Angioedema

Definitions

  • Angioedema: well-demarcated, localized edema involving 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, [[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, [[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, [[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
  • Stings/Bites/Envenomations
    • Phylum Arthropoda -> Class Insecta -> Order Hymenoptera
      • Bumble Bee Sting (see Bee Sting, [[Bee Sting]])
      • Fire Ant Bite
      • Honey Bee Sting (see Bee Sting, [[Bee Sting]])
      • Hornet Sting (see Hornet Sting, [[Hornet Sting]])
      • Paper Wasp Sting (see Wasp Sting, [[Wasp Sting]])
      • Wood Ant Bite
      • Yellowjacket Sting (see Bee Sting, [[Bee Sting]])
    • 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, [[Mosquito Bite]])
      • Tsetse Fly Bite
    • Phylum Arthropoda -> Class Insecta -> Order Lepidoptera
      • Pine Processionary Caterpillar Envenomation
      • Puss Caterpillar Envenomation (see Puss Caterpillar Envenomation, [[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, [[Scorpion Sting]]): particularly Centruroides (common striped scorpion)
      • Western Black-Legged Tick Bite
    • Phylum Cnidaria
      • Box Jellyfish (Carybdea Alata) Sting (see Jellyfish Sting, [[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, [[Poisonous Lizard Bite]]): may induce an anaphylaxis-like reaction (unknown if IgE-mediated)
      • Mexican Beaded Lizard Bite (see Poisonous Lizard Bite, [[Poisonous Lizard Bite]]): may induce an anaphylaxis-like reaction (unknown if IgE-mediated)
      • Rattlesnake (Crotalus) Bite (see Rattlesnake Bite, [[Rattlesnake Bite]])
    • Phylum Chordata -> Class Mammalia
      • Gerbil Bite
      • Hamster Bite
      • Mouse Bite
      • Rat Bite
  • Drugs
    • Abacavir (see Abacavir, [[Abacavir]])
    • Acetaminophen (Tylenol) (see Acetaminophen, [[Acetaminophen]])
      • Epidemiology: cases of anaphylaxis have been reported
    • Angiotensin Converting Enzyme (ACE) Inhibitors (see Angiotensin Converting Enzyme Inhibitors, [[Angiotensin Converting Enzyme Inhibitors]])
    • Acyclovir (Zovirax) (see Acyclovir, [[Acyclovir]])
    • Anti-Thymocyte Globulin (ATG) (see Anti-Thymocyte Globulin, [[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
    • Non-Steroidal Anti-Inflammatory Drugs (NSAID) (see Non-Steroidal Anti-Inflammatory Drug, [[Non-Steroidal 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, [[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 Anti-TNF Therapy, [[Anti-TNF Therapy]])
    • 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 Non-Steroidal Anti-Inflammatory Drugs (NSAID) (see Non-Steroidal Anti-Inflammatory Drug, [[Non-Steroidal 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

  • Non-Steroidal Anti-Inflammatory Drugs (NSAID) (see Non-Steroidal Anti-Inflammatory Drug, [[Non-Steroidal 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 cause 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
    • 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
  • 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 Anti-TNF Therapy, [[Anti-TNF Therapy]])
  • 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

  • Mast Cell-Mediated Angioedema is Pathologically Similar to Urticaria (see Urticaria, [[Urticaria]]): although it occurs in the deeper dermis and subcutaneous tissues
  • Mast Cell Release of Mediators: resulting in dermal venule vasodilation and increased permeability -> tissue edema
    • Heparin
    • Histamine
    • Leukotriene C4
    • Prostaglandin D2

IgE-Mediated Mast Cell Activation

Bradykinin-Mediated Angioedema

  • Bradykinin is an Immune Mediator Which Induces Vasodilation and Increased Vascular Permeability
    • Mast Cells are Not Involved: therefore, pruritus and urticaria are notably absent
    • Bradykinin-Mediated Angioedema Frequently Affects the Gastrointestinal Mucosa, Resulting in Bowel Wall Edema: in contrast to histamine-mediated angioedema

Diagnosis

C4 Level

  • Indications for Testing
    • Suspected Acquired C1 Inhibitor Deficiency
  • Interpretation
    • Decreased: in most cases of acquired C1 inhibitor deficiency

