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Angioedema (AE)

Basics

  • Acute localized swelling of skin, mucosa, submucosa due to extravasation of fluid.
  • May occur with or without urticaria; without wheals = distinct diagnosis.
  • Rapid onset (minutes to hours), resolution in hours to days.
  • Potentially life-threatening if airway involved.

Classifications

  • Acquired Angioedema (AAE)
  • Idiopathic histaminergic (IH-AAE): responds to antihistamines.
  • Idiopathic non-histaminergic (InH-AAE): no antihistamine response.
  • ACE inhibitor related (ACEI-AAE).

  • C1-inhibitor deficiency-related AAE (C1-INH-AAE).

  • Hereditary Angioedema (HAE)

  • C1-INH-HAE: Type I (low C1-INH), Type II (dysfunctional C1-INH).
  • FXII-HAE: normal C1-INH, mutation in coagulation factor XII gene (female predominant).
  • U-HAE: normal C1-INH, unknown cause.

Epidemiology

  • IH-AAE most common acquired type.
  • ACEI-AAE incidence: 0.1-2.2% of ACEI users; higher in Black individuals.
  • C1-INH-AAE rare (1:500,000).
  • HAE prevalence: 1:10,000 to 100,000; C1-INH-HAE accounts for 85%.
  • HAE types I/II: autosomal dominant; FXII-HAE: X-linked dominant; 25% spontaneous mutation.

Etiology and Pathophysiology

  • AAE:
  • IH-AAE: vasoactive substance release.
  • ACEI-AAE: elevated bradykinin levels due to ACE inhibition.

  • C1-INH-AAE: autoantibodies impair C1-INH function.

  • HAE:

  • Triggered by trauma, stress, hormones (menses, pregnancy), cold, heat, illness.
  • Deficiency or dysfunction of C1-INH leads to excessive bradykinin production → vascular permeability and edema.

Risk Factors

  • Medication and food allergens.
  • Positive family history.

Prevention

  • Avoid known triggers.
  • Avoid ACE inhibitors in HAE types I and II.
  • ARBs are safe substitutes for ACEI-AAE.

Associated Conditions

  • Quincke disease (uvula AE).
  • Urticaria (if wheals present, diagnosis changes).

Diagnosis

  • Primarily clinical assessment plus detailed history including triggers and family history.
  • Laboratory tests for C4, C1-INH antigen and function, allergy testing, and paraprotein screening.
  • Low C4 is sensitive screening for C1-INH deficiency.
  • Imaging (CT, radiography) for GI involvement or malignancy workup.
  • Differentiate AE types based on complement tests and genetics.

History

  • Rapid, asymmetric swelling without wheals.
  • Painful or burning sensation, often non-pruritic.
  • Recent allergen or medication exposure.
  • Family history of recurrent AE.

Physical Exam

  • Nonpitting, tense swelling (skin-colored or erythematous).
  • Common sites: face, periorbital, lips, tongue, larynx.
  • Assess airway involvement (stridor, drooling).
  • GI symptoms more common in HAE.

Differential Diagnosis

  • Urticaria, anaphylaxis, contact dermatitis, erysipelas.
  • Connective tissue diseases, lymphedema, insect bites, infiltrative processes.

Treatment

General

  • Secure airway; intubate if threatened.
  • Remove triggers.
  • Volume resuscitation if unstable.

Medications

  • If anaphylaxis or airway involvement:
  • Epinephrine IM 0.1 mg/kg q5-15 min (max 0.3 mg children, 0.5 mg adults).
  • H1 antihistamines (diphenhydramine IV or oral).
  • H2 antagonists (ranitidine).

  • Corticosteroids (hydrocortisone or methylprednisolone).

  • AAE (IH-AAE):

  • Acute: above first-line therapies.

  • Prevention: second-generation antihistamines (up to 4× dose).

  • AAE (InH-AAE):

  • Corticosteroids, epinephrine if airway involved.

  • Prevention: tranexamic acid or immunosuppressive therapy.

  • ACEI-AAE:

  • Stop ACE inhibitor.
  • Off-label: bradykinin receptor antagonists (icatibant), C1-INH concentrate, kallikrein inhibitors.

  • ARBs safe alternative.

  • C1-INH-AAE:

  • Off-label: icatibant, C1-INH replacement, kallikrein inhibitors.
  • H1/H2 antagonists, corticosteroids, epinephrine ineffective.

  • Treat underlying condition.

  • HAE:

  • C1-INH replacement (Berinert, Ruconest).
  • Icatibant, ecallantide, progesterone, danazol, tranexamic acid for prophylaxis/therapy.
  • Avoid corticosteroids and antihistamines for HAE.
  • FFP if first-line unavailable (use cautiously).

Referral

  • Recurrent AE or positive family history warrants allergy/immunology specialist evaluation.

Admission Criteria

  • Based on airway involvement severity (use Ishoo criteria).
  • ICU admission for respiratory distress or airway support.

Ongoing Care and Education

  • Educate on trigger avoidance, treatment options, emergency care recognition.
  • Medical alert bracelet recommended.

Prognosis

  • AE resolves within hours to days, but airway involvement can be fatal.
  • HAE patients average 20 attacks/year lasting 3-5 days; prophylaxis reduces frequency and work/school impact.

References

  1. Cicardi M, Aberer W, Banerji A, et al. Classification, diagnosis, and treatment of angioedema: consensus report. Allergy. 2014;69(5):602-616.
  2. Patel G, Pongracic JA. Hereditary and acquired angioedema. Allergy Asthma Proc. 2019;40(6):441-445.

ICD10 Codes

  • T78.3XXA Angioneurotic edema, initial encounter
  • D84.1 Defects in the complement system

Clinical Pearls

  • AE without wheals is a distinct diagnosis from urticaria.
  • AE can be life-threatening if upper airway involved; early airway management critical.
  • Two major classifications: acquired and hereditary angioedema.
  • ARBs are preferred substitutes in ACEI-induced AE due to low cross-reactivity.
  • Recurrent AE always requires specialist referral.