Angioedema


Definitions

Angioedema

  • Well-Demarcated, Localized Edema Involving the Subcutaneous/Submucosal Layers of the Skin, Pharynx/Larynx, and/or Gastrointestinal Tract
    • Angioedema May Occur in Isolation or in Conjunction with Urticaria or Anaphylaxis

Urticaria (see Urticaria)

  • Inflammation Confined to the Superficial Dermis
    • Wheals with Raised Serpiginous Borders and Blanched Centers

Etiology

Mast Cell-Mediated Angioedema

IgE-Mediated Mast Cell Activation (Type I Hypersensitivity) (see Immune Hypersensitivity)

  • Foods/Food Additives
    • General Comments: specific food triggers vary geographically (due to different foods consumed and methods of preparation)
      • North America/Some Countries in Europe and Asia: cow milk, hen’s egg, peanut, tree nuts, shellfish, and fish are common triggers
      • European Countries: peach is a common triggers
      • Middle East: sesame is common trigger
      • Asia: buckwheat, chickpea, rice, and bird’s nest soup are common triggers
    • Annatto (see Annatto): yellow food colorant
    • Carmine: insect-derived red colorant
    • Egg
    • Legumes: beans, lentils, peanuts, peas, soybeans/soy
    • Milk: cow milk, goat milk, sheep milk
    • Peach
    • Seafood: crustaceans, shellfish, finned fish, shrimp
    • Sesame
    • Spices
    • Tree Nuts: almonds, cashews, walnuts
    • Vegetable Gums
    • Wheat
  • Infection
    • Strongyloidiasis (see Strongyloidiasis)
      • Epidemiology: may occur in chronic Strongyloidiasis
  • Stings/Bites/Envenomations
    • Phylum Arthropoda -> Class Insecta -> Order Hymenoptera
    • Phylum Arthropoda -> Class Insecta -> Order Hemiptera
      • Bed Bug (Cimex) Bite: may induce an anaphylaxis-like reaction (unknown if IgE-mediated)
      • Kissing Bug Bite (Triatoma)
    • Phylum Arthropoda -> Class Insecta -> Order Diptera
      • Black Fly Bite
      • Deer Fly Bite
      • Mosquito Bite (see Mosquito Bite)
      • Tsetse Fly Bite
    • Phylum Arthropoda -> Class Insecta -> Order Lepidoptera
      • Pine Processionary Caterpillar Envenomation
      • Puss Caterpillar Envenomation (see Puss Caterpillar Envenomation): may induce an anaphylaxis-like reaction (unknown if IgE-mediated)
    • Phylum Arthropoda -> Class Arachnida
      • Australian Paralysis Tick Bite
      • Pigeon Tick Bite
      • Scorpion Sting (see Scorpion Sting): particularly Centruroides (common striped scorpion)
      • Western Black-Legged Tick Bite
    • Phylum Cnidaria
      • Box Jellyfish (Carybdea Alata) Sting (see Jellyfish Sting): may induce an anaphylaxis-like reaction (unknown if IgE-mediated)
      • Portuguese Man-of-War (Physalia Physalis) Sting: may induce an anaphylaxis-like reaction (unknown if IgE-mediated)
      • Sea Nettle Sting
    • Phylum Chordata -> Class Reptila
      • European Viper (Vipera) Snake Bite
      • Gila Monster Bite (see Poisonous Lizard Bite): may induce an anaphylaxis-like reaction (unknown if IgE-mediated)
      • Mexican Beaded Lizard Bite (see Poisonous Lizard Bite): may induce an anaphylaxis-like reaction (unknown if IgE-mediated)
      • Rattlesnake (Crotalus) Bite (see Rattlesnake Bite)
    • Phylum Chordata -> Class Mammalia
      • Gerbil Bite
      • Hamster Bite
      • Mouse Bite
      • Rat Bite
  • Drugs
    • Abacavir (see Abacavir)
    • Acetaminophen (Tylenol) (see Acetaminophen)
      • Epidemiology: cases of anaphylaxis have been reported
    • Angiotensin Converting Enzyme (ACE) Inhibitors (see Angiotensin Converting Enzyme Inhibitors)
    • Acyclovir (Zovirax) (see Acyclovir)
    • Anti-Thymocyte Globulin (ATG) (see Anti-Thymocyte Globulin)
    • Antivenoms
    • β-Lactam Antibiotics (see β-Lactam Antibiotics, [[β-Lactam Antibiotics]])
      • Cephalosporins (see Cephalosporins, [[Cephalosporins]])
      • Imipenem (see Imipenem, [[Imipenem]]): cross-reactivity in 50% of patients with allergy to penicillins
