Angioedema

Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Clinically, angioedema presents with swelling around the eyes, lips, tongue, mouth, bowel wall, extremities, or genitalia. Angioedema may also compromise the airway. Urticaria will be present when the angioedema is mediated by mast cells, but not when it is due to increases in bradykinin. Diagnosis is usually clinical but additional testing may include skin/serum testing for specific antigens and C4 level assessment. Management depends on the underlying mechanism but may include treatment for anaphylaxis, removing any offending agents, antihistamines, glucocorticoids, and/or therapies that target bradykinin.

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Overview

Definition

  • Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue.
  • May occur with or without urticaria:
    • With urticaria: indicates an IgE-mediated type I hypersensitivity reaction
    • Without urticaria: mediated by substances other than IgE, usually bradykinin
  • Acute or chronic:
    • Acute angioedema: < 6 weeks duration
    • Chronic angioedema: 2–3 episodes per week for ≥ 6 weeks duration

Epidemiology

  • Incidence: 
    • Data on overall incidence are limited.
    • Relatively common
    • Occurs in 40%–50% of patients with chronic urticaria
    • Approximately 10%–20% of people will experience an episode of angioedema at some point.
  • Age range: 
    • Occurs in any age group
    • ↑ Incidence after adolescence (highest at 20–30 years old)
  • No gender bias
  • Most commonly seen in African Americans

Etiology and Pathophysiology

Classification

Angioedema may result from 3 primary mechanisms:

  • Mast cell-mediated angioedema (most common and associated with urticaria):
    • Mast cells are activated by:
      • IgE to specific antigens
      • Physical stimuli
      • Medications (non–IgE-mediated direct activation of mast cells)
    • Once activated, mast cells release inflammatory mediators:
      • Histamine
      • Leukotrienes
      • Prostaglandins
      • Heparin
  • Bradykinin-mediated angioedema (not associated with urticaria):
    • Bradykinin is an inflammatory mediator that can lead to vasodilation and vascular permeability.
    • ↑ Bradykinin → ↑ vasodilation and ↑ vascular permeability
    • Due to:
      • ↓ C1 inhibitor → ↓ inhibition of kinin generation → ↑ bradykinin
      • ↑ Angiotensin-converting enzyme (ACE) inhibition → ↓ bradykinin degradation → ↑ bradykinin
  • Idiopathic or unknown mechanism

General pathophysiology

  • Inflammatory mediators → ↑ vascular permeability and dilation of capillaries and venules
  • Extravasation of fluid from vasculature → asymmetric edema in the subcutaneous tissue and deep dermis:
    • Occurs in areas of affected vasculature
    • Not gravitationally dependent

Mast cell-mediated etiologies

Mast cell-mediated angioedema is typically associated with urticaria.

  • IgE to specific antigens (type I hypersensitivity reactions): 
    • Pollen and mold
    • Foods, most commonly:
      • Peanuts
      • Tree nuts
      • Shellfish
      • Dairy
      • Eggs
    • Drugs:
      • Penicillin
      • Sulfa drugs
      • NSAIDs
    • Environmental:
      • Insect stings (venom) and bites
      • Latex
    • Physical stimuli: 
      • Cold
      • Heat
      • Exercise
      • Vibrations
      • Pressure
  • Medications (directly stimulate mast cells without IgE)
    • Opioids
    • NSAIDs 
      • Most commonly due to aspirin
      • Note: IgE-mediated allergy and direct mast cell stimulation are both possible.
    • Radiocontrast agents

Bradykinin-mediated etiologies

These etiologies are not associated with histamine release or urticaria.

  • Dysfunctional C1 inhibitor:
    • Hereditary angioedema (HAE): an autosomal dominant abnormality in the quantity or function of C1 inhibitor
    • Acquired C1 inhibitor deficiency angioedema: development of antibodies against C1 inhibitor
  • Medications (both via ↓ bradykinin degradation):
    • ACE inhibitors (ACEI)
    • Dipeptidyl peptidase-4 inhibitors

Other etiologies

  • Urticaria may or may not be present.
  • Idiopathic angioedema: 
    • An etiology is not determined after a thorough evaluation.
    • Commonly associated with chronic angioedema
  • Other causes of angioedema with unknown mechanisms:
    • Infections:
      • Common cold
      • Streptococcal pharyngitis
      • Urinary tract infections
    • Calcium channel blockers
    • Other drugs or herbal medicine (uncommon)

Clinical Presentation

  • Swelling in deep cutaneous and mucosal tissue:
    • Face
    • Lips, mouth, tongue
    • Throat, larynx, and uvula
    • Extremities
    • Genitalia
    • Bowel wall:
      • Colicky abdominal pain
      • Nausea and vomiting
      • Diarrhea
  • Characteristics of swelling:
    • Onset:
      • Mast cell-mediated: minutes to hours
      • Bradykinin-mediated: hours to days
    • Spontaneous resolution (hours to days)
    • Asymmetric distribution
    • Form in nongravitationally dependent areas
  • Urticaria (in mast cell-mediated cases only)
    • Coalescing, well-circumscribed wheals
    • Intensely pruritic
    • Erythematous
    • Edematous
    • Raised borders
    • Central blanching
  • Anaphylaxis: 
    • Life-threatening throat and airway swelling → impaired airflow
    • Signs and symptoms:
      • Shortness of breath
      • Wheezing and stridor
      • Tachycardia
      • Hypotension

Diagnosis

The diagnosis of angioedema is usually clinical, but testing can help to clarify the etiology. Most cases of chronic angioedema are idiopathic.

