Angioedema

Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema occurring in the deep layers of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Clinically, angioedema presents with swelling around the eyes, lips Lips The lips are the soft and movable most external parts of the oral cavity. The blood supply of the lips originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue, tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue, mouth, bowel wall, extremities, or genitalia. Angioedema may also compromise the airway. Urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives) will be present when the angioedema is mediated by mast cells, but not when it is due to increases in bradykinin. Diagnosis is usually clinical but additional testing may include skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin/serum testing for specific antigens and C4 level assessment. Management depends on the underlying mechanism but may include treatment for anaphylaxis, removing any offending agents, antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines, glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids, and/or therapies that target bradykinin.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

  • Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema occurring in the deep layers of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and mucosal tissue.
  • May occur with or without urticaria:
    • With urticaria: indicates an IgE-mediated type I hypersensitivity reaction Type I hypersensitivity reaction Type I hypersensitivity reaction is an abnormal immune response triggered by exposure to specific antigens known as allergens. In this type of hypersensitivity reaction, the presentation of the antigen to the T-helper cells (Th cells) initiates a cascade of immunologic events leading to the production of antigen-specific IgE antibodies. Type I Hypersensitivity Reaction
    • Without urticaria: mediated by substances other than IgE, usually bradykinin
  • Acute or chronic:
    • Acute angioedema: < 6 weeks duration
    • Chronic angioedema: 2–3 episodes per week for ≥ 6 weeks duration

Epidemiology

  • Incidence: 
    • Data on overall incidence are limited.
    • Relatively common
    • Occurs in 40%–50% of patients with chronic urticaria
    • Approximately 10%–20% of people will experience an episode of angioedema at some point.
  • Age range: 
    • Occurs in any age group
    • ↑ Incidence after adolescence (highest at 20–30 years old)
  • No gender bias Bias Epidemiological studies are designed to evaluate a hypothesized relationship between an exposure and an outcome; however, the existence and/or magnitude of these relationships may be erroneously affected by the design and execution of the study itself or by conscious or unconscious errors perpetrated by the investigators or the subjects. These systematic errors are called biases. Types of Biases
  • Most commonly seen in African Americans

Etiology and Pathophysiology

Classification

Angioedema may result from 3 primary mechanisms:

  • Mast cell-mediated angioedema (most common and associated with urticaria):
    • Mast cells are activated by:
      • IgE to specific antigens
      • Physical stimuli
      • Medications (non–IgE-mediated direct activation of mast cells)
    • Once activated, mast cells release inflammatory mediators:
      • Histamine
      • Leukotrienes
      • Prostaglandins
      • Heparin
  • Bradykinin-mediated angioedema (not associated with urticaria):
    • Bradykinin is an inflammatory mediator that can lead to vasodilation and vascular permeability.
    • ↑ Bradykinin → ↑ vasodilation and ↑ vascular permeability
    • Due to:
      • ↓ C1 inhibitor → ↓ inhibition of kinin generation → ↑ bradykinin
      • ↑ Angiotensin-converting enzyme (ACE) inhibition → ↓ bradykinin degradation → ↑ bradykinin
  • Idiopathic or unknown mechanism

General pathophysiology

  • Inflammatory mediators → ↑ vascular permeability and dilation of capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries and venules
  • Extravasation of fluid from vasculature → asymmetric edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema in the subcutaneous tissue and deep dermis:
    • Occurs in areas of affected vasculature
    • Not gravitationally dependent

Mast cell-mediated etiologies

Mast cell-mediated angioedema is typically associated with urticaria.

  • IgE to specific antigens (type I hypersensitivity reactions): 
    • Pollen and mold
    • Foods, most commonly:
      • Peanuts
      • Tree nuts
      • Shellfish
      • Dairy
      • Eggs
    • Drugs:
      • Penicillin
      • Sulfa drugs
      • NSAIDs
    • Environmental:
      • Insect stings Insect stings Insect and scorpion stings are a rare cause of mortality. Hymenoptera insects and Centruroides scorpions can potentially lead to serious symptoms due to envenomation. Pain, swelling, erythema, and warmth are common at the site of a sting. Insect and Scorpion Stings (venom) and bites
      • Latex
    • Physical stimuli: 
      • Cold
      • Heat
      • Exercise
      • Vibrations
      • Pressure
  • Medications (directly stimulate mast cells without IgE)
    • Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
    • NSAIDs 
      • Most commonly due to aspirin
      • Note: IgE-mediated allergy and direct mast cell stimulation are both possible.
    • Radiocontrast agents

Bradykinin-mediated etiologies

These etiologies are not associated with histamine release or urticaria.

