Angioedema
BASIC INFORMATION
Also known as hives, urticaria and angioedema are common allergic reactions. Urticaria is an episodic, rapidly occurring, usually self-limiting skin reaction. It involves only the superficial portion of the dermis, which erupts with local wheals surrounded by an erythematous flare. Angioedema, another dermal eruption, involves additional skin layers (including subcutaneous tissue) and produces deeper, larger wheals (usually on the hands, feet, lips, genitalia, and eyelids). Angioedema causes diffuse swelling of loose subcutaneous tissue and may affect the upper respiratory and GI tracts.
Urticaria and angioedema can occur separately or simultaneously, but angioedema may persist longer. Urticaria and angioedema affect about 20% of the general population at some time. Episodes are more common after adolescence, with the highest incidence in people who are in their 30s. Recurrent acute episodes last less than 6 weeks; if episodes persist longer than 6 weeks, the condition is considered chronic.
• The cutaneous swelling caused by the release of vasoactive mediators is called urticaria and angioedema.
• Urticaria causes edema of the superficial dermis.
• Angioedema involves the deep layers of the dermis and the subcutaneous tissue.
Fig. 3.8 Quincke edema of the lower lip.
SYNONYMS
Angioneurotic edema
The characteristics of this distinctive form of edema are that it is transient (episodes lasting minutes or hours), starts suddenly in any part of the body (Fig. 3.8) and causes itching. If the cutis alone is affected, it is referred to as urticaria. If the subcutaneous layer and the mucuous membranes are affected, it is referred to as angioedema. The lips and eyelids are most commonly affected and it is, therefore, important not to confuse the diagnosis with Melkersson-Rosenthal syndrome (recurrent facial swelling, facial paresis, lingua plicata), the etiology of which is unknown. Angioedema of the upper respiratory tract may lead to lifethreatening compression of the glottis. When the intestine is involved, colic and vomiting may be present.
* In allergic edema (Quincke edema), blood tests may show eosinophilia and raised IgE antibody levels immediately and/or at a subsequent time. Usually the cause can be identified. Nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, ACE inhibitors, contrast dyes, blood products, and penicillin may trigger the development of allergic edema.
* Drug-induced angioedema may also be the result of a process induced by IgE, by circulating immune complexes or a direct activation of the complement pathway. Urticaria and angioedema may also be accompanied by cutaneous or systemic angiitis and paraproteinemia.
* Hereditary angioedema (“angioneurotic” edema) is a disturbance of the capillary permeability due to a congenital, autosomal dominantly inherited enzyme deficiency (C1-esterase inhibitor). The disease manifests itself in distinctive attacks of edema occurring mainly in the extremities, the face, the laryngeal area (causing death by asphyxia in approximately one quarter of cases), and in the gastrointestinal tract. In addition to family history, it is essential to determine the C1-esterase inhibitor level in order to obtain a definitive diagnosis.
Angioneurotic edema
Clinical Symptoms.
The characteristics of this distinctive form of edema are that it is transient (episodes lasting minutes or hours), starts suddenly in any part of the body (Fig. 3.8) and causes itching. If the cutis alone is affected, it is referred to as urticaria. If the subcutaneous layer and the mucuous membranes are affected, it is referred to as angioedema. The lips and eyelids are most commonly affected and it is, therefore, important not to confuse the diagnosis with Melkersson-Rosenthal syndrome (recurrent facial swelling, facial paresis, lingua plicata), the etiology of which is unknown. Angioedema of the upper respiratory tract may lead to lifethreatening compression of the glottis. When the intestine is involved, colic and vomiting may be present.
* In allergic edema (Quincke edema), blood tests may show eosinophilia and raised IgE antibody levels immediately and/or at a subsequent time. Usually the cause can be identified. Nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, ACE inhibitors, contrast dyes, blood products, and penicillin may trigger the development of allergic edema.
* Drug-induced angioedema may also be the result of a process induced by IgE, by circulating immune complexes or a direct activation of the complement pathway. Urticaria and angioedema may also be accompanied by cutaneous or systemic angiitis and paraproteinemia.
