioedema attacks. Ascites may be seen.

Treatment of Angioedema

Emergency Care

Patients with moderate to severe angioedema often present to the emergency. Supportive care should also be provided.

Epinephrine should be used in suspected laryngeal angioedema.

For patients with a known history of hereditary angioedema, a suitable agent should be administered as soon as an angioedema attack is recognized. These agents could be any of the following

• C1 esterase inhibitor [C1-INH] concentrate
• Ecallantide
  • Reversible inhibitor of plasma kallikrein
  • Blocks its binding site and inhibits kininogen conversion to bradykinin
• Icatibant
  • Inhibits the binding of bradykinin
  • Treats the clinical symptoms
  • The recommended dose is 30 mg subcutaneously in the abdominal area.

Airway protection is the most important consideration with laryngeal involvement.

Early intubation may be preferred. When intubation is required, the patient should be sent to intensive care unit.

Non-emergency care

Without urticaria, clinicians must rule out hereditary angioedema, acquired C1-INH deficiency, and ACE inhibitor−induced angioedema. The following triggers may be confirmed or excluded. If present and possible [like the use of drugs] the triggers should be removed.

• Food allergies
• Drugs
• Physical factors (eg, vibrations, cold or heat, or pressure)
• Nonsteroidal anti-inflammatory drugs
• Angiotensin-converting enzyme inhibitors

Depending on the etiology of the angioedema, management can vary. Angioedema with unidentifiable causes can be regarded as histaminergic or nonhistaminergic.

Treatment of Histaminergic Angioedema 

Histaminergic angioedema could be either immunoglobulin E (IgE)-dependent (eg, an allergic reaction to a food or drug) or IgE-independent (eg, a reaction to radiocontrast medium). NSAID-related angioedema and most cases of idiopathic angioedema are treated with the same measures.

These patients can mostly be managed well with outpatient treatment alone. Treatment includes the following

• Antihistamines, usually second-generation agents
  • Cetirizine
  • Desloratadine
  • Fexofenadine
  • Levocetirizine
  • Loratadine
• Monitoring esp. in moderate to severe cases is often necessary
• First-generation antihistamines as add-on therapy when a second-generation antihistamine fails
• Doxepin is used in recalcitrant forms [One that does not respond to histamines]
  • Tricyclic antidepressant
  • Has potent H1-blocking activity.
• Corticosteroid use in severe cases

Read more about Side Effects of Corticosteroid Therapy

Nonhistaminergic 

This includes bradykinin-mediated angioedema like ACE inhibitor, hereditary, acquired, estrogen-dependent, and certain types of idiopathic angioedema.

Antihistamines have no role in these. The following agents are used in their treatment

• In C1-INH deficiency treatment of the underlying disorder usually results in the correction of the abnormality.
• C1-INH deficiency can be helped by fresh frozen plasma transfusion [contains C1-INH]
• Antifibrinolytic agents
  • Aminocaproic acid
  • Tranexamic acid
  • Mechanism not known
  • Not effective in the histaminergic form

Prophylaxis of Angioedema

Drugs used in the acute attack are also used for prophylaxis. Androgen derivatives as a prophylactic option may help in hereditary angioedema.

Removal of triggers should be considered such as ACE inhibitor or allergen.

Corticosteroid treatment is reserved for very recalcitrant cases.