Hives

Aka: Hives, Urticaria, Chronic Urticaria, Acute Urticaria

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II. Definition

  1. Urticaria (Hives)
    1. Pruritic, raised wheals up to cm in size

III. Epidemiology

  1. Acute Urticaria (<6 weeks) Prevalence: 25% in United States
  2. Chronic Urticaria (>6 weeks) Prevalence: 1% in United States

IV. 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 [PubMed]

V. Pathophysiology

  1. Response to Histamine release from cutaneous Mast Cells and Basophils
    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
  3. Chronic Urticaria may have autoimmune component against IgE and IgE receptors
    1. Similar IgE antibodies are seen in Atopic Patients

VI. Precautions

  1. Observe for Anaphylaxis and Angioedema
    1. Emergently manage potentially life-threatening findings associated with hives
  2. Allergy may be the cause of hives, BUT most hives are not due to allergy
    1. Allergic Reactions occur in close proximity to the inciting agent (typically within minutes)
  3. Most Antibiotic reactions that have onset days after starting, are due to the infection, not Allergic Reaction
    1. Example: AmoxicillinMorbilliform rash (not Urticarial) is not allergic

VII. History

  1. Anaphylaxis symptoms (critical to exclude)
    1. Shortness of Breath
    2. Stridor
    3. Sinus Tachycardia
    4. Hypotension
    5. Light Headedness
    6. Abdominal Pain
  2. Travel and work history
  3. Ingestion of foods, medications, Herbals, Vitamins
  4. Recent infection
    1. Upper Respiratory Infection
    2. Urinary Tract Infection
  5. Known allergies
  6. Family History of allergy or atopy
  7. High risk sexual activity or Illicit Drug use
    1. Viral Hepatitis
    2. HIV Infection
  8. Pregnancy
    1. Pruritic Urticarial Papules and Plaques of Pregnancy
  9. Premenstrual status
    1. Autoimmune Progesterone dermatitis
  10. Physical Urticaria history (e.g. Dermatographism, Cholinergic Urticaria)
  11. Thyroid disease
    1. Hypothyroidism
    2. Hashimoto's Thyroiditis
  12. Malignancy symptoms (e.g. Lymphoma)
    1. Unintentional Weight Loss
    2. Fever
    3. Night Sweats

VIII. Causes

  1. Allergic Urticaria
    1. Type I Hypersensitivity (IgE mediated immediate)
      1. See Allergic Reaction
      2. Medication reaction (e.g. Penicillins)
      3. Airborne Allergens (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. Rheumatoid Arthritis
    4. Chronic active hepatitis
    5. Mastocytosis
    6. Lymphoma
    7. Celiac Disease (Gluten Sensitive Enteropathy)
    8. Sjogren Syndrome
  3. Viral Infection
    1. Herpes Simplex Virus (HSV)
    2. Cytomegalovirus (CMV)
    3. Epstein-Barr Virus (EBV)
    4. Viral Hepatitis (Hepatitis A, Hepatitis B, Hepatitis C)
    5. Rhinovirus
    6. Rotavirus
    7. Human Immunodeficiency Virus (HIV Infection)
    8. Covid19
  4. Bacterial Infection
    1. Group A Beta Hemolytic Streptococcus (especially in children)
    2. Mycoplasma
    3. Helicobacter Pylori
    4. Urinary Tract Infection
  5. Fungal infections
  6. Direct Mast Cell degranulation
    1. Opiates
    2. Vancomycin
    3. Aspirin
    4. Anaphylactoid Reaction to Radiocontrast
    5. Dextran
    6. Muscle relaxants
    7. NSAIDs
  7. 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
  8. Emotional Stress
  9. Physical Urticaria
    1. Cold Urticaria
      1. Onset within minutes of cold exposure
      2. Histamine-mediated pruritic hives or wheals affecting hands, ear, nose and lateral thighs
      3. Systemic symptoms may occur (Tachycardia, Headache, Syncope, Anaphylaxis)
      4. Treated with Doxepin, Cyproheptadine or other Antihistamines
      5. Alangari (2004) Pediatrics 113(4): e313-7 [PubMed]
    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

IX. Symptoms

  1. Pruritus

X. Signs

  1. Characteristics
    1. Pruritic, round hives or wheals up to several centimeters in size (that may coalesce with other wheals)
      1. Cholinergic Urticaria are small (millimeters) and tend to itch or burn in response to heat, Exercise
      2. Vasculitis-related Urticaria last longer than 24 hours, may burn, and are associated with Arthralgias, fever
    2. Pale to bright red lesions (may also be surrounded by erythema)
    3. Spread with scratching and coalesce into large patch
  2. Course of Lesions
    1. Individual Urticarial lesions last 90 minutes to 24 hours (however new crops of lesions may arise in their place)
    2. Angioedema may persist up to 72 hours
  3. Associated findings
    1. See Allergic Reaction
    2. Angioedema
      1. Localized non-pitting subcutaneous edema of face, lips, upper airway, genitalia or extremities
    3. Dermatographism (Urticaria form in response to pressure)
      1. Physical Urticaria

XI. Labs: Only as indicated based on history (do not obtain routinely)

  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)

XII. Evaluation

  1. Recommended diagnostics
    1. Careful History
      1. Negative history makes finding cause very unlikely (esp. Chronic Urticaria)
      2. See History as above
    2. Lab Tests
      1. Only if suggested by specific symptoms or signs
      2. Consider brief panel if suggested by history (see labs above)
    3. Skin biopsy if lesion present >24 hours (or if Bruising, Purpura deep to hive)
      1. Consider Urticarial Vasculitis
      2. Painful or burning leg lesions
      3. Biopsy may 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