* Hereditary angioedema (“angioneurotic” edema) is a disturbance of the capillary permeability due to a congenital, autosomal dominantly inherited enzyme deficiency (C1-esterase inhibitor). The disease manifests itself in distinctive attacks of edema occurring mainly in the extremities, the face, the laryngeal area (causing death by asphyxia in approximately one quarter of cases), and in the gastrointestinal tract. In addition to family history, it is essential to determine the C1-esterase inhibitor level in order to obtain a definitive diagnosis.
Acquired forms of C1- esterase inhibitor deficiency occur in lymphoproliferative diseases and in systemic lupus erythematosus. In these cases, of course, there is no positive family history of the disease. In both the inherited and the acquired forms there are low levels of complement components.
EPIDEMIOLOGY & DEMOGRAPHICS
• Approximately 20% of the population experiences urticaria and/or angioedema at some time during life.
• Race: No predilection.
• Sex: More occurrences in women than men.
• Angioedema can occur together with urticaria (50%) or alone (10%).
• Angioedema commonly occurs after adolescence in the third decade of life.
• Incidence of hereditary angioedema is 1/150,000 persons.
PHYSICAL FINDINGS & CLINICAL PRESENTATION
• Angioedema may be acute or chronic.
1. Acute angioedema is defined as symptoms lasting <6 wk.
2. Chronic angioedema is defined as symptoms lasting >6 wk.
• Urticaria is commonly known as “hives” and is characterized by:
1. Pruritus
2. Palpable
3. Erythematous
4. Millimeters to centimeters in size
5. Multiple in number
6. Fades within 12 to 24 hr
7. Reappears at other sites
• Angioedema is characterized by the following:
1. Nonpruritic
2. Burning
3. Not well demarcated
4. Involves eyelids, lips, tongue and extremities
5. Can involve the larynx causing respiratory distress
6. Resolves slowly
ETIOLOGY
• Angioedema, with or without urticaria, is classified as allergic, heredity, or idiopathic.
• Angioedema is primarily due to mast cell activation and degranulation with release of vasoactive mediators (e.g., histamine, serotonin, bradykinins) resulting in postcapillary venule inflammation, vascular leakage, and edema in the deep layers of the dermis and subcutaneous tissue.
• Pathologically angioedema has both immunological and nonimmunological mediated mechanisms
1. Immunoglobulin E(Ig E)- mediated angioedema may result from antigen exposure (e.g., foods [milk, eggs, peanuts, shell fish, tomatoes, chocolate, sulfites] or drugs [penicillin, aspirin, NSAIDs, phenytoin, sulfonamides]).
2. Complement-mediated angioedema involving immune complex mechanisms can also lead to mast cell activation that manifests as serum sickness.
3. Hereditary angioedema is an autosomal dominant disease due to a deficiency of C1 esterase inhibitor (C1-INH). C1-INH is a protease inhibitor that is normally present in high concentrations in the plasma. C1-INH serves many functions, one of which is to inhibit plasma kallikrein, a protease that cleaves kininogen and releases bradykinin. A deficiency in C1-INH results in excess concentration of kininogen and the subsequent release of kinin mediators.
4. Acquired angioedema is usually associated with other diseases, most commonly B-cell lympho-proliferative disorders, but may also result from the formation of auto-antibodies directed against C1 inhibitor protein.
5. Other causes of angioedema include infection (e.g., herpes simplex, hepatitis B, cox sackie AandB, streptococcus, candida, ascoris, and strongyloides), insect bites and stings, stress, physical factors (e.g., cold, exercise, pressure, and vibration), collagen vascular diseases (e.g., SLE, Henoich-Schoonlein purpura), and idiopathic causes.
DIAGNOSIS
A detailed history and physical examination usually makes the diagnosis of angioedema. Extensive lab testing is of limited value.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of angioedema includes:
1. Cellulitis
2. Hypothyroidism
3. Contact dermatitis
4. Atopic dermatitis
5. Mastocytosis
6. Granulomatous cheilitis
7. Bullous pemphigoid
8. Urticaria pigmentosa
9. Anaphylaxis
10. Erythema multiforme
11. Epiglottitis
12. Peritonsillar abscess
WORKUP
• An extensive workup searching for the cause of angioedema is often unrevealing (90%).