C1 Inhibitor Level

  • Indications for Testing
    • Suspected Acquired C1 Inhibitor Deficiency
  • Interpretation
    • Decreased-Normal: in acquired C1 inhibitor deficiency

C1 Inhibitor Function

  • Indications for Testing
    • Suspected C1 Inhibitor Deficiency with Confirmed Low C4 + Low-Normal C1 Inhibitor Level + Low C1q
  • Interpretation: low result is required for the diagnosis of acquired C1 inhibitor deficiency
    • Decreased to 50% of Normal*: confirms the diagnosis of acquired C1 inhibitor deficiency

C1q Level

  • Indications for Testing
    • Suspected Acquired C1 Inhibitor Deficiency in Patient >30 y/o and Without a Family History of Angioedema
  • Interpretation
    • Decreased to <50% of Normal: seen in 70% of acquired C1 inhibitor deficiency cases
      • However, may be mildly decreased in 30% of cases or normal in rare cases

Plasma Anti-C1 Inhibitor Antibodies

  • Indications for Testing
    • Suspected Acquired C1 Inhibitor Deficiency
  • Interpretation: note that the absence of the antibody does not rule out the diagnosis of acquired C1 inhibitor deficiency
    • Detectable in approximately 74% of patients with acquired C1 inhibitor deficiency
    • Detectable in 30% of hereditary angioedema patients
    • Detectable in 3% of normal controls

Clinical Manifestations

General Clinical Features of Angioedema

Anatomic Sites of Involvement

  • General Comments: angioedema usually affects body regions with loose connective tissue (face, lips, mouth, throat, pharynx/larynx, uvula, extremities, genitalia, and bowel wall)
  • Larynx
    • Difficulty Swallowing/Dysphagia (see Dysphagia, [[Dysphagia]])
    • Hoarseness (see Hoarseness, [[Hoarseness]])
    • Throat Tightness
  • Lips/Tongue/Uvula
    • Airway Compromise
  • Skin/Mucous Membranes
    • Subcutaneous/Submucosal Involvement
    • Normal or Mildly Erythematous Overlying Skin
    • Minimal Pain/Warmth: this is in contrast to cellulitis, where these features are more prominent
    • Burning Sensation: may be reported
    • Absence of Pruritus: however, urticaria (if also present) are intensely pruritic
    • Absence of Residua Following Resolution
  • Bowel Wall
    • Bowel Wall Edema: may be noted on ultrasound or CT scan
      • Occasionally seen in ACE inhibitor-induced cases
      • Frequently seen in hereditary angioedema/acquired C1 inhibitor angioedema cases
    • Colicky Abdominal Pain (see Abdominal Pain, [[Abdominal Pain]])
    • Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]])
    • Diarrhea (see Diarrhea, [[Diarrhea]])

Characteristics of Angiodema

  • Onset Over Minutes-Hours
  • Resolution Over Hours-Days
  • Asymmetric Distribution
  • Tendency to Not Involve Gravitationally-Dependent Areas
  • Involvement of Face/Lips/Larynx/Gastrointestinal Tract
    • ACE inhibitor-associated angioedema commonly involves the lips/tongue/face
    • In contrast, swelling of the floor of the mouth is more likely to be due to tumor, lithiasis, or infection
  • Association of Some Types of Angioedema with Allergic Reactions/Anaphylaxis

Mast Cell-Mediated Angioedema

General Comments

  • Onset: usually begins within min-2 hrs after exposure (and builds over a period of hrs)
    • However, allergic reactions to meats (lamb, beef, pork) may be delayed in some cases up to 2-6 hrs after ingestion
  • Reolution: within 24-48 hrs

Allergic/Immunologic Manifestations

  • Allergic Reaction/Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]]): may co-exist with angioedema
    • Symptoms/Signs Suggesting Co-Existing Anaphylaxis
    • Note: isolated angioedema may rarely occur as a manifestation of an allergic reaction/anaphylaxis

Dermatologic Manifestations

  • Angioedema (see Angioedema, [[Angioedema]])
  • Pruritus (see Pruritus, [[Pruritus]]): common
  • Urticaria (see Urticaria, [[Urticaria]]): common

Bradykinin-Mediated Angioedema

General Comments

  • Onset: 24-36 hrs (slower than that of mast cell-mediated angioedema)
  • Resolution: 2-4 days (slower than that of mast cell-mediated angioedema)

