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Angioedema
Michelle T. Martin, PharmD, BCPS, BCACP
Jamie L. Berkes, MD
image BASICS
DESCRIPTION
  • Angioedema (AE) is an acute, localized swelling of skin, mucosa, and submucosa caused by extravasation of fluid into the affected tissues. It often resolves in hours to days, but it can be life-threatening if the upper airway is involved.
  • Hereditary AE (HAE) and acquired AE (AAE) are diseases of the complement cascade that result in recurrent episodes of AE of the skin, upper airway, and GI tract.
  • Synonym(s): angioneurotic edema; Quincke edema
EPIDEMIOLOGY
  • Predominant age
    • Allergen, medication, or other triggers can affect all ages.
    • HAE: infancy to 2nd decade of life
    • AAE: Typically patients in 4th decade of life
  • Predominant gender: male = female (except type III HAE, which affects more women than men)
Prevalence
  • AE occurs in ˜15% of the population over a lifetime.
  • AE: 0.1-2.2% of patients receiving ACE inhibitors: African Americans have a four to five times greater risk of ACE inhibitor-induced AE than Caucasians.
  • HAE: 1:10,000 to 50,000 population in the United States
ETIOLOGY AND PATHOPHYSIOLOGY
  • Idiopathic
  • Medication-induced
    • ACE inhibitors cause 10-25% of AE cases, mostly occurring within the 1st month of use. However, onset may be delayed by years.
    • Angiotensin-receptor blockers (ARBs) also can cause AE but more rarely than ACE inhibitors.
  • Allergic triggers
    • Food allergens such as shellfish, nuts, eggs, milk, wheat, soy
    • Medications such as aspirin, NSAIDs, antibiotics, narcotics, and oral contraceptives
    • Latex, venom
  • Physically induced: cold, heat, pressure, vibration, trauma, emotional stress, ultraviolet light
  • Hereditary or acquired C1 INH deficiency
  • Thyroid autoimmune disease-associated AE
  • Type I hypersensitivity reaction
  • Increase in vascular permeability secondary to IgE-mediated mast cell-stimulated histamine release or from activation of the complement system and an elevation in bradykinin (HAE)
  • Attacks of HAE are triggered by prolonged mechanical pressure, cold, heat, trauma, emotional stress, menses, illness, and inflammation:
    • Type I HAE, the most common form, caused by decreased production of C1 esterase inhibitor (C1 INH), has autosomal dominant inheritance.
    • Type II HAE has functionally impaired C1 INH and autosomal dominant inheritance.
    • Type III (HAE-FXII) involves mutations in coagulation factor XII gene (occurs more frequently in women, often estrogen dependent, associated with estrogen administration); also, type III HAE-unknown exists.
  • AAE is a rare condition:
    • Type I is associated with lymphoproliferative diseases or paraneoplastic diseases.
    • Type II is due to autoimmune disorders (anti-C1 INH antibody).
    • Affected patients have circulating antibodies directed either against specific immunoglobulins expressed on B cells (type I) or against C1 INH (type II).
    • AAE typically presents later in life (>40 years), and patients lack family history of AE.
Genetics
  • HAE types I and II are autosomal dominant, whereas type III is dominant X-linked.
  • HAE occurs in 25% of patients as a result of spontaneous genetic mutations.
RISK FACTORS
  • Consuming medications and foods that can cause allergic reactions
  • Preexisting diagnosis of HAE or AAE
GENERAL PREVENTION
  • Avoid known triggers.
  • Do not use ACE inhibitors in patients with C1 INH deficiency.
COMMONLY ASSOCIATED CONDITIONS
  • Quincke disease (AE of the uvula)
  • Urticaria
image DIAGNOSIS
PHYSICAL EXAM
  • Acute onset of asymmetric localized swelling, usually of the face (eyelids, lips, ears, nose), tongue, larynx, and, less often, of the extremities or genitalia
  • GI tract involvement may manifest as intermittent unexplained abdominal pain.
DIFFERENTIAL DIAGNOSIS
Urticaria (with AE in 40-50% of patients); allergic contact dermatitis; connective tissue disease: lupus, dermatomyositis; anaphylaxis; cellulitis, erysipelas; lymphedema; diffuse SC infiltrative process
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • If AE with urticaria and/or anaphylaxis, check for allergen-specific IgE to verify suspected trigger. Serum tryptase is elevated during acute AE (1)[C].
  • Without a clear etiology and recurrence in AE and urticaria, check CBC and ESR:
    • Macrocytosis implies a pernicious anemia.
    • Eosinophilia may imply atopy or, rarely, a parasitic infection.
    • Elevated ESR may imply systemic disorders (1)[C].
  • In recurrent AE without a clear etiology and without urticaria, consider ordering serum C4 level:
    • Low serum C4 is a sensitive but nonspecific screening test for hereditary and acquired C1 INH deficiency.
    • If C4 is normal, determine C1 INH level and function and recheck C4 during an acute attack.
