Basics
Description
- Nonpruritic, well-demarcated, nonpitting edema of the dermis
- Due to the release of inflammatory mediators that cause dilation and increased permeability of capillaries and venules:
- Mast cell mediated
- Kinin related from the generation of bradykinin and complement-derived mediators
- Similar in pathologic basis to urticaria except that affected tissue lies deeper:
- Urticaria affects superficial tissue and causes irritation to mast cells and nerves in the epidermis leading to intense itching.
- Angioedema occurs in deeper layers, which have fewer mast cells and nerves, therefore causing less itching.
- Angioedema can affect tissues other than the skin, for example, the gut.
- Angioedema may be seen in a mixed picture along with urticaria
- Hereditary and acquired etiologies are due to deficiencies in the quantity and/or function of C1-INH rather than classic hypersensitivity reactions
- Hereditary angioedema (HAE):
- An autosomal dominant disorder caused by a deficiency of C1-INH
- The prevalence of HAE is estimated to range from 1:10,000 to 1:150,000.
- C1-INH has a regulatory role in the contact, fibrinolytic, and coagulation pathways.
- Deficiency results in unregulated activity of the vasoactive mediators bradykinin, kallikrein, and plasmin.
- More than 100 mutations of the C1-INH gene have been reported.
- Type 1: Decreased expression of C1-INH
- Type 2: Normal plasma levels of C1-INH but the protein is dysfunctional
- Type 3: Mutation in coagulation factor XII resulting in increased kinin production:
- Symptoms increased by estrogen-containing medications
- Episodes occur in all 3 types when inflammation, trauma, or other factors lead to depletion of C1-INH.
- Acquired angioedema:
- Normal quantities and function of C1-INH
- Type 1 is associated with lymphoproliferative diseases and caused by consumption of the C1-INH protein by malignant cells.
- Type 2 is autoimmune caused by circulating antibodies that inactivate C1-INH.
- ACE inhibitor-induced angioedema:
- Accounts for 2030% of all angioedema cases presenting to ER reported in 0.1-2.2% of patients taking ACE inhibitors
- Usually occurs during the 1st mo of taking the medication, however the 1st event may occur spontaneously after many years.
Etiology
- Kinin-related etiologies:
- HAE
- Acquired angioedema:
- Lymphoproliferative
- Autoimmune
- ACE inhibitor induced
- Mast cell-mediated etiologies:
- Food allergies:
- Additives
- Nuts
- Eggs/milk
- Shellfish
- Soy/wheat
- Drug allergies:
- Aspirin
- NSAID
- Antihypertensives
- Narcotics
- Oral contraceptives
- Insect stings
- Physically induced:
- Cold/heat
- Exercise/trauma/vibrations
- Stress
- UV light
- Hypereosinophilic syndromes such as Gleich syndrome
- Thyroid autoimmune disease
- Idiopathic recurrent AE
Diagnosis
Signs and Symptoms
History
- A family history or history of recurrent episodes can be useful in the diagnosis. Use of culprit foodstuffs or medications, especially ACEIs should increase index of suspicion
- Abdominal pain associated with nausea, vomiting, and diarrhea
- Attacks of HAE are not associated with hives or itching
- Emotional stress or physical trauma can trigger attacks.
Physical Exam
- The lesions of angioedema are large, swollen, and nonpitting wheals.
- The eyelids and lips are frequently involved.
- Involvement of the pharynx and larynx may cause airway obstruction.
- Lesions are often asymmetric and do not typically involve gravitationally dependent areas
Essential Workup
- Diagnosis is made of clinical grounds based on the presentation of large nonpitting, nonpruritic wheals.
- A family history need not be present: 25% of HAE patients have a new mutation and may not have a positive family history.
Diagnosis Tests & Interpretation
Lab
- CBC with differential, ESR, ANA, rheumatoid factor, C4 and C3 levels.
- Skin biopsy if an urticarial lesion is accessible
Diagnostic Procedures/Surgery
Measurement of C1-INH levels (not routinely available in EDs):
- Patients affected with HAE type 1 have very low levels; carriers will have half-normal levels.
- C4 and C2 levels are low during attacks in both hereditary and acquired forms.
Differential Diagnosis
- Edema:
- SVC syndrome
- Right heart failure
- Constrictive pericarditis
- Renal failure
- Nephrotic syndrome
- Allergic contact dermatitis
- Blepharochalasis
- Facial cellulitis
- Facial lymphedema
- Edema secondary to autoimmune disorders:
- Dermatomyositis
- Lupus
- Polymyositis
- Sj ¶gren syndrome
- Hypothyroidism
Recurrent angioedema presenting around puberty should raise suspicion of HAE.
Treatment
Pre-Hospital
- Establish IV access
- Early intubation may be necessary due to the rapid progression of laryngeal swelling.
- Administration of H1 blocker when available
- Epinephrine to be considered for laryngeal edema especially if itching or other signs of a mast cell etiology with histamine release is suspected.
Initial Stabilization/Therapy
- Active airway management and supportive measures are the primary goals of emergency treatment.
- Intubation may be necessary in severe cases:
- Orotracheal intubation is the technique of choice but may be difficult because of laryngeal edema, spasm, or soft-tissue swelling.
- Consider advanced airway adjuncts such as the gum elastic bougie to assist in securing endotracheal tube placement.
- Blind nasotracheal intubation if soft tissue swelling prohibits an oral approach
- Transtracheal jet insufflation or cricothyrotomy may be necessary to control the airway.
- Epinephrine, antihistamines, and steroids in obstructive airway swelling, although patient response can be variable.
Ed Treatment/Procedures
- Acute angioedema with features of a type 1 hypersensitivity reaction:
- Treat similarly to an allergic reaction with H1 and H2 blockers along with corticosteroids.
