Urticaria

Definitions

Angioedema (see 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

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

Epidemiology

Prevalence

Urticaria Occurs in up to 20% of the Population (at Some Point in Their Lifetimes)

Etiology

Mast Cell-Mediated Urticaria

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

Foods/Food Additives
- General Comments
  - Specific Food Triggers Vary by Age
    - Most Commonly-Implicated Foods in Children: milk, eggs, peanuts, tree nuts, soy, and wheat
    - Most Commonly-Implicated Foods in Adults: fish/shellfish, peanuts, and tree nuts
  - 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
- Eggs
- 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)
  - Fire Ant Bite
  - Honey Bee Sting (see Bee Sting)
  - Hornet Sting (see Hornet Sting)
  - Paper Wasp Sting (see Wasp Sting)
  - Wood Ant Bite
  - Yellowjacket Sting (see 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)
  - 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
Contact Allergens (Contact Urticaria-Immunologic/Allergic Type)
- General Comments
  - Allergic Mechanism: IgE-dependent, complement-mediated, requires prior sensitization
    - Urticaria may involve non-contacted areas
    - May be severe, resulting in anaphylaxis
  - Onset: urticaria usually appears within 30 min of exposure
- Animal Saliva
  - Mechanism: allergic mechanism
- Bacitracin (see Bacitracin): antibiotic
  - Mechanism: allergic or non-allergic mechanism
- Benzoic Acid: used as preservative
  - Mechanism: allergic or non-allergic mechanism
- Chlorhexidine (see Chlorhexidine)
  - Mechanism: allergic mechanism
- Copper (see Copper)
  - Mechanism: allergic mechanism
- Formaldehyde (see Formaldehyde)
  - Mechanism: allergic or non-allergic mechanism
- Nickel (see Nickel)
  - Mechanism: allergic mechanism
- Parabens
  - Mechanism: allergic mechanism
- Paraphenylenediamine (PPD) (see Paraphenylenediamine): used in hair dyes, inks, photographic chemicals, black henna tattoos
  - Mechanism: allergic mechanism
- Natural Rubber Latex (see Latex): found in condoms, balloons, gloves, etc
  - Mechanism: allergic mechanism
- Salicylic Acid (see Salicylic Acid)
  - Mechanism: allergic mechanism
- Short-Chain Alcohols
  - Mechanism: allergic mechanism
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)
- Alpha-1 Antitrypsin (Aralast, Glassia, Prolastin, Zemaira) (see Alpha-1 Antitrypsin): occurs in 3.2-4.1% of cases
- Anti-Thymocyte Globulin (ATG) (see Anti-Thymocyte Globulin)
- Antivenin
  - Crofab (see Crofab and Rattlesnake Bite): incidence from meta-analyses has been reported to be 8% [MEDLINE]
  - Widow Spider Antivenom (see Widow Spider Bite)
- β-Lactam Antibiotics (see β-Lactam Antibiotics): most common antibiotic-associated cause of urticaria
  - Cephalosporins (see Cephalosporins)
  - Imipenem (see Imipenem): cross-reactivity in 50% of patients with allergy to penicillins
  - Penicillins (see Penicillins): occurs in 0.05% of cases, fatal in 5-10% of cases
- Demeclocycline (see Demeclocycline)
- Gemcitabine (Gemzar) (see Gemcitabine): cases of laryngeal edema have been reported
- Heparin (see Heparin): anaphylaxis is a manifestation of heparin-induced thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia)
- Insulin (see Insulin)
- Intradermal Allergen Immunotherapy (see Allergen Immunotherapy)
- Iodinated Drugs/Contrast (see Radiographic Contrast)
- Local Anesthetics
  - Lidocaine (see Lidocaine)
  - Procaine (Novocaine, Novocain) (see Procaine)
- Monoclonal Antibodies/Biologics
  - Cetuximab (Erbitux) (see Cetuximab)
  - Intravenous Immunoglobulin (IVIG) (see Intravenous Immunoglobulin)
  - Omalizumab (Xolair) (see Omalizumab): rare etiology of anaphylaxis
  - Rituximab (Rituxan) (see Anti-CD20 Therapy)
- N-Acetylcysteine (Mucomyst, Acetadote, Fluimucil, Parvolex) (see N-Acetylcysteine)
  - Epidemiology: associated with intravenous administration
  - Physiology: histamine release has been implicated
- Non-Dextran Intravenous Iron
  - Ferumoxytol (Feraheme) (see Ferumoxytol)
    - Risk of First-Exposure Anaphylaxis (see Anaphylaxis) [MEDLINE]: 24 per 100k patients
  - Iron Gluconate (Ferrous Gluconate, Fergon, Ferralet, Simron) (see Iron Gluconate)
    - Risk of First-Exposure Anaphylaxis (see Anaphylaxis) [MEDLINE]: 24 per 100k patients
  - Iron Sucrose (Venofer) (see Iron Sucrose)
    - Risk of First-Exposure Anaphylaxis (see 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’s)* (see Nonsteroidal Anti-Inflammatory Drug)
  - Epidemiology: NSAID’s rarely cause allergic reactions via this mechanism
- Platins
  - Carboplatin (see Carboplatin)
  - Cisplatin (see Cisplatin)
  - Oxaliplatin (Eloxatin, Oxaliplatin Medac) (see Oxaliplatin): anaphylaxis occurs in 1.3% of cases
- Progesterone (Progesterone-Associated Urticaria) (see Progesterone)
- Protamine (see Protamine)
- Prothrombin Complex Concentrate-3 Factor (Profilnine SD) (see Prothrombin Complex Concentrate-3 Factor)
- Sorafenib (Nexavar) (see Sorafenib)
- Streptomycin (see Streptomycin)
- Sulfobromophthalein
- Taxanes (see Taxanes)
  - Docetaxel (Taxotere) (see Docetaxel)
  - Paclitaxel (Taxol) (see Paclitaxel)
- Tiotropium + Olodaterol (Stiolto Respimat) (see Tiotropium + Olodaterol)
- Vaccines: may be due to either egg or gelatin components of the vaccine
- Vitamin K (see Vitamin K)
Other
- Aeroallergens: rarely involved in angioedema/anaphylaxis
  - Cat Dander
  - Grass Pollen
  - Horse Dander
- Allergen Immunotherapy (see Allergen Immunotherapy)
- Blood Products
  - Packed Red Blood Cells (PRBC) (see Packed Red Blood Cells)
- Fluorescein (see Fluorescein)
- Hemodialysis (see 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
- Vaccines

