Hives

1. See Also
   1. Allergic Reaction
   2. Angioedema
   3. Anaphylaxis
2. Epidemiology
   1. Acute Urticaria Prevalence: 25% in United States
   2. Chronic Urticaria Prevalence: 1% in United States
3. Pathophysiology
   1. Response to histamine release from cutaneous mast cells
      1. Both IgE and non-IgE, non immune mediated histamine release
   2. Depth of mast cell degranulation affects the type of lesions
      1. Urticaria involves mast cell degranulation in the superficial Dermis
      2. Angioedema involves mast cell degranulation in the deeper Dermis and subcutaneous tissue
4. Precautions
   1. Observe for Anaphylaxis
5. Causes
   1. Allergic Urticaria
      1. Type I Hypersensitivity (IgE mediated immediate)
         1. See Allergic Reaction
         2. Medication reaction (e.g. Penicillins)
         3. Airborne allergans (e.g. pollens, mold spores)
         4. Hymenoptera Stings
         5. Parasitic Infection
         6. Illness
            1. Acute Infection
            2. Generalized inflammation
         7. Food reaction (e.g. Eggs, Nuts, gluten, shellfish)
            1. Transient in children (rare in adults)
            2. Must occur within minutes of exposure
      2. Type II Hypersensitivity (Cell mediated cytotoxicity)
         1. Transfusion Reaction
      3. Type III Hypersensitivity (Antigen-Antibody complex)
         1. Serum Sickness
   2. Autoimmune of hematologic condition
      1. Hashimoto's Thyroiditis (causes up to 30% of chronic Urticaria cases)
      2. Systemic Lupus Erythematosus
      3. Chronic active hepatitis
      4. Mastocytosis
      5. Lymphoma
   3. Viral Infection
      1. Herpes Simplex Virus (HSV)
      2. Cytomegalovirus (CMV)
      3. Epstein-Barr Virus (EBV)
   4. Bacterial Infection
      1. Group A Beta Hemolytic Streptococcus (especially in children)
   5. Direct mast cell degranulation
      1. Narcotics
      2. Vancomycin
      3. Aspirin
      4. Anaphylactoid Reaction to Radiocontrast
      5. Dextran
      6. Muscle relaxants
      7. NSAIDs
   6. Ingestion of foods concentrated in histamine
      1. Strawberries
      2. Tomatoes
      3. Shrimp or lobster
      4. Cheese
      5. Spinach
      6. Eggplant
      7. Preservatives
      8. Coloring agents
   7. Emotional Stress
   8. Physical Urticaria
      1. Cold Urticaria
         1. Affects hands, ear, nose and lateral thighs
      2. Cholinergic Urticaria
         1. Fever
         2. Hot baths
         3. Exercise-Induced Urticaria
      3. Solar Urticaria (Sun induced)
      4. Pressure
         1. Tight clothing
         2. Soles of foot and other weight bearing points
         3. Dermatographism
6. Types
   1. Acute Urticaria
      1. Wheals resolve within hours, but recur up to 6 weeks
      2. Idiopathic in up to 75% of cases, although much more likely to identify trigger than in chronic cases
   2. Chronic Urticaria (persistent beyond 6 weeks)
      1. Idiopathic in 90-95% of cases
      2. May be related to autoantibody to IgE
      3. Hashimoto's Thyroiditis causes up to 30% of chronic Urticaria cases
         1. Najib (2009) Ann Allergy Asthma Immunol 103(6): 496-501
7. Symptoms
   1. Pruritus
8. Signs
   1. Characteristics
      1. Hives or wheals up to 1-2 centimeters in size
      2. Redness and edema of Dermis
      3. Spread with scratching and coalesce into large patch
   2. Course of Lesions
      1. Lesions last 90 minutes to 24 hours (Angioedema may persist up to 72 hours)
   3. Associated findings
      1. See Allergic Reaction
      2. Angioedema
9. Evaluation
   1. Recommended diagnostics
      1. Careful History
         1. Negative history makes finding cause very unlikely
         2. Travel and work history
         3. Ingestion of foods, medications, herbals, vitamins
         4. Recent infection
         5. Known allergies
         6. Family History of allergy or Thyroid disease
      2. Lab Tests
         1. Only if suggested by specific symptoms or signs
         2. Consider brief panel if suggested by history
            1. Complete Blood Count with differential
            2. Erythrocyte Sedimentation Rate (ESR
            3. C-Reactive Protein (C-RP)
            4. Urinalysis
            5. Liver Function Tests
            6. Thyroid Stimulating Hormone (TSH)
      3. Skin biopsy if lesion present >24 hours
         1. Consider Urticarial Vasculitis
         2. Painful or burning leg lesions
         3. Biopsy show Neutrophilic infiltrate
   2. Diagnostic tests that are not recommended
      1. Radiologic studies