• Workup including diagnostic blood tests and allergy testing is performed based on the history and physical examination.
LABORATORY TESTS
• CBC, ESR, and urinalysis are sometimes helpful as part of the initial evaluation.
• Stools for ova and parasites
• Serology testing
• C1 esterase inhibitor concentration in suspected hereditary angioedema
• Complement C4 measurements is decreased in C1-INH deficiency.
• Skin and radioallergosorbent (RAST) testing may be done if food allergies are suspected.
• Skin biopsy is usually done in patients with chronic angioedema refractory to corticosteroid treatment.
TREATMENT
NONPHARMACOLOGIC THERAPY
• Eliminate the offending agent
• Avoid triggering factors (e.g., cold, stress)
• Cold compresses to affected areas
ACUTE GENERAL Rx
• Acute life-threatening angioedema involving the larynx is treated with:
1. Epinephrine 0.3 mg in a solution of 1:1000 given SC
2. Diphenhydramine 25 to 50 mg IV or IM
3. Cimetidine 300 mg IV or ranitidine 50 mg IV
4. Methylprednisolone 125 mg IV
• Mainstay therapy in angioedema is H1 antihistamines.
1. Diphenhydramine 25 to 50 mg q6h
2. Chlorpheniramine 4 mg q6h
3. Hydroxyzine 10 to 25 mg q6h
4. Cetirizine 5 to 10 mg qd
5. Loratidine 10 mg qd
6. Fexofenadine 60 mg qd
• H2 antihistamines can be added to H1 antihistamines.
1. Ranitidine 150 mg bid
2. Cimetidine 400 mg bid
3. Famotidine 20 mg bid
• Tricyclic antidepressants
1. Doxepin 25 to 50 mg qd can be tried.
• Corticosteroids are rarely required for symptomatic relief of acute angioedema.
CHRONIC Rx
• Chronic angioedema is treated as described under “Acute General Rx.”
• Corticosteroids are used more often in chronic angioedema.
• Prednisone 1 mg/kg/day for 5 days and then tapered over a period of weeks.
• Androgens are used for the treatment of hereditary angioedema.
DISPOSITION
• Antihistamines achieve symptomatic relief in over 80% of patients with angioedema.
• In chronic angioedema, corticosteroid is given in addition to antihistamines.
• A small percentage of people will have recurrence of symptoms after steroid treatment.
• Chronic angioedema can last for months and even years.
EPIDEMIOLOGY & DEMOGRAPHICS
• Approximately 20% of the population experiences urticaria and/or angioedema at some time during life.
• Race: No predilection.
• Sex: More occurrences in women than men.
• Angioedema can occur together with urticaria (50%) or alone (10%).
• Angioedema commonly occurs after adolescence in the third decade of life.
• Incidence of hereditary angioedema is 1/150,000 persons.
PHYSICAL FINDINGS & CLINICAL PRESENTATION
• Angioedema may be acute or chronic.
1. Acute angioedema is defined as symptoms lasting <6 wk.
2. Chronic angioedema is defined as symptoms lasting >6 wk.
• Urticaria is commonly known as “hives” and is characterized by:
1. Pruritus
2. Palpable
3. Erythematous
4. Millimeters to centimeters in size
5. Multiple in number
6. Fades within 12 to 24 hr
7. Reappears at other sites
• Angioedema is characterized by the following:
1. Nonpruritic
2. Burning
3. Not well demarcated
4. Involves eyelids, lips, tongue and extremities
5. Can involve the larynx causing respiratory distress
6. Resolves slowly
ETIOLOGY
• Angioedema, with or without urticaria, is classified as allergic, heredity, or idiopathic.
• Angioedema is primarily due to mast cell activation and degranulation with release of vasoactive mediators (e.g., histamine, serotonin, bradykinins) resulting in postcapillary venule inflammation, vascular leakage, and edema in the deep layers of the dermis and subcutaneous tissue.
• Pathologically angioedema has both immunological and nonimmunological mediated mechanisms
1. Immunoglobulin E(Ig E)- mediated angioedema may result from antigen exposure (e.g., foods [milk, eggs, peanuts, shell fish, tomatoes, chocolate, sulfites] or drugs [penicillin, aspirin, NSAIDs, phenytoin, sulfonamides]).