  • Important history:
    • Recent allergen exposure
    • Stings or bites
    • Medication history
  • Mast cell-mediated angioedema with urticaria:
    • CBC/DIFF: 
      • Possible eosinophilia
      • Normal WBC count
    • With anaphylaxis: ↑ tryptase confirms mast cell activation
    • Allergy skin testing
    • Medication withdrawal and challenge
    • Repeat physical stimuli (if suspected as triggering event).
    • Serum IgE antibodies to specific antigens
  • Isolated angioedema without urticaria:
    • ↑ CRP → infection, ACEI-induced angioedema
    • ↓ Complement protein C4 → evaluate for HAE or acquired C1 inhibitor deficiency:
      • C1 inhibitor antigen
      • C1 inhibitor function levels

Management

General management

  • Assess airway → intubate if there are signs of airway compromise
  • Assess for anaphylaxis → stabilize if present:
    • Epinephrine
    • Intravenous fluids
    • Oxygen
  • Discontinue any potential causative medications.

Management of mast cell-mediated angioedema

  • Identify and remove triggers.
  • H1 antihistamines (1st line): to suppress histamine released by mast cells:
    • Diphenhydramine
    • Cetirizine
    • Loratadine
  • Systemic glucocorticoids:
    • Methylprednisolone
    • Prednisone
    • Prednisolone

Management of bradykinin-mediated angioedema

  • HAE:
    • 1st-line options to attempt to ↓ bradykinin:
      • Purified C1 inhibitor concentrate
      • Kallikrein inhibitor: ecallantide
      • Bradykinin B2 receptor antagonist: icatibant
    • 2nd-line options:
      • FFP
      • Only used when 1st-line options are not available
  • ACEI-associated angioedema:
    • The above therapies for HAE can be used, but their efficacy has not been proven.
    • Most cases resolve 24–72 hours after discontinuing the ACEI.

Management of chronic idiopathic angioedema

  • Patients should be referred to an allergy specialist.
  • Medical therapy:
    • Nonsedating antihistamines: 
      • Cetirizine
      • Loratadine
    • Leukotriene receptor antagonist (montelukast) can be added.
    • For acute episodes:
      • Prednisone
      • Diphenhydramine

Differential Diagnosis

  • Contact dermatitis: inflammation of the skin in response to contact irritants, which can affect the face in some circumstances (often cosmetics or topical pharmaceuticals). Edema and pruritus may develop mimicking angioedema. Microvesiculation (formation of small vesicles), pain, and a burning sensation can help distinguish contact dermatitis from angioedema. Management involves removing the offending agent and reducing skin inflammation with steroids or topical calcineurin inhibitors.
  • Cellulitis and erysipelas: skin infections presenting with well-demarcated erythema, edema, and warmth. Cellulitis involves the deeper dermis and subcutaneous fat while erysipelas involves the upper dermis. Cellulitis and erysipelas tend to be accompanied by a fever, are more painful than angioedema, and have more pronounced demarcation than angioedema. The diagnosis is clinical, and management is with antibiotics.
  • Autoimmune conditions: systemic lupus erythematosus, polymyositis, dermatomyositis, and Sjogren’s syndrome, which may all present with edema of the face, periorbital areas, and hands. The presence of other findings (e.g., Raynaud’s phenomenon, dry eyes/mouth, and characteristic rashes) differentiates the autoimmune conditions from angioedema. The diagnosis is based on clinical findings and antibody testing. Management varies, but often includes steroids and immunosuppressants.
  • Superior vena cava (SVC) syndrome: tumors involving the right lung, lymph nodes, or mediastinal structures that may obstruct blood flow through the SVC by direct invasion or external compression, causing swelling in the face or neck and dyspnea. Other symptoms (e.g., chest pain, respiratory, or neurologic) help distinguish SVC syndrome from angioedema. Diagnosis is with imaging and venography. Management involves treatment for the malignancy and techniques to relieve the obstruction.

References

  1. Frank Austen, K. (2008). Allergies, anaphylaxis, and systemic mastocytosis. In Fauci, A. S., Braunwald, E., Kasper, D.L., et al. (Eds.). Harrison’s Internal Medicine. 17th Ed., pp. 2065-2067.
  2. Zuraw, B. (2019). An overview of angioedema: Pathogenesis and causes. In Feldweg, A. M. (Ed.). UpToDate. Retrieved February 18, 2021, from https://www.uptodate.com/contents/an-overview-of-angioedema-pathogenesis-and-causes
  3. Zuraw, B. (2019). An overview of angioedema: Clinical features, diagnosis, and management. In Feldweg, A. M. (Ed.). UpToDate. Retrieved February 18, 2021, from https://www.uptodate.com/contents/an-overview-of-angioedema-clinical-features-diagnosis-and-management
  4. Zuraw, B. (2018). Hereditary angioedema: Pathogenesis and diagnosis. In Feldweg, A. M. (Ed.). UpToDate. Retrieved February 18, 2021, from https://www.uptodate.com/contents/hereditary-angioedema-pathogenesis-and-diagnosis
  5.  Zuraw, B., Farkas, H. (2020). Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis. In Feldweg, A. M. (Ed.). UpToDate. Retrieved February 18, 2021, from https://www.uptodate.com/contents/hereditary-angioedema-epidemiology-clinical-manifestations-exacerbating-factors-and-prognosis 
  6. Delves, P.J. (2020). Angioedema. MSD Manual Professional Version. Retrieved February 21, 2021, from https://www.msdmanuals.com/professional/immunology-allergic-disorders/allergic,-autoimmune,-and-other-hypersensitivity-disorders/angioedema
  7. Li, H.H. (2018). Angioedema. In Kaliner, M.A. (Ed.). Medscape. Retrieved February 21, 2021, from https://emedicine.medscape.com/article/135208-overview
  8. Memon, R.J. (2020). Angioedema. StatPearls. Retrieved February 21, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK538489/

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