Dermatologic Manifestations

  • Absence of Urticaria (see Urticaria, [[Urticaria]])
  • Angioedema

Gastrointestinal Symptoms

Pulmonary Manifestations

  • Absence of Bronchospasm

Angioedema with Unknown Mechanism

General Comments

  • Variable Clinical Manifestations

Dermatologic Manifestations

  • Angioedema (see Angioedema, [[Angioedema]])
  • Urticaria (see Urticaria, [[Urticaria]]): may be present

Treatment

General Treatment

  • Airway Management/Mechanical Ventilation (see General Ventilator Management, [[General Ventilator Management]]): as required
  • Intravenous Fluid Management: as required
  • Eliminate Source (If Known): crucial

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]])

  • Diphenhydramine (Benadryl) (see Diphenhydramine, [[Diphenhydramine]]): 25-50 mg IV PRN

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

  • Cimetidine (Tagamet) (see Cimetidine, [[Cimetidine]])
  • Famotidine (Pepcid) (see Famotidine, [[Famotidine]])
    • Administration: 20 mg IV q12hrs
  • Ranitidine (Zantac) (see Ranitidine, [[Ranitidine]])

Corticosteroids (see Corticosteroids, [[Corticosteroids]])

  • Administration
    • PO: Prednisone (see Prednisone, [[Prednisone]])
      • Dose: 40-50 mg qday PO with taper
    • IV: Methylprednisolone (Solumedrol) (see Methylprednisolone, [[Methylprednisolone]])
      • Dose: 125 mg IV x1, then 60 mg IV q6hrs with taper

Epinephrine (see Epinephrine, [[Epinephrine]])

  • Indications: anaphylaxis
  • Pharmacology
    • Bronchodilation
    • Vasoconstriction
  • Adverse Effects
  • Dose: 0.3 mg SQ/IM/IV (1:1000)
    • May repeat PRN
    • Max single dose = 1 mg
  • Preferred Route of Administration
    • Non-Code Blue Situation: IM into thigh is preferred over SQ route
    • Code Blue Situation: IV route is preferred

Preloaded Epinephrine Injectable Devices

  • Advantages: patient can keep nearby at home, etc for emergency use
  • Adult Dose: 0.3 mg IM (1:1000)
  • Brands
    • Epipen
      • Hold like a pen, not like a knife (to avoid inadvertent injection into the thumb)
      • Remove blue safety cap -> firmly push orange tip against lateral thigh (don’t need to remove clothes to use), until it clicks -> hold in place for 5-10 sec
    • Auvi-Q: provides verbal instructions
    • Adrenaclick: pen-like device

Specific Treatment of ACE Inhibitor-Associated Angioedema

  • Discontinue ACE Inhibitor: angioedema usually resolves within 24-72 hrs
    • Failure to discontinue ACE inhibitor promptly at first signs of angioedema may result in the angiodema resolving, but an unpredictable increase in the frequency/severity of future attacks (or even life-threatening angioedema)
    • After discontinuation, do not re-challenge with ACE inhibitors
    • Recurrent Angioedema Episodes After ACE Inhibitor Discontinuation: patients may experience occasional angioedema episodes in the first few months after ACE inhibitor discontinuation (this may be due to residual effects of the drug vs an alternative etiology of the angioedema)
  • Antihistamines (H1-Histamine Receptor Antagonists) (see H1-Histamine Receptor Antagonists, [[H1-Histamine Receptor Antagonists]]): although these would not be expected to be effective, there are some studies which cite efficacy [MEDLINE] [MEDLINE]
  • H2-Histamine Receptor Antagonists (see H2-Histamine Receptor Antagonists, [[H2-Histamine Receptor Antagonists]]): not effective
  • Corticosteroids (see Corticosteroids, [[Corticosteroids]]): not effective
  • Epinephrine (see Epinephrine, [[Epinephrine]]): not effective
  • Ecallantide (Kalbitor) (see Ecallantide, [[Ecallantide]])
    • Physiology: inhibition of plasma kallikrein -> inhibits the conversion of high molecular weight kininogen to bradykinin
    • Clinical Efficacy: studies show weak benefit (at best)
  • Icatibant (Firazyr) (see Icatibant, [[Icatibant]])
    • Physiology: synthetic bradykinin B2-receptor antagonist
    • Administration: 30 mg in 3 mL SQ (slowly, preferably in abdomen)
      • Cost: $8-9k per dose
      • Timing of Administration: based on studies in hereditary angioedema, icatibant is most likely to be effective if given in the first few hours of the attack, when the edema is increasing (as compared to when after the angioedema has peaked and stabilized)
    • Clinical Efficacy: decreases time to resolution of angioedema
  • Fresh Frozen Plasma (FFP) (see Fresh Frozen Plasma, [[Fresh Frozen Plasma]])
    • Physiology
      • Contains angiotensin converting enzyme
      • Degrade high levels of bradykinin
    • Administration: 2 units
    • Clinical Efficacy: in reports, angioedema decreased within 2-4 hrs of FFP administration
  • C1 Inhibitor Concentrate (see C1 Inhibitor Concentrate, [[C1 Inhibitor Concentrate]])
    • Physiology: C1 inhibitor functions to inhibit kallikrein
    • Clinical Efficacy: shown to be effective in case reports