  • Dysfunctional C1 inhibitor:
    • Hereditary angioedema (HAE): an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance abnormality in the quantity or function of C1 inhibitor
    • Acquired C1 inhibitor deficiency angioedema: development of antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins against C1 inhibitor
  • Medications (both via ↓ bradykinin degradation):
    • ACE inhibitors (ACEI)
    • Dipeptidyl peptidase-4 inhibitors

Other etiologies

  • Urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives) may or may not be present.
  • Idiopathic angioedema: 
    • An etiology is not determined after a thorough evaluation.
    • Commonly associated with chronic angioedema
  • Other causes of angioedema with unknown mechanisms:
    • Infections:
      • Common cold
      • Streptococcal pharyngitis Pharyngitis Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis
      • Urinary tract infections Urinary tract infections Urinary tract infections (UTIs) represent a wide spectrum of diseases, from self-limiting simple cystitis to severe pyelonephritis that can result in sepsis and death. Urinary tract infections are most commonly caused by Escherichia coli, but may also be caused by other bacteria and fungi. Urinary Tract Infections
    • Calcium channel blockers Calcium Channel Blockers Calcium channel blockers (CCBs) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBs: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers)
    • Other drugs or herbal medicine (uncommon)

Clinical Presentation

  • Swelling in deep cutaneous and mucosal tissue:
    • Face
    • Lips, mouth, tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue
    • Throat, larynx Larynx The larynx, also commonly called the voice box, is a cylindrical space located in the neck at the level of the C3-C6 vertebrae. The major structures forming the framework of the larynx are the thyroid cartilage, cricoid cartilage, and epiglottis. The larynx serves to produce sound (phonation), conducts air to the trachea, and prevents large molecules from reaching the lungs. Larynx, and uvula
    • Extremities
    • Genitalia
    • Bowel wall:
      • Colicky abdominal pain
      • Nausea and vomiting
      • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Characteristics of swelling:
    • Onset:
      • Mast cell-mediated: minutes to hours
      • Bradykinin-mediated: hours to days
    • Spontaneous resolution (hours to days)
    • Asymmetric distribution
    • Form in nongravitationally dependent areas
  • Urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives) (in mast cell-mediated cases only)
    • Coalescing, well-circumscribed wheals
    • Intensely pruritic
    • Erythematous
    • Edematous
    • Raised borders
    • Central blanching
  • Anaphylaxis: 
    • Life-threatening throat and airway swelling → impaired airflow
    • Signs and symptoms:
      • Shortness of breath
      • Wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing and stridor
      • Tachycardia
      • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension

Diagnosis

The diagnosis of angioedema is usually clinical, but testing can help to clarify the etiology. Most cases of chronic angioedema are idiopathic.

  • Important history:
    • Recent allergen exposure
    • Stings or bites
    • Medication history
  • Mast cell-mediated angioedema with urticaria:
    • CBC/DIFF: 
      • Possible eosinophilia
      • Normal WBC count
    • With anaphylaxis: ↑ tryptase confirms mast cell activation
    • Allergy skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin testing
    • Medication withdrawal and challenge
    • Repeat physical stimuli (if suspected as triggering event).
    • Serum IgE antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins to specific antigens
  • Isolated angioedema without urticaria:
    • ↑ CRP → infection, ACEI-induced angioedema
    • ↓ Complement protein C4 → evaluate for HAE or acquired C1 inhibitor deficiency:
      • C1 inhibitor antigen
      • C1 inhibitor function levels

Management

General management

  • Assess airway → intubate if there are signs of airway compromise
  • Assess for anaphylaxis → stabilize if present:
    • Epinephrine
    • Intravenous fluids Intravenous Fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids
    • Oxygen
  • Discontinue any potential causative medications.

Management of mast cell-mediated angioedema

  • Identify and remove triggers.
  • H1 antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines (1st line): to suppress histamine released by mast cells:
    • Diphenhydramine
    • Cetirizine
    • Loratadine
  • Systemic glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids:
    • Methylprednisolone
    • Prednisone
    • Prednisolone

Management of bradykinin-mediated angioedema

  • HAE:
    • 1st-line options to attempt to ↓ bradykinin:
      • Purified C1 inhibitor concentrate
      • Kallikrein inhibitor: ecallantide
      • Bradykinin B2 receptor antagonist: icatibant
    • 2nd-line options:
      • FFP
      • Only used when 1st-line options are not available
  • ACEI-associated angioedema:
    • The above therapies for HAE can be used, but their efficacy has not been proven.
    • Most cases resolve 24–72 hours after discontinuing the ACEI.

