ANGIOEDEMA

ANGIOEDEMA - Anatoli Freiman, MD
BASICS
DESCRIPTION
• Dermal (subcutaneous or submucosal) extravasation of fluid, leading to localized edema
• The release of inflammatory vasoactive mediators increases vascular permeability.
• The skin, gastrointestinal tract, and respiratory tract are most commonly involved. It is life threatening if the upper airway is affected. It usually resolves in hours to days.
• Can be idiopathic or induced by medications, allergens (e.g., food), or physical agents (e.g., vibration, cold)
• 2 rare but well-described categories of angioedema result from deficiency of C1 esterase inhibitor (C1 INH) of the compliment and kallikrein-kinin systems: Hereditary angioedema (HAE) and acquired angioedema (AAE).
- HAE type I (80-85%): Due to hereditary deficiency of C1-INH; recurrent episodes of angioedema, involving both skin and mucous membranes or intestinal mucosa (25% mortality)
- HAE type II (15-20%): Normal or elevated quantities of functionally impaired C1-INH
- HAE type III: Rare, recently described estrogen-dependent form
- AAE type I: Increased destruction of C1-INH, which occurs in patients with rheumatologic disorders and B-cell lymphoproliferative malignancies, such as leukemia, T-cell lymphoma, multiple myeloma, and essential cryoglobulinemia
- AAE type I is also reported with carcinomas, infections, and vasculitides. Immune complexes continuously activate C1, leading to consumption of C1-INH and precipitating angioedema.
- AAE type II: B cells secrete autoantibodies against C1-INH, leading to its inactivation
• Medication-induced angioedema
- Immunologic hypersensitivity, as in penicillin reaction
- Nonimmunologic, as in reactions to NSAIDs (e.g., aspirin)
- Angiotensin converting enzyme (ACE) inhibitors decrease levels of angiotensin II and stimulate production of bradykinin, a potent vasodilator, thus leading to angioedema. This may occur immediately or months after starting the drug.
• System(s) Affected: Skin/Exocrine
• Synonym(s): Angioneurotic edema; Quincke edema
GENERAL PREVENTION
• If etiology known, avoidance
• Avoid ACE inhibitors in patients with a history of angioedema.
EPIDEMIOLOGY
• Predominant age
- HAE: Infancy to second decade of life
- AAE: Typically patients > 40 years old.
• Predominant sex: Male = Female (idiopathic)
Incidence
• 1 in 5,000
• Accompanies urticaria 40-50% of time
RISK FACTORS
• Medications and foods that can cause allergic reactions
• ACE inhibitors are contraindicated in patients with C1-INH deficiency
Genetics
HAE types I and II are inherited in autosomal dominant mode, whereas type III is X-linked. HAE occurs in 25% of the patients as a result of spontaneous mutations.
PATHOPHYSIOLOGY
Similar pathophysiology for urticaria and angioedema: Localized anaphylaxis causes vasodilatation and vascular permeability of superficial (urticaria) or subcutaneous/deeper dermal tissue (angioedema)
ETIOLOGY
• Idiopathic
• Medication-induced: ACE inhibitors, NSAIDs, antibiotics, or estrogen contraceptives
- ACE inhibitors (ACEI) are ascribed to 10-25% of angioedema cases and mostly occur within the 1st 3-4 weeks of use. However, the 1st onset may be delayed years. Failure to react to re-challenge with drug does not rule out a cause-effect relationship between the ACEI and angioedema.
- Losartan (Cozaar), valsartan (Diovan), and irbesartan (Avapro), which are all angiotensin receptor blockers (ARB), can also cause angioedema. It can occur within 24 hours to 16 months after initiating losartan therapy.
• Allergen-induced: Food allergens, such as fish, nuts, and preservatives
• Physically induced: Cold, pressure, vibration
• Hereditary or acquired C1-INH deficiency
• Thyroid autoimmunity has been reported to be associated with angioedema.
ASSOCIATED CONDITIONS
• Urticaria
• Anaphylaxis

DIAGNOSIS
SIGNS AND SYMPTOMS
• Occurs alone or in association with urticaria in 50% of cases
• Angioedema usually does not cause itching in comparison to urticaria, but can cause burning.
• Relatively rapid onset of presentation; usually resolves spontaneously in 72 hours
• Skin
- Localized swelling; may occur anywhere on body; usually face, extremities, or genitalia; often asymmetric
- Frequently disfiguring and frightening to the patient
• Gastrointestinal
- May present with intermittent unexplained abdominal pain
• Respiratory
- May be associated with generalized anaphylactic reaction, potentially fatal if upper airway is compromised
History
• Acute onset of asymmetric localized swelling
• GI tract involvement may manifest as intermittent unexplained abdominal pain.
• In comparison to urticaria, angioedema is typically nonpruritic, but can cause burning.
Physical Exam
Subcutaneous swelling, usually of the face (eyelids, lips, ears, nose), and less often of the extremities or genitalia
TESTS
Lab
• If angioedema with urticaria and/or anaphylaxis, no testing is needed, but history should be directed to exposures: Foods, medications, exposures, etc.