2. Complement-mediated angioedema involving immune complex mechanisms can also lead to mast cell activation that manifests as serum sickness.
3. Hereditary angioedema is an autosomal dominant disease due to a deficiency of C1 esterase inhibitor (C1-INH). C1-INH is a protease inhibitor that is normally present in high concentrations in the plasma. C1-INH serves many functions, one of which is to inhibit plasma kallikrein, a protease that cleaves kininogen and releases bradykinin. A deficiency in C1-INH results in excess concentration of kininogen and the subsequent release of kinin mediators.
4. Acquired angioedema is usually associated with other diseases, most commonly B-cell lympho-proliferative disorders, but may also result from the formation of auto-antibodies directed against C1 inhibitor protein.
5. Other causes of angioedema include infection (e.g., herpes simplex, hepatitis B, cox sackie AandB, streptococcus, candida, ascoris, and strongyloides), insect bites and stings, stress, physical factors (e.g., cold, exercise, pressure, and vibration), collagen vascular diseases (e.g., SLE, Henoich-Schoonlein purpura), and idiopathic causes.
DIAGNOSIS
A detailed history and physical examination usually makes the diagnosis of angioedema. Extensive lab testing is of limited value.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of angioedema includes:
1. Cellulitis
2. Hypothyroidism
3. Contact dermatitis
4. Atopic dermatitis
5. Mastocytosis
6. Granulomatous cheilitis
7. Bullous pemphigoid
8. Urticaria pigmentosa
9. Anaphylaxis
10. Erythema multiforme
11. Epiglottitis
12. Peritonsillar abscess
WORKUP
• An extensive workup searching for the cause of angioedema is often unrevealing (90%).
• Workup including diagnostic blood tests and allergy testing is performed based on the history and physical examination.
LABORATORY TESTS
• CBC, ESR, and urinalysis are sometimes helpful as part of the initial evaluation.
• Stools for ova and parasites
• Serology testing
• C1 esterase inhibitor concentration in suspected hereditary angioedema
• Complement C4 measurements is decreased in C1-INH deficiency.
• Skin and radioallergosorbent (RAST) testing may be done if food allergies are suspected.
• Skin biopsy is usually done in patients with chronic angioedema refractory to corticosteroid treatment.
TREATMENT
NONPHARMACOLOGIC THERAPY
• Eliminate the offending agent
• Avoid triggering factors (e.g., cold, stress)
• Cold compresses to affected areas
ACUTE GENERAL Rx
• Acute life-threatening angioedema involving the larynx is treated with:
1. Epinephrine 0.3 mg in a solution of 1:1000 given SC
2. Diphenhydramine 25 to 50 mg IV or IM
3. Cimetidine 300 mg IV or ranitidine 50 mg IV
4. Methylprednisolone 125 mg IV
• Mainstay therapy in angioedema is H1 antihistamines.
1. Diphenhydramine 25 to 50 mg q6h
2. Chlorpheniramine 4 mg q6h
3. Hydroxyzine 10 to 25 mg q6h
4. Cetirizine 5 to 10 mg qd
5. Loratidine 10 mg qd
6. Fexofenadine 60 mg qd
• H2 antihistamines can be added to H1 antihistamines.
1. Ranitidine 150 mg bid
2. Cimetidine 400 mg bid
3. Famotidine 20 mg bid
• Tricyclic antidepressants
1. Doxepin 25 to 50 mg qd can be tried.
• Corticosteroids are rarely required for symptomatic relief of acute angioedema.
CHRONIC Rx
• Chronic angioedema is treated as described under “Acute General Rx.”
• Corticosteroids are used more often in chronic angioedema.
• Prednisone 1 mg/kg/day for 5 days and then tapered over a period of weeks.
• Androgens are used for the treatment of hereditary angioedema.
DISPOSITION
• Antihistamines achieve symptomatic relief in over 80% of patients with angioedema.
• In chronic angioedema, corticosteroid is given in addition to antihistamines.
• A small percentage of people will have recurrence of symptoms after steroid treatment.
• Chronic angioedema can last for months and even years.
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