         1. Sinus XRay and Dental XRay have low yield
      2. Allergy Testing
         1. Not helpful in chronic Urticaria
10. Differential Diagnosis
    1. See also Wheal
    2. Urticarial Vasculitis (Leukocytoclastic Vasculitis)
       1. Painful burning leg lesions last 3-5 days and leave residual Hyperpigmentation on resolution
       2. Consider immediate biopsy (shows Neutrophilic infiltrate)
    3. Cutaneous mastocytosis
       1. Orange to brown Hyperpigmentation of small diameter Urticaria
    4. Erythema Multiforme
    5. Fixed Drug Eruption or Morbilliform Drug Reaction
    6. Henoch-Schonlein Purpura
    7. Arthropod Bite
    8. Allergic Contact Dermatitis or Irritant Contact Dermatitis
    9. Eczematous Dermatitis
    10. Pityriasis Rosea
    11. Viral Exanthem
11. Management: General
    1. Observe for severe Allergic Reaction
       1. See Anaphylaxis
    2. Discontinue offending drugs, food, or behavior
    3. Avoid exacerbating factors
       1. Avoid Aspirin and NSAIDs
       2. Avoid Alcohol
    4. Offer Reassurance
       1. Discuss idiopathic nature of chronic Urticaria
       2. Unlikely to identify a specific cause
    5. Explain that diagnostics and labs are not indicated
12. Management: Acute Urticaria
    1. Step 0: Anaphylaxis is an emergency
       1. Rule this out first and if present treat with Epinephrine
       2. See Anaphylaxis for management
    2. Step 1: Non-Sedating Antihistamines
       1. Expensive: $2 per capsule
       2. Agents
          1. Loratadine (Claritin)
          2. Desloratadine (Clarinex)
          3. Fexofenadine (Allegra)
          4. Cetirizine (Zyrtec)
          5. Levocetirizine (Xyzal)
       3. Less effective antipruritic as Sedating Antihistamine
          1. Zyrtec, as analog of Atarax, may be more effective
       4. Consider for daytime Urticaria symptom control
    3. Step 2: Sedating Antihistamines
       1. Consider for nighttime or severe symptoms or refractory to step 1
       2. Agents
          1. Diphenhydramine (Benadryl)
          2. Hydroxyzine (Atarax)
             1. Most potent of the class
          3. Chlorpheniramine (Chlor-Trimeton)
       3. Beware Sedation in older patients and fall risk
       4. Indications and effects
          1. Helpful in Acute Hives in first few weeks
          2. Suppresses itching, and reduces lesions
          3. Does not completely eradicate lesions
    4. Step 3: Add H2 Receptor Antagonist
       1. H2 Blockers are rarely helpful
       2. Ranitidine 150 mg PO bid or
       3. Cimetidine 400 mg PO bid
    5. Step 4: Add combined H1 and H2 Receptor Antagonist
       1. Doxepin (Sinequan)
          1. Dose: 25-75 mg PO qhs
          2. Very potent Antihistamine (H1 and H2 Blocker)
             1. Doxepin is 700 times more potent than Benadryl
             2. Doxepin is 50 times more potent than Atarax
       2. Cyproheptadine (Periactin) 4 mg PO tid
    6. Step 5: Leukotriene modifier
       1. Montelukast (Singulair) 10 mg PO qd
       2. Zafirlukast (Accolate) 20 mg PO bid
    7. Step 6: Systemic Corticosteroids
       1. Prednisone 20-40 mg PO qd
       2. Indication
          1. Acute Angioedema
          2. Chronic Urticaria not responding to Antihistamines
          3. Unlikely to help in early or acute Urticaria
       3. Efficacy
          1. Process will flare when steroids are weaned
    8. Step 7: Consult allergy or dermatology
13. Management: Chronic Urticaria
    1. Step 1: Week 1
       1. Start second generation Antihistamine (e.g. Zyrtec)
    2. Step 2: Week 3
       1. Titrate dosing up (may require 2-4 fold increase over the normal dose)
    3. Step 3: Week 7
       1. Consider first generation Antihistamine at night (e.g. Hydroxyzine)
       2. Consider Leukotriene Receptor Antagonist (e.g. Singulair or Accolate)
       3. Consider Prednisone 20-40 mg daily tapered over 7 days
    4. Step 4: Week 11
       1. Consider referral to allergy or dermatology for third-line therapies (e.g. Plaquenil)
14. Resources
    1. Wanderer (2003) Hives: Road to Diagnosis and Treatment
       1. Paid link to Amazon.com (ISBN 0972794808)
15. References
    1. Frank in Goldman (2000) Cecil Medicine, p. 1440-5
    2. Kaplan in Middleton (1998) Allergy, p. 1104-18
    3. Habif (1996) Clinical Dermatology, p. 122-47
    4. Brodell (2008) Ann Allergy Asthma Immunol 100(3): 181-8
    5. Greaves (2000) J Allergy Clin Immunol 105:664-72
    6. Morgan (2008) Ann Allergy Asthma Immunol 100(5): 403-11
    7. Muller (2004) Am Fam Physician 69(5):1123-8
    8. Schaefer (2011) Am Fam Physician 83(9): 1078-84