      • Penicillins (see Penicillins, [[Penicillins]]): occurs in 0.05% of cases, fatal in 5-10% of cases
    • Demeclocycline (see Demeclocycline, [[Demeclocycline]])
    • Gemcitabine (Gemzar) (see Gemcitabine, [[Gemcitabine]]): cases of laryngeal edema have been reported
    • Heparin (see Heparin, [[Heparin]]): anaphylaxis is a manifestation of heparin-induced thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia, [[Heparin-Induced Thrombocytopenia]])
    • Insulin (see Insulin, [[Insulin]])
    • Intradermal Allergen Immunotherapy
    • Iodinated Drugs/Contrast (see Radiographic Contrast, [[Radiographic Contrast]])
    • Local Anesthetics
      • Lidocaine (see Lidocaine, [[Lidocaine]])
      • Procaine (Novocaine, Novocain) (see Procaine, [[Procaine]])
    • Monoclonal Antibodies/Biologics
    • N-Acetylcysteine (Mucomyst, Acetadote, Fluimucil, Parvolex) (see N-Acetylcysteine, [[N-Acetylcysteine]])
      • Epidemiology: associated with intravenous administration
      • Physiology: histamine release has been implicated
    • Non-Dextran Intravenous Iron
      • Ferumoxytol (Feraheme) (see Ferumoxytol, [[Ferumoxytol]])
        • Risk of First-Exposure Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]]) [MEDLINE]: 24 per 100k patients
      • Iron Gluconate (Ferrous Gluconate, Fergon, Ferralet, Simron) (see Iron Gluconate, [[Iron Gluconate]])
        • Risk of First-Exposure Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]]) [MEDLINE]: 24 per 100k patients
      • Iron Sucrose (Venofer) (see Iron Sucrose, [[Iron Sucrose]])
        • Risk of First-Exposure Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]]) [MEDLINE]: 24 per 100k patients
        • Cumulative Risk of Anaphylaxis (Over 12 wk Period) [MEDLINE]: iron sucrose has lowest risk of all of the intravenous iron agents
    • Nonsteroidal Anti-Inflammatory Drugs (NSAID) (see Nonsteroidal Anti-Inflammatory Drug, [[Nonsteroidal Anti-Inflammatory Drug]]): NSAID’s rarely cause allergic reactions via this mechanism (in these cases, the reaction is usually to a single NSAID agent)
    • Pirfenidone (Esbriet) (see Pirfenidone, [[Pirfenidone]]): few cases have been reported (unclear if mechanism involves IgE)
    • Platins
      • Carboplatin (see Carboplatin, [[Carboplatin]])
      • Cisplatin (see Cisplatin, [[Cisplatin]])
      • Oxaliplatin (Eloxatin, Oxaliplatin Medac) (see Oxaliplatin, [[Oxaliplatin]])
    • Progesterone (see Progesterone, [[Progesterone]])
    • Protamine (see Protamine, [[Protamine]])
    • Sorafenib (Nexavar) (see Sorafenib, [[Sorafenib]])
    • Streptomycin (see Streptomycin, [[Streptomycin]])
    • Sulfobromophthalein
    • Taxanes (see Taxanes, [[Taxanes]])
      • Docetaxel (Taxotere) (see Docetaxel, [[Docetaxel]])
      • Paclitaxel (Taxol) (see Paclitaxel, [[Paclitaxel]])
    • Vaccines: usually related to excipient such as gelatin or dextran (rather than the microbial content itself)
    • Vitamin K (see Vitamin K, [[Vitamin K]])
  • Other
    • Aeroallergens: rarely involved in angioedema/anaphylaxis
      • Cat Dander
      • Grass Pollen
      • Horse Dander
    • Allergen Immunotherapy (see Allergen Immunotherapy, [[Allergen Immunotherapy]])
    • Blood Products
    • Fluorescein (see Fluorescein, [[Fluorescein]])
    • Hemodialysis (see Hemodialysis, [[Hemodialysis]]): due to reaction to dialysis membranes
      • Cellulose Membranes: predominant type of membrane associated with anaphylaxis
        • Membranes are ethylene oxide sterilized
        • Membranes can activate complement
    • Polyacrylonitrile AN69 High Flux Membranes: fewer reported cases of anaphylaxis
    • Human Seminal Fluid
      • Epidemiology: rare etiology of anaphylaxis in females
    • Intradermal Allergen Skin Testing
    • Natural Rubber Latex (see Latex, [[Latex]]): condoms, balloons, gloves, etc
    • Occupational Allergens
    • Vaccines