Management of chronic idiopathic angioedema

  • Patients should be referred to an allergy specialist.
  • Medical therapy:
    • Nonsedating antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines
      • Cetirizine
      • Loratadine
    • Leukotriene receptor antagonist (montelukast) can be added.
    • For acute episodes:
      • Prednisone
      • Diphenhydramine

Differential Diagnosis

  • Contact dermatitis: inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin in response to contact irritants, which can affect the face in some circumstances (often cosmetics or topical pharmaceuticals). Edema and pruritus may develop mimicking angioedema. Microvesiculation (formation of small vesicles), pain, and a burning sensation can help distinguish contact dermatitis from angioedema. Management involves removing the offending agent and reducing skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation with steroids or topical calcineurin inhibitors.
  • Cellulitis Cellulitis Cellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis and erysipelas Erysipelas Erysipelas is a bacterial infection of the superficial layer of the skin extending to the skin's superficial lymphatic vessels. This infection presents as a raised, well-defined, tender, and bright red rash. Typically on the legs or face, but erysipelas can occur anywhere on the skin. Erysipelas: skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin infections presenting with well-demarcated erythema, edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, and warmth. Cellulitis Cellulitis Cellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis involves the deeper dermis and subcutaneous fat while erysipelas Erysipelas Erysipelas is a bacterial infection of the superficial layer of the skin extending to the skin's superficial lymphatic vessels. This infection presents as a raised, well-defined, tender, and bright red rash. Typically on the legs or face, but erysipelas can occur anywhere on the skin. Erysipelas involves the upper dermis. Cellulitis Cellulitis Cellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis and erysipelas Erysipelas Erysipelas is a bacterial infection of the superficial layer of the skin extending to the skin's superficial lymphatic vessels. This infection presents as a raised, well-defined, tender, and bright red rash. Typically on the legs or face, but erysipelas can occur anywhere on the skin. Erysipelas tend to be accompanied by a fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, are more painful than angioedema, and have more pronounced demarcation than angioedema. The diagnosis is clinical, and management is with antibiotics.
  • Autoimmune conditions: systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus, polymyositis Polymyositis Polymyositis (PM) is an autoimmune inflammatory myopathy caused by T cell-mediated muscle injury. The etiology of PM is unclear, but there are several genetic and environmental associations. Polymyositis is most common in middle-aged women and rarely affects children. Polymyositis, dermatomyositis, and Sjogren’s syndrome, which may all present with edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema of the face, periorbital areas, and hands. The presence of other findings (e.g., Raynaud’s phenomenon, dry eyes/mouth, and characteristic rashes Rashes Rashes are a group of diseases that cause abnormal coloration and texture to the skin. The etiologies are numerous but can include irritation, allergens, infections, or inflammatory conditions. Rashes that present in only 1 area of the body are called localized rashes. Generalized rashes occur diffusely throughout the body. Generalized and Localized Rashes) differentiates the autoimmune conditions from angioedema. The diagnosis is based on clinical findings and antibody testing. Management varies, but often includes steroids and immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants.
  • Superior vena cava Superior vena cava The venous trunk which returns blood from the head, neck, upper extremities and chest. Mediastinum and Great Vessels (SVC) syndrome: tumors involving the right lung, lymph nodes, or mediastinal structures that may obstruct blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure through the SVC by direct invasion or external compression, causing swelling in the face or neck and dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea. Other symptoms (e.g., chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain, respiratory, or neurologic) help distinguish SVC syndrome from angioedema. Diagnosis is with imaging and venography. Management involves treatment for the malignancy and techniques to relieve the obstruction.

References

  1. Frank Austen, K. (2008). Allergies, anaphylaxis, and systemic mastocytosis. In Fauci, A. S., Braunwald, E., Kasper, D.L., et al. (Eds.). Harrison’s Internal Medicine. 17th Ed., pp. 2065-2067.
  2. Zuraw, B. (2019). An overview of angioedema: Pathogenesis and causes. In Feldweg, A. M. (Ed.). UpToDate. Retrieved February 18, 2021, from https://www.uptodate.com/contents/an-overview-of-angioedema-pathogenesis-and-causes
  3. Zuraw, B. (2019). An overview of angioedema: Clinical features, diagnosis, and management. In Feldweg, A. M. (Ed.). UpToDate. Retrieved February 18, 2021, from https://www.uptodate.com/contents/an-overview-of-angioedema-clinical-features-diagnosis-and-management
  4. Zuraw, B. (2018). Hereditary angioedema: Pathogenesis and diagnosis. In Feldweg, A. M. (Ed.). UpToDate. Retrieved February 18, 2021, from https://www.uptodate.com/contents/hereditary-angioedema-pathogenesis-and-diagnosis
  5.  Zuraw, B., Farkas, H. (2020). Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis. In Feldweg, A. M. (Ed.). UpToDate. Retrieved February 18, 2021, from https://www.uptodate.com/contents/hereditary-angioedema-epidemiology-clinical-manifestations-exacerbating-factors-and-prognosis 
  6. Delves, P.J. (2020). Angioedema. MSD Manual Professional Version. Retrieved February 21, 2021, from https://www.msdmanuals.com/professional/immunology-allergic-disorders/allergic,-autoimmune,-and-other-hypersensitivity-disorders/angioedema
  7. Li, H.H. (2018). Angioedema. In Kaliner, M.A. (Ed.). Medscape. Retrieved February 21, 2021, from https://emedicine.medscape.com/article/135208-overview
  8. Memon, R.J. (2020). Angioedema. StatPearls. Retrieved February 21, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK538489/

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