Specific Treatment of Hereditary Angioedema

  • Ecallantide (Kalbitor) (see Ecallantide, [[Ecallantide]])
  • Fresh Frozen Plasma (FFP) (see Fresh Frozen Plasma, [[Fresh Frozen Plasma]])
  • Icatibant (Firazyr) (see Icatibant, [[Icatibant]])
  • Purified C1 Inhibitor Concentrate (Cinryze, Berinert, or Ruconest) (see xxxx, [[xxxx]])
  • Testosterone and Attenuated Androgens (Danazol): allow the gene (within hepatocytes) to produce enough sufficient functional C1 inhibitor
    • Effective acutely and as prophylaxis

Specific Treatment of Recurrent, Idiopathic Angioedema

  • Allergy Evaluation
  • Antihistamines (H1-Histamine Receptor Antagonists) (see H1-Histamine Receptor Antagonists, [[H1-Histamine Receptor Antagonists]]): may decrease frequency of episodes
  • Corticosteroids (see Corticosteroids, [[Corticosteroids]]): prednisone may be used (although has not been formally studied) to abort attacks if used early in the course
  • Dapsone (see Dapsone, [[Dapsone]]): for refractory cases
  • Icatibant (Firazyr) (see Icatibant, [[Icatibant]]): for refractory cases
  • Rituximab (Rituxan) (see Anti-CD20 Therapy, [[Anti-CD20 Therapy]]): for refractory cases

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

  • Renin Inhibitors: Aliskiren (see Aliskiren, [[Aliskiren]])
    • Overall Risk of Angioedema: merits cautious use in patients with prior ACE inhibitor-associated amgioedema (until further studies are performed)
  • Angiotensin II Receptor Blockers (ARB) (see Angiotensin II Receptor Blockers, [[Angiotensin II Receptor Blockers]])
    • Overall Risk of Angioedema with ARB’s is Believed to Be Lower Than That of ACE Inhibitors
    • Risk of ARB-Related Angioedema After ACE Inhibitor-Associated Angioedema: 1.5-10% (however, this may be artifactually high due to residual angioedema that may occur after ACE inhibitor discontinuation)
  • Dipeptidyl Peptidase-4 Inhibitors (DPP-4 Inhibitors, Gliptins) (see Dipeptidyl Peptidase-4 Inhibitors, [[Dipeptidyl Peptidase-4 Inhibitors]])
    • Increased Risk of Angioedema When Used Alone or in Combination with ACE Inhibitors or ARB’s

References

  • Critical overview: adverse cutaneous reactions to psychotropic medications. J Clin Psychiatry. 1999 Oct;60(10):714-25; quiz 726 [MEDLINE]
  • Clinical experience with angiotensin-converting enzyme inhibitor-induced angioedema. Otolaryngol Head Neck Surg. 2007 Dec;137(6):931-5 [MEDLINE]
  • Analysis of recurrent angiotensin converting enzyme inhibitor-induced angioedema. Laryngoscope. 2008 Dec;118(12):2115-20. doi: 10.1097/MLG.0b013e318182f805 [MEDLINE]
  • Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system. Arch Intern Med. 2012 Nov 12;172(20):1582-9. doi: 10.1001/2013.jamainternmed.34 [MEDLINE]
  • Angioedema induced by cardiovascular drugs: new players join old friends. Allergy. 2015 Oct;70(10):1196-200. doi: 10.1111/all.12680. Epub 2015 Jul 15 [MEDLINE]