Immunologic Non-IgE-Mediated Mast Cell Activation

  • Heparin Contaminated with Oversulfated Chondroitin Sulfate (see Heparin, [[Heparin]])
    • Physiology: mediated by coagulation system activation
  • Dextrans
    • Dextran (see Dextran)
    • Iron Dextran (Dexferrum, INFeD) (see Iron Dextran, [[Iron Dextran]])
      • Risk of First-Exposure Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]] [MEDLINE]): 68 per 100k patients
      • Cumulative Risk of Anaphylaxis (Over 12 wk Period) [MEDLINE]: iron dextrose has highest risk of all of the intravenous iron agents
  • Idiopathic Histaminergic Angioedema
    • Clinical: recurrent angioedema often associated with chronic spontaneous urticaria or inducible (physical) urticaria
  • Infliximab (Remicade) (see Infliximab, [[Infliximab]])
    • Physiology: IgG-mediated
  • Packed Red Blood Cells (PRBC) (see Packed Red Blood Cells, [[Packed Red Blood Cells]])
    • Epidemiology: rare cases of patients with very low levels of IgA and anti-IgA Ab’s, may develop anaphylaxis upon receiving blood with IgA present (these patients need IgA-deficient blood products)

Non-Immunologic Direct Mast Cell/Basophil Activation

  • Ethanol (see Ethanol, [[Ethanol]]): rarely induces anaphylaxis by itself, but may augment mast cell activation
  • Foods: these “pseudoallergens” may cause urticaria (or contact urticaria) via IgE-mediated or via non-immunologic mechanisms, especially in children
    • Strawberries
    • Tomatoes
  • Neuromuscular Junction Antagonists (see Neuromuscular Junction Antagonists, [[Neuromuscular Junction Antagonists]])
  • Opiates (see Opiates, [[Opiates]])
  • Physical Factors
    • Cold
    • Heat
    • Exercise: usually associated with a co-trigger (such as a food, NSAID, or exposure to cold air or water)
    • Sunlight/Ultraviolet Radiation
  • Radiographic Contrast (see Radiographic Contrast, [[Radiographic Contrast]])
  • Some Nonsteroidal Anti-Inflammatory Drugs (NSAID) (see Nonsteroidal Anti-Inflammatory Drug, [[Nonsteroidal Anti-Inflammatory Drug]])
  • Stinging Nettle (Urtica Dioica) (see Stinging Nettle, [[Stinging Nettle]]): urticaria was named after this weed (which is commonly found in North America, South Americam Europe, and parts of Africa
    • Physiology: histamine (and pain-causing mediators) contained in the plant
  • Vancomycin (see Vancomycin, [[Vancomycin]])

Altered Arachidonic Acid Metabolism

  • Nonsteroidal Anti-Inflammatory Drugs (NSAID) (see Nonsteroidal Anti-Inflammatory Drug, [[Nonsteroidal Anti-Inflammatory Drug]]): NSAID’s most commonly cause angioedema via this mechanism