Immunologic Non-IgE-Mediated Mast Cell Activation

Heparin Contaminated with Oversulfated Chondroitin Sulfate (see Heparin)
- Physiology: mediated by coagulation system activation
Dextrans
- Dextran (see Dextran)
- Iron Dextran (Dexferrum, INFeD) (see Iron Dextran)
  - Risk of First-Exposure Anaphylaxis (see 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)
- Physiology: IgG-mediated
Packed Red Blood Cells (PRBC) (see 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

Contact Allergens (Contact Urticaria-Non-Immunologic/Non-Allergic Type)
- General Comments
  - Non-Allergic Mechanism: substance directly induces mast cell mediator release (substances do not require prior sensitization)
    - Urticaria remains localized to site of contact
  - Onset: urticaria usually appears within 30 min of exposure
- Balsam of Peru: used as perfume
  - Mechanism: non-allergic mechanism
- Benzoic Acid: used as preservative
  - Mechanism: allergic or non-allergic mechanism
- Formaldehyde (see Formaldehyde)
  - Mechanism: allergic or non-allergic mechanism
- Sorbic Acid: used as preservative
  - Mechanism: non-allergic mechanism
- Cinnamic Acid
  - Mechanism: non-allergic mechanism
- Nicotinic Acid
  - Mechanism: non-allergic mechanism
Ethanol (see 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)
- Atracurium (see Atracurium)
- Curare (see Curare)
- Succinylcholine (see Succinylcholine)
- Vecuronium (see Vecuronium)
Opiates (see Opiates)
- Codeine (see Codeine)
- Dextromethorphan (see Dextromethorphan)
- Morphine (see Morphine)
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)
Some Nonsteroidal Anti-Inflammatory Drugs (NSAID) (see Nonsteroidal Anti-Inflammatory Drug)
Stinging Nettle (Urtica Dioica) (see Stinging Nettle): urticaria was named after this weed (which is commonly found in North America, South America, Europe, and parts of Africa
- Physiology: histamine (and pain-causing mediators) contained in the plant
Vancomycin (see Vancomycin)

Altered Arachidonic Acid Metabolism

Nonsteroidal Anti-Inflammatory Drugs (NSAID) (see Nonsteroidal Anti-Inflammatory Drug)

Infection

General Comments

Infection-Associated Urticaria Occurs Most Commonly in Children: may involve immune complex formation (although the exact mechanism is unclear)

Viral

Hepatitis A (see Hepatitis A Virus): urticaria may occur during the prodrome (preicteric) phase
Hepatitis B (see Hepatitis B Virus): urticaria may occur during the prodrome (preicteric) phase
Hepatitis C (see Hepatitis C Vius): urticaria may occur during the prodrome (preicteric) phase
Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus)

Bacterial

Mycoplasma Pneumoniae (see Mycoplasma Pneumoniae)
Urinary Tract Infection (UTI) (see Urinary Tract Infection)

Parasitic

General Comments: acute self-limited urticaria is usually accompanied by prominent eosinophilia in these cases
Ancylostoma (see Ancylostoma)
Anisakis Simplex (see Anisakiasis): associated with sushi ingestion
Blastomycosis (see Blastomycosis)
Echinococcosis (see Echinococcosis)
Fasciola (see Fascioliasis)
Schistosomiasis (see Schistosomiasis): due to Schistosoma Mansoni
Strongyloidiasis (see Strongyloidiasis)
Toxocariasis (see Toxocariasis)
Trichinellosis (see Trichinellosis)