• Without clear etiology and recurrence in angioedema and urticaria, CBC and ESR; macrocytosis implies a pernicious anemia; eosinophilia my imply atopy or rarely parasitic infection. Elevated ESR may imply systemic disorders.
• In recurrent angioedema without clear etiology and without urticaria, consider ordering C4. Low serum C4 is a very sensitive, but nonspecific, screening test for hereditary and acquired C1-INH deficiency. If C4 is normal, urticaria work-up is recommended.
• If C4 is low, C1-INH assay (immunoreactive) is performed for HAE type I and C1-INH assay (functional) for HAE type II.
• C1q is decreased in acquired C1-INH deficiency.
• If C4 and C1q are low (as in AAE), neoplastic and autoimmune work-up are warranted. Routine blood tests, a smear, protein electrophoresis, immunophenotyping of lymphocytes, and imaging studies are often undertaken to rule out hematological malignancies or cancer.
• May alter lab results
- Antihistamines
- H2-blockers
- Tricyclic antidepressants
Imaging
As part of neoplastic work-up if relevant
Diagnostic Procedures/Surgery
Skin biopsy (may be nonspecific)
Pathological Findings
Edema of deep dermis and subcutaneous tissue. Variable perivascular and interstitial infiltrate
DIFFERENTIAL DIAGNOSIS
• Urticaria
• Allergic contact dermatitis
• Connective tissue disease: Lupus, dermatomyositis
• Anaphylaxis
• Cellulitis, erysipelas
• Lymphedema
• Diffuse subcutaneous infiltrative process
TREATMENT
PRE-HOSPITAL
• Ensure airway patency 1st! Protect the airway if the mouth, tongue, and/or throat are involved.
• Perform CPR and transport to an emergency facility, if necessary.
STABILIZATION
If anaphylaxis (circulatory collapse or airway compromise), consider epinephrine (1:1000) SC 0.3-0.5 q15min.
GENERAL MEASURES
• Symptomatic, supportive management
• Avoid known triggers.
• Cool, moist compresses to control itching or burning
MEDICATION (DRUGS)
First Line
• 1st generation antihistamines for acute angioedema
- Older children and adults: hydroxyzine (Vistaril 5 mg/5 cc, 25 tablets) 10-25 mg t.i.d. or diphenhydramine (Benadryl) 25-50 mg q6h
- Children under 6 years of age: Diphenhydramine 12.5 mg (elixir) q6-8h (5 mg/kg/day)
• 2nd generation H1 blockers are less sedating because they do not cross the blood-brain barrier.
- Fexofenadine (Allegra) 60 mg b.i.d.
- Loratadine (Claritin) 10 mg daily
- Acrivastine (Semprex) 8 mg t.i.d.
- Cetirizine (Zyrtec) 10 mg daily, which is more sedating than others in this class
• Anaphylaxis
- Intubation if airway is threatened
- Epinephrine 1:1,000, 0.2-0.3 mL IV or SQ
- Specific HAE and AAE therapy
- C1-INH concentrate
- Attenuated androgens: Danazol or stanozolol are particularly effective for prevention of HAE because they increase the amount of active C1-INH. Give 200-600 mg daily for 1 month, then 5 days on, 5 days off. The side effects are headaches, weight gain, and hematuria.
- Antifibrinolytic agents (plasmin inhibitors), such as tranexamic acid and aminocaproic acid, may also be used, but are not as effective as attenuated androgens in the management of HAE. On rare occasions they can cause thrombophlebitis, embolism, or myositis.
• Contraindications
- Danazol not to be used in childhood, pregnancy, lactation, and prostate cancer
• Precautions
- Drowsiness with 1st generation drugs
- Second generation H1 blockers should be used with caution in pregnancy and the elderly.
Second Line
Doxepin (Sinequan) may be effective for angioedema (10-25 mg at bedtime)
FOLLOW-UP
PROGNOSIS
Most patients with idiopathic angioedema do well. Chronic forms depend on underlying pathology.
COMPLICATIONS
• Anaphylaxis
• Respiratory compromise
PATIENT MONITORING
• Diagnostic work-up if symptoms are severe, persistent, or recurrent
• Protect airway if mouth, tongue, or throat is involved
REFERENCES
1. Bowen T, et al. Canadian 2003 international consensus algorithm for the diagnosis, therapy, and management of hereditary angioedema. J Allergy Clin Immunol. 2004;114(3):629-637.
2. Charlesworth EN. Differential diagnosis of angioedema. Allergy Asthma Proc. 2002;23:337-339.
3. Frigas E, Nzeako UC. Angioedema. Clin Rev Allerg Immunol. 2002;23:217-231.
4. Heymann WR. Acquired angioedema. J Am Acad Dermatol. 1997;26:611-615.
5. Kim JS, Pongracic JA. Hereditary and aquired angioedema. Allergy Asthma Proc. 2004;25:S47-S49.
6. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med. 2001;161:2417-2429.