Other

Bradykinin-Mediated Angioedema

Alteration of Bradykinin Metabolism

  • Angiotensin Converting Enzyme (ACE) Inhibitors (see Angiotensin Converting Enzyme Inhibitors, [[Angiotensin Converting Enzyme Inhibitors]])
    • Epidemiology
      • ACE Inhibitors are the Most Common Etiology of Drug-Induced Angioedema in the US (Due to Their Frequent Use)
      • ACE Inhibitors Account for 20-30% of All Angioedema Cases Presenting to Emergency Departments
      • ACE Inhibitors May Also Unmask C1 Inhibitor Deficiency
      • ACE Inhibitor-Induced Angioedema Occurs in <1% of Treated Patients: higher incidence is observed in patients of African descent
    • Physiology: inhibition of bradykinin degradation enzymes
    • Clinical
      • Angioedema May Occur Idiosyncratically (on Initiation of Medication or with Dosage Increase After Years of Use)
      • Most Commonly Involves the Lips/Tongue/Face
      • Intestinal Angioedema May Occur in Some Cases (with Abdominal Pain)
  • Angiotensin II Receptor Blockers (ARB) (see Angiotensin II Receptor Blockers, [[Angiotensin II Receptor Blockers]])
    • Epidemiology: incidence of angioedema is lower than that of ACE inhibitors
      • ARB’s May Also Unmask C1 Inhibitor Deficiency
    • Physiology: inhibition of binding of angiotensin II to AT1 receptors
  • Aliskiren (see Aliskiren, [[Aliskiren]])
    • Epidemiology: probably equivalent risk of angioedema to that of the ACE inhibitors [MEDLINE]
    • Physiology: theoretically, aliskiren should not cause bradykinin-induced angioedema because it has no known effect on bradykinin metabolism
  • Dipeptidyl Peptidase-4 Inhibitors (DPP-4 Inhibitors, Gliptins) (see Dipeptidyl Peptidase-4 Inhibitors, [[Dipeptidyl Peptidase-4 Inhibitors]])
    • Possibly Increased Risk of Angioedema when Used in Combination with Angiotensin Converting Enzyme (ACE) Inhibitors [MEDLINE]

Hereditary Angioedema (Hereditary C1 Inhibitor Deficiency/Dysfunction)

  • Epidemiology
    • Age of Onset: typically presents in childhood/early adolescence
      • Over 90% of patients experience their first symptoms before age 20 y/o
  • Physiology: deficiency/dysfunction of complement C1 inihibitor due to mutation
  • Clinical
    • Precipitating Factors
      • Dental Procedures
      • Emotional Stress
      • Infection
      • Trauma
    • Relationship of Symptomatology to Puberty: increasing frequency and severity of episodes with puberty
    • Estrogen Exposure (Contraception, Hormone Replacement Therapy, Pregnancy): may trigger attacks

Acquired C1 Inhibitor Deficiency (Acquired Angioedema)

  • Epidemiology: rare disorder (first case reports in 1972 in lymphoma patients)
    • Age of Onset: typically presents at an older age (4th decade or later in life) than hereditary angioedema
    • Most Patients Have an Associated Lymphoproliferative Disorder
  • Etiology
    • Lymphoma (see Lymphoma, [[Lymphoma]]): lymphatic malignancy is present in 35% of cases
      • Usually Associated with B-Cell Lymphoma
    • Monoclonal Gammopathy of Unclear Significance (MGUS) (see Monoclonal Gammopathy of Unclear Significance, [[Monoclonal Gammopathy of Unclear Significance]]): present in 35% of cases
    • idiopathic Acquired C1 Inhbitor Decifiency: accounts for <10% of cases
      • Some of These Cases also Lack Anti-C1 Inhibitor Antibodies
    • Autoimmune Disease: autoimmune disease is present in 8% of cases
    • Adenocarcinoma/Other Malignancy: present in 6% of cases
    • Echinococcosis (see Echinococcosis, [[Echinococcosis]]): case report
    • Helicobacter Pylori Infection (see Helicobacter Pylori, [[Helicobacter Pylori]]): case reports
  • Physiology: deficiency/dysfunction of complement C1 inhibitor due to anti-C1 inhibitor antibody or malignancy

Angioedema with Unknown Mechanism

Infection

  • General Comments: more commonly described in children
  • Acute Rhinosinusitis (Common Cold) (see Acute Rhinosinusitis, [[Acute Rhinosinusitis]])
  • Streptococcal Pharyngitis (see Pharyngitis, [[Pharyngitis]])
  • Urinary Tract Infection (UTI) (see Urinary Tract Infection, [[Urinary Tract Infection]])