XIII. 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
  6. Morbilliform Drug Reaction (e.g. Amoxicillin rash)
  7. Henoch-Schonlein Purpura
  8. Arthropod Bite
    1. Bite sites last for days
  9. Atopic Dermatitis
  10. Allergic Contact Dermatitis or Irritant Contact Dermatitis
  11. Eczematous Dermatitis
  12. Pityriasis Rosea
  13. Viral Exanthem
  14. Bullous Pemphigoid
    1. Blistering lesions lasting longer than 24 hours

XIV. Management: General

  1. Observe for severe Allergic Reaction or Angioedema
    1. See Anaphylaxis
    2. See Angioedema
  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
  6. Avoid Elimination Diet trials

XV. Management: Acute Urticaria

  1. Step 0: Anaphylaxis is an emergency
    1. Rule this out first and if present start with Epinephrine, Diphenhydramine, airway management
    2. See Anaphylaxis for management
    3. See Angioedema
  2. Step 1: Non-Sedating Antihistamines
    1. Overall, less effective antipruritic as Sedating Antihistamine (but better tolerated)
    2. Recommended for daytime Urticaria symptom control
    3. Higher than typical doses may be required (e.g. see Cetirizine, Loratidine, Fexofenadine below)
    4. Agents
      1. Cetirizine (Zyrtec)
        1. Adult dose (>6 yo) is 10 mg orally daily (increase to twice daily in Adults if needed, off label)
        2. Doses up to 4 tablets per day have been used by allergists in Adults
        3. As an analog of Atarax, is more sedating than other "Non-Sedating Antihistamines"
        4. However, may be more effective than the other agents (since Zyrtec is an analog of Atarax)
      2. Loratadine (Claritin)
        1. Adult dose (>6 yo) is 10 mg orally daily (increase to twice daily in Adults if needed, off label)
      3. Fexofenadine (Allegra)
        1. Adult dose (>12 yo) is 180 mg orally daily (increase to twice daily in Adults if needed, off label)
      4. Desloratadine (Clarinex)
      5. Levocetirizine (Xyzal)
  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 postulated to adjunctively block Histamine receptors
      1. However are without evidence in Urticaria and are rarely helpful
    2. Ranitidine 150 mg orally twice daily or
    3. Cimetidine 400 mg orally twice daily
  5. Step 4: Leukotriene Modifier
    1. Typically used for Chronic Urticaria, but may be considered for acute, refractory cases
    2. Consider in hives worsened by NSAIDs or Aspirin
    3. Montelukast (Singulair) 10 mg orally daily
    4. Zafirlukast (Accolate) 20 mg orally twice daily
  6. Step 5: Add combined H1 and H2 Receptor Antagonist
    1. Doxepin (Sinequan)
      1. Dose: 25-75 mg orally at bedtime
      2. Very sedating agent (limit to night-time use)
      3. Risk of cardiotoxicity and QT Prolongation
      4. 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 orally three times daily
  7. Step 6: Systemic Corticosteroids
    1. Prednisone 20-40 mg orally daily for 3-10 days, up to 3 weeks (tapered off)
    2. Indication
      1. Acute Angioedema
      2. Chronic Urticaria not responding to Antihistamines
      3. Unlikely to help in early or acute simple Urticaria
        1. Barniol (2018) Ann Emerg Med 71(1): 125-31 [PubMed]
    3. Efficacy
      1. Process will flare when steroids are weaned
  8. Step 7: Consult allergy or dermatology

XVI. 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)
      1. Montelukast is associated with increased risk of Major Depression and Suicide
        1. https://www.fda.gov/news-events/press-announcements/fda-requires-stronger-warning-about-risk-neuropsychiatric-events-associated-asthma-and-allergy
    3. Consider Prednisone 1 mg/kg up to 20-40 mg daily tapered over 7 days
    4. Consider Doxepin (Sinequan) for nighttime symptoms
      1. Caution: Very sedating, and risk of cardiotoxicity and QT Prolongation
  4. Step 4: Week 11
    1. Consider referral to allergy or dermatology for third-line therapies
    2. Xolair (omalizumba) or Cyclosporine (Sandimmune) have been used in refractory cases

XVII. Prognosis

  1. Chronic Urticaria tends remits over the first 1 year (35%) and 3 years (48%)

XVIII. Resources

  1. Wanderer (2003) Hives: Road to Diagnosis and Treatment
    1. Paid link to Amazon.com (ISBN 0972794808)

XIX. References

  1. Claudius, Behar, Kelso in Herbert (2016) EM:Rap 16(12): 2-3
  2. Frank in Goldman (2000) Cecil Medicine, p. 1440-5
  3. Kaplan in Middleton (1998) Allergy, p. 1104-18
  4. Habif (1996) Clinical Dermatology, p. 122-47
  5. Swadron and DeClerck in Herbert (2019) EM:Rap 19(2): 8-10
  6. Bernstein (2014) J Allergy Clin Immunol 133(5):1270-7 [PubMed]
  7. Brodell (2008) Ann Allergy Asthma Immunol 100(3): 181-8 [PubMed]
  8. Greaves (2000) J Allergy Clin Immunol 105:664-72 [PubMed]
  9. Morgan (2008) Ann Allergy Asthma Immunol 100(5): 403-11 [PubMed]
  10. Muller (2004) Am Fam Physician 69(5):1123-8 [PubMed]
  11. Schaefer (2011) Am Fam Physician 83(9): 1078-84 [PubMed]
  12. Schaefer (2017) Am Fam Physician 95(11): 717-24 [PubMed]

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