- Epinephrine should be used in refractory cases where the benefits outweigh the risks.
- For abdominal attacks consider the addition of parenteral pain relief, antiemetics, and IV fluid replacement.
- HAE and acquired angioedema:
- C1-INH
- Fresh frozen plasma (FFP) may be used as an alternative to C1-INH.
- The kallikrein inhibitor ecallantide (Kalbitor) was approved in 2009 for the treatment of acute attacks of HAE.
- Tranexamic acid (Cyklokapron), an antifibrinolytic agent, is not as effective for acute attacks and is used primarily in prevention.
- C1 inhibition has been standard therapy in Europe for many years; however, the US FDA has only recently been approving these medications for use in the US, therefore clinician and pharmacist recognition of the utility of these drugs may be limited.
- Therapy with FFP (as a source of nonpurified C1-HN) is advised with caution as it may paradoxically worsen some attacks due to its high concentration of complement components.
- Attenuated androgens, such as the anabolic steroids and gonadotropin inhibitor danazol, are used in the long-term prophylactic treatment. They may not have any effect for 24-48 hr in the acute setting.
- Angioedema associated with ACE inhibitors occurs in 0.1-0.2% of cases and requires immediate withdrawal of the ACE inhibitor. ACE inhibitor-related angioedema usually occurs within a week after starting ACE inhibitor therapy, but may occur much later.
Medication
General principles of pharmacologic treatment are based on suspected underlying cause:
- Suspected HAE:
- Non-HAE:
- H1 blockers
- H2 blockers
- Corticosteroids
- C1 esterase inhibitor replacement proteins (C1INHRP):
- In the US currently only plasma-derived products:
- Cinryze: 20 U/kg U slow IV infusion
- Berinert: 20 U/kg IV slow IV infusion with additional doses if no improvement in 2 h, sooner if worsening or if laryngeal symptoms
- In the EU recombinant C1INHRP is also available (at this time not yet approved by US FDA)
- Ruconest (not yet FDA approved) 50 U/kg, generally does not require repeat dosing
- Cimetidine: 300 mg IV
- Danazol: 400-600 mg PO up to 1 g/d. Contraindicated in children and pregnancy.
- Diphenhydramine: Adult: 50 mg IV; peds: 1-2 mg/kg slow IVP
- Ecallantide (kallikrein inhibitor available US only): 30 mg SC given as 3 separate injections (about 1 mL each anatomically distant from AE affected area)
- Epinephrine: 0.3-0.5 mg (use 1:1,000 dilution for SC route, and 1:10,000 for IV route); peds: 0.01 mg/kg SC/IV
- Racemic epinephrine: 2.25% solution (0.5 mL placed in a nebulizer in 2.5 mL of NS)
- FFP (if C1-INH is unavailable): Adult: 2 U
- Hydrocortisone: Adult: 500 mg IV; peds: 4-8 mg/kg/dose IV.
- Icatibant (bradykinin B2 receptor antagonist): 30 mg SC once
- Methylprednisolone: Adult: 125 mg IV; peds: 1-2 mg/kg IV
- Prednisone: Adult: 60 mg PO; peds: 1 mg/kg PO
- Ranitidine: Adult: 50 mg IV
- Stanozolol: 2 mg PO up to 16 mg/d:
- Discontinued in the US
- Contraindicated in children and in pregnancy
- Tranexamic acid: 1 g PO q3-4h for up to 48 h if necessary
Safety and efficacy of newer HAE treatment agents (such as C1-INH Cinryze and Berinert) have not been established in children as of this writing. Dosing for adolescents is suggested to be weight based at 20 U/kg.
Follow-Up
Disposition
Admission Criteria
- Patients with systemic symptoms that do not resolve completely will need to be hospitalized for observation.
- A monitored bed is recommended for those with airway involvement.
Discharge Criteria
- Patients presenting with minor symptoms of angioedema without progression after 4-6 hr of observation may be safely discharged home on a short course of steroids and antihistamines.
- Patients should be provided with an EpiPen and instructions on its use.
Issues for Referral
Patients should be evaluated by an allergist/immunologist after the initial presentation, especially if there is a family history of angioedema, or if the angioedema is accompanied by abdominal pain, or triggered by trauma.
Followup Recommendations
Patients without systemic symptoms who are stable for discharge should been seen in outpatient follow-up in a few days.
Pearls and Pitfalls
- Early measures should be employed to maintain the patients airway.
- Consider use of newer agents in HAE patients (e.g., C1-INH and Kallikrein inhibition).
Additional Reading
- Austen K. Allergies, anaphylaxis, and systemic mastocytosis. In: Fauci AS, Braunwald E, Kasper DL, et al., eds. Harrisons Principles of Internal Medicine, 17th ed. New York, NY: McGraw-Hill; 2008.
- Temi ±o VM, Stokes Peebles R. The spectrum and treatment of angioedema. Am J Med. 2008;121:282-286.
- Wahn V, Aberer W, Eberl W, et al. Hereditary angioedema (HAE) in children and adolescents-a consensus on therapeutic strategies. Eur J Pediatr. 2012;171(9):1339-1348.
- Zuraw B. Hereditary angioedema. N Engl J Med. 2008;359:1027-1036.
See Also (Topic, Algorithm, Electronic Media Element)
Codes
ICD9
- 277.6 Other deficiencies of circulating enzymes
- 995.1 Angioneurotic edema, not elsewhere classified
ICD10
- D84.1 Defects in the complement system
- T78.3XXA Angioneurotic edema, initial encounter
SNOMED
- 41291007 angioedema (disorder)
- 82966003 Hereditary angioneurotic edema (disorder)