Drug/Toxin

  • Amiodarone (see Amiodarone, [[Amiodarone]]): present with angioedema without urticaria
  • Calcium Channel Blockers (see Calcium Channel Blockers, [[Calcium Channel Blockers]]): present with angioedema of skin or small intestine
    • Dihydropyridines
      • Amlodipine (Norvasc) (see Amlodipine, [[Amlodipine]])
      • Nifedipine (Adalat, Procardia) (see Nifedipine, [[Nifedipine]])
    • Non-Dihydropyridines
      • Diltiazem (Cardizem, Tiazac, Dilt-CD) (see Diltiazem, [[Diltiazem]])
      • Verapamil (Isoptin, Verelan, Verelan PM, Calan, Bosoptin, Covera-HS) (see Verapamil, [[Verapamil]])
  • Cocaine (Inhaled) (see Cocaine, [[Cocaine]]): may cause uvular angioedema
  • Echballium Elaterium (Squirting Cucumber) (see Echballium Elaterium, [[Echballium Elaterium]])
  • Etanercept (Enbrel) (see Etanercept, [[Etanercept]])
  • Everolimus (Afinitor) (see Everolimus, [[Everolimus]]): present with angioedema without urticaria
  • Garlic (see Garlic, [[Garlic]])
  • Metoprolol (see Metoprolol, [[Metoprolol]]): present with angioedema without urticaria
  • Paroxetine (Paxil) (see Paroxetine, [[Paroxetine]]): present with angioedema without urticaria
  • Risperidone (Risperdal) (see Risperidone, [[Risperidone]]): present with angioedema without urticaria
  • Sanyak (Dioscorea Batatas) (see Sanyak, [[Sanyak]])
  • Sirolimus (Rapamune, Rapamycin) (see Sirolimus, [[Sirolimus]]): present with angioedema without urticaria
  • Thrombolytics (see Thrombolytics, [[Thrombolytics]]): present with angioedema without urticaria

Other

  • Gleich Syndrome (Episodic Angioedema with Eosinophilia) (see Gleich Syndrome, [[Gleich Syndrome]])
  • Hypereosinophilic Syndrome (see Hypereosinophilic Syndrome, [[Hypereosinophilic Syndrome]])
    • Epidemiology: 15% of hypereosinophilic syndrome patients have angioedema
    • Physiology: may involve eosinophil release of mediators or activation of cutaneous mast cells by eosinophil-derived mediators
  • Idiopathic Non-Histaminergic Angioedema
    • Clinical: recurrent angioedema without urticaria

Physiology

Mast Cell-Mediated Angioedema

General Comments

IgE-Mediated Mast Cell Activation

Bradykinin-Mediated Angioedema


Diagnosis

C4 Level

C1 Inhibitor Level

C1 Inhibitor Function

C1q Level

Plasma Anti-C1 Inhibitor Antibodies


Clinical Manifestations

General Clinical Features of Angioedema

Anatomic Sites of Involvement

Characteristics of Angiodema

Mast Cell-Mediated Angioedema

General Comments

Allergic/Immunologic Manifestations

Dermatologic Manifestations

Bradykinin-Mediated Angioedema

General Comments

Dermatologic Manifestations

Gastrointestinal Symptoms

Pulmonary Manifestations

Angioedema with Unknown Mechanism

General Comments

Dermatologic Manifestations


Treatment

General Treatment

Specific Treatment of Mast Cell-Mediated Angioedema (Angioedema with Associated Allergic Reaction/Anaphylaxis)

Antihistamines (H1-Histamine Receptor Antagonists) (see H1-Histamine Receptor Antagonists, [[H1-Histamine Receptor Antagonists]])

H2-Histamine Receptor Antagonists (see H2-Histamine Receptor Antagonists, [[H2-Histamine Receptor Antagonists]])

Corticosteroids (see Corticosteroids, [[Corticosteroids]])

Epinephrine (see Epinephrine, [[Epinephrine]])

Preloaded Epinephrine Injectable Devices

Specific Treatment of Angiotensin Converting Enzyme (ACE) Inhibitor-Associated Angioedema

Specific Treatment of Hereditary Angioedema

Specific Treatment of Recurrent, Idiopathic Angioedema

Future Use of Other Related Medications Which Have Been Associated with Angioedema


References

General

Treatment

Antihistamines (see H1-Histamine Receptor Antagonists, [[H1-Histamine Receptor Antagonists]])

H2-Histamine Receptor Antagonists (see H2-Histamine Receptor Antagonists, [[H2-Histamine Receptor Antagonists]])

Epinephrine (see Epinephrine, [[Epinephrine]])

Corticosteroids (see Corticosteroids, [[Corticosteroids]])

Icatibant

Fresh Frozen Plasma (FFP) (see Fresh Frozen Plasma, [[Fresh Frozen Plasma]])

C1 Inhibitor Concentrate (see C1 Inhibitor Concentrate, [[C1 Inhibitor Concentrate]])