    • If C4 level and C1 INH level and function are still normal, consider other causes (i.e., medications or HAE type III) for AE (2)[C].
    • If C4 level, C1 INH level, and C1 INH function are low, this indicates HAE type I.
    • HAE type II is characterized by low C4 and low C1 INH function, but C1 INH level can be normal or elevated (2)[C].
  • C1q is decreased in ˜75% of AAE but is usually normal in all types of HAE (2)[C].
  • Abdominal radiographs and CT scan can demonstrate GI AE or ileus.
  • C1 INH deficiency may occur in association with internal malignancy, so AE rarely can be a paraneoplastic disease. Imaging (CT scan, radiography, etc.) then would be done as part of a neoplastic workup for patients with AAE.
Follow-Up Tests & Special Considerations
If C4 and C1q are low (as in AAE), neoplastic and autoimmune workup is warranted. CBC, a peripheral smear, protein electrophoresis, immunophenotyping of lymphocytes, and imaging studies are often undertaken to rule out hematologic malignancies or cancer (1)[C].
Diagnostic Procedures/Other
Skin biopsy (may be nonspecific)
Test Interpretation
  • Edema of deep dermis and SC tissue
  • Variable perivascular and interstitial infiltrate
image TREATMENT
GENERAL MEASURES
Intubation if airway is threatened
MEDICATION
First Line
  • Acute allergic AE (with airway compromise)
    • Epinephrine 1:1,000; 0.3 mL IV or SC (1)[C]
    • Glucocorticoids (hydrocortisone 200 mg IV or Solu-Medrol 40 mg IV) (1)[C]
    • Diphenhydramine 50 mg IV
    • If medication induced, stop the causative agent.
  • Idiopathic recurrent AE
    • 1st-generation antihistamines for acute AE (cause drowsiness)
    • Older children and adults: hydroxyzine (Vistaril) 5 mg/5 mL, 25-mg tablets 10 to 25 mg TID, or diphenhydramine (Benadryl) 25 to 50 mg q6h (3)[C]
    • Children <6 years of age: diphenhydramine 12.5 mg (elixir) q6-8h (5 mg/kg/day) (2)[C]
    • 2nd-generation H1 blockers: fexofenadine (Allegra) 180 mg/day BID, cetirizine (Zyrtec) 10 mg/day, desloratadine (Clarinex) 5 mg/day (3)[C]; use with caution in pregnancy and in the elderly.
  • P.55

  • HAE chronic prophylaxis
    • A nanofiltered plasma-derived C1 INH (pdC1 INH) concentrate (Cinryze) dosed at 1,000 units/10 mL IV, rate of 1 mL/min (for 10 min) q3-4d. Administration setting options include clinic, home health care, and after proper training, home self-administration; risk of thromboembolic events (4)[C],(5)[B].
    • Attenuated androgens increase hepatic production of C1 INH: oral danazol 50 to 200 mg/day or oral stanozolol 2 mg/day; use lowest effective dose. Side effects include, but are not limited to, headache, weight gain, liver dysfunction, hirsutism, and menstrual disturbances. Monitor CBC, liver function tests, creatinine kinase, lactic dehydrogenase, fasting lipid profile, and urinalysis at baseline and q6mo. Abdominal US to be performed annually or q6mo if dose of danazol >200 mg/day. Danazol is not to be used in children, during the first 2 trimesters of pregnancy, during lactation, and in patients with hepatitis or cancer (2)[C].
  • HAE short-term prophylaxis
    • Minor procedures (dental work): If C1 INH is available, no prophylaxis; otherwise, danazol 2.5 to 10 mg/kg/day (max 600 mg/day) and stanozolol 4 to 6 mg/day for 5 days prior to and 2 to 5 days after event (2)[C].
    • Major procedures (including intubation): C1 INH 1 (max 6) hour prior with additional dose on hand during procedure. If unavailable, danazol 2.5 to 10 mg/kg/day (max 600 mg/day) and solvent/detergent-treated plasma (SDP). If SDP unavailable, use fresh frozen plasma (FFP) 10 mL/kg; 2 to 4 units (400 to 800 mL) for an adult 1 to 6 hours prior
  • Acute HAE treatment
    • C1 INH concentrate IV, dosed at 1,000 units if <50 kg; 1,500 units if 50 to 100 kg; 2,000 units if > 100 kg (2)[C]
    • Recombinant human C1 INH isolated from the milk of transgenic rabbits (Ruconest—formerly Rhucin) was approved for acute HAE attacks. Trained patients may self-administer 50 IU/kg if <84 kg and 4,200 IU if ≥84 kg IV over 5 minutes. No more than two doses may be administered over 24 hours. Headache, nausea, and diarrhea may occur; and thromboembolic events or anaphylaxis are possible (6)[C].
    • Pasteurized human pdC1 INH (Berinert), dosed at 20 units/kg (available in 500 units/10 mL, max infusion rate of 4 mL/min IV via peripheral vein (4,7)[B]; DO NOT SHAKE (will denature the protein). Worsening of HAE pain was reported as the most severe adverse event.