Physical Stimuli

Aquagenic Urticaria
- Epidemiology: associated with water contact (regardless of temperature)
Cholinergic Urticaria
- Epidemiology: associated with fever, hot bath or shower, exercise
- Physiology: probably related to increase in body temperature
- Clinical: distinctly small 1-2 mm wheals surrounded by large area of erythema
Cold-Induced Urticaria
- Epidemiology: acquired or hereditary
- Clinical: usually occurs locally at the cold-exposed site (but can lead to vascular collapse in cases with whole-body cold water immersion during swimming)
Dermatographism
- Epidemiology: occurs in 1-4% of population
  - Peak Prevalence: teens-20’s
  - Usually lasts <5 years
- Clinical: linear wheal at site of a firm skin stroke
Heat-Induced Urticaria
- Epidemiology: associated with local heat application
Exercise-Induced Urticaria
- Clinical: begins with erythema and pruritic urticaria -> progresses to angioedema of face/larynx/intestine/vascular collapse
Pressure-Induced Urticaria
- Epidemiology: associated with a sustained stimulus from shoulder strap, running (on feet), or manual labor (on hands)
Solar Urticaria: three subtypes, distinguished by spectrum of UV light
Vibratory Urticaria
- Epidemiology:
  - Can occur after years of oocupational exposure or may be idiopathic
  - Can be accompanied by cholinergic urticaria

Autoimmune Disease

General Comments: unclear pathophysiology, but possible mechanisms include direct mast cell activation via complement receptors or generation of autoantibodies that cause anaphylactoid degranulation
Autoimmune Thyroid Disease
Celiac Disease (see Celiac Disease)
Henoch-Schonlein Purpura (see Henoch-Schonlein Purpura): lesions may appear urticarial in early stages
IgM (and Sometimes IgG) Paraproteinemia: may be due to complement-mediated pathways
Rheumatoid Arthritis (RA) (see Rheumatoid Arthritis)
Sjogren’s Syndrome (see Sjogren’s Syndrome)
Systemic Lupus Erythematosus (SLE) (see Systemic Lupus Erythematosus)

Other

Cytokine Release Syndrome (see Cytokine Release Syndrome)
Scombroid (see Scombroid)
Serum Sickness (see Serum Sickness)
Systemic Mastocytosis (see Systemic Mastocytosis)
Hypocomplementemic Urticarial Vasculitis
- Physiology
  - Presence of Anti-C1q IgG Antibody
- Clinical
  - Fever (see Fever)
  - Urticarial Lesions: may be painful, eccyhmotic, and purpuric (leaving ecchymoses after resolution)

Physiology

Activation of Superficial Dermis Mast Cells (and Basophils): release of inflammatory mediators (histamine, etc)
- Histamine: causes pruritus
- Vasodilatory Mediators: localized edema in superficial dermis
Angioedema: represents the same pathologic process, except involving the mast cells deeper in the dermis and subcutaneous tissues

Diagnosis

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Clinical Manifestations

General Comments

Onset
- Food-Associated Urticaria: onset is usually within 30 min of ingestion
Classification of Urticaria Based on Chronicity
- Acute Urticaria: urticaria present for <6 wks
- Chronic Urticaria: urticaria present for 6 wks or longer (recurrent and occurring on most days of the week)

Dermatologic Manifestations

Urticaria: localized, well-circumscribed, erythematous plaques with central pallor
- Shape: round, oval, or serpiginous
- Size: vary from <1 cm to several cm in diameter
- Distribution: predominate in areas where clothing compresses the skin (under waistband, etc) or where skin rubs together (axilla)
- Number: wheals may occur individually or coalesce
- Time Course: urticarial lesions progress over min-hrs, regressing over 24 hrs (without leaving any residual ecchymoses)
  - Presence of residual ecchymoses suggests the alternative diagnosis of vasculitis
- Symptoms: may be particularly severe at night
- Urticarial Lesions are Intensely Pruritic (see Pruritus)
  - Urticarial lesions are not usually painful: presence of pain suggests the alternative diagnosis of vasculitis
- Association with Angioedema/Anaphylaxis (see Angioedema and Anaphylaxis): urticaria may occur without associated angioedema/anaphylaxis

Treatment

Antihistamines (H1-Histamine Receptor Antagonists) (see H1-Histamine Receptor Antagonists)

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H2-Histamine Receptor Antagonists (see H2-Histamine Receptor Antagonists)

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Corticosteroids (see Corticosteroids)

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References

Occupational contact urticaria. Clin Rev Allergy Immunol. 2006 Feb;30(1):39-46 [MEDLINE]