    • Ecallantide (Kalbitor), a kallikrein inhibitor, is dosed in patients aged ≥ 16 years at 30 mg SC with three separate 10 mg/mL injections in the abdomen, thigh, or upper arm, and a second 30-mg dose may be repeated within 24 hours if needed (4,8)[B]. Injection-site rotation is not necessary but must be 2 inches away from attack site. A black box warning of anaphylaxis (potential adverse event) mandates administration in health care setting.
    • Icatibant (Firazyr), a bradykinin receptor-2 antagonist, is dosed at 30 mg SC over at least 30 seconds in the abdomen in patients aged ≥ 18 years and supplied in a prefilled 10 mg/mL (3 mL) syringe for home administration. Subsequent doses of 30 mg may be repeated in 6-hour intervals (max 90 mg/24 hours) (4)[C],(9)[B].
    • Antihistamines and glucocorticoids typically do not benefit patients with HAE. Epinephrine can offer transient stabilization/improvement in laryngeal AE but is not sufficient for full treatment and does not alter the course of attack.
  • Therapy under investigation for acute HAE treatment:
    • Cinryze has been studied for use during acute attacks (4)[C].
  • Acute AAE treatment
    • C1 INH concentrate and FFP
    • Treatment of underlying lymphoproliferative disease is often curative in AAE type I.
    • Immunosuppressive therapy to suppress antibody production
Second Line
  • HAE chronic prophylaxis: If pdC1 INH is unavailable and if patient cannot tolerate attenuated androgens, antifibrinolytic agents (plasmin inhibitors) such as tranexamic acid (not approved by the FDA in United States) 25 to 50 mg/kg/day divided BID or TID (3 to 6 g/day max) or ε-aminocaproic acid could be used. They are less effective than attenuated androgens and have many side effects. On rare occasions, they have been linked to (but not proven to cause) thrombophlebitis, embolism, or myositis (2)[C].
  • Acute HAE: FFP if C1 INH concentrate is not available, but it can potentially worsen attack.
  • Idiopathic AE: Oral doxepin (Sinequan) may be effective for AE (10 to 25 mg at bedtime).
  • H2RA: Oral ranitidine (Zantac) 150 mg/day BID
SURGERY/OTHER PROCEDURES
Tracheostomy if progressive laryngeal edema prevents endotracheal intubation
INPATIENT CONSIDERATIONS
Admission Criteria
Ensure patent airway. If anaphylaxis, epinephrine (1:1,000) SC 0.3 to 0.5 mg q10-15min
IV Fluids
Given if needed to stabilize patient
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Diagnostic workup if symptoms are severe, persistent, or recurrent
  • Protect airway if mouth, tongue, or throat is involved.
DIET
Avoid known dietary allergens.
PATIENT EDUCATION
Educate on avoidance of triggers (i.e., food, medication, other physical stimuli), types of treatment, when to seek emergency care, and wearing Medic Alert bracelet.
PROGNOSIS
  • AE symptoms often resolve in hours to 2 to 4 days. If airway is compromised, AE can be life-threatening.
  • Patients with HAE have an average of 20 attacks/year; each may last 3 to 5 days. Prophylaxis can decrease the frequency of events and number of missed days of school or work.
REFERENCES
1. Temiño VM, Peebles RS Jr. The spectrum and treatment of angioedema. Am J Med. 2008;121(4):282-286.
2. Zuraw BL, Bernstein JA, Lang DM, et al. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 2013;131(6):1491-1493.
3. Frigas E, Park M. Idiopathic recurrent angioedema. Immunol Allergy Clin North Am. 2006;26(4):739-751.
4. Altman KA, Naimi DR. Hereditary angioedema: a brief review of new developments. Curr Med Res Opin. 2014;30(5):923-930.
5. Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010;363(6):513-522.
6. Riedl MA, Bernstein JA, Li H, et al. Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol. 2014;112(2):163.e1-169.e1.
7. Craig TJ, Levy RJ, Wasserman RL, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol. 2009;124(4):801-808.
8. Cicardi M, Levy RJ, McNeil DL, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. 2010;363(6):523-531.
9. Lumry WR, Li HH, Levy RJ, et al. Randomized placebo-controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol. 2011;107(6):529-537.
See Also
Urticaria; Anaphylaxis
Codes
ICD10
  • T78.3XXA Angioneurotic edema, initial encounter
  • D84.1 Defects in the complement system
Clinical Pearls
  • AE is an acute, localized swelling of skin, mucosa, and submucosa caused by extravasation of fluid into the affected tissues. It often resolves in hours to days, but it can be life-threatening if the upper airway is involved.
  • HAE and AAE are diseases of the complement cascade that result in recurrent episodes of AE of the skin, upper airway, and GI tract.
  • Trigger identification and avoidance are key in the prevention of AE.
  • Patients with a history of allergies and AE should be prescribed an epinephrine autoinjector.