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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Related Studies

Ontology: Urticaria (C0042109)

Definition (MEDLINEPLUS)

Hives are red and sometimes itchy bumps on your skin. An allergic reaction to a drug or food usually causes them. Allergic reactions cause your body to release chemicals that can make your skin swell up in hives. People who have other allergies are more likely to get hives than other people. Other causes include infections and stress.

Hives are very common. They usually go away on their own, but if you have a serious case, you might need medicine or a shot. In rare cases, hives can cause a dangerous swelling in your airways, making it hard to breathe - which is a medical emergency.
Definition (SNOMEDCT_US) A raised, erythematous papule or cutaneous plaque, usually representing short-lived dermal edema
Definition (NCI_CTCAE) A disorder characterized by an itchy skin eruption characterized by wheals with pale interiors and well-defined red margins.
Definition (NCI_NCI-GLOSS) Itchy, raised red areas on the skin. Urticaria are caused by a reaction to certain foods, drugs, infections, or emotional stress.
Definition (NCI_FDA) Urticaria.
Definition (NCI) A transient, itchy skin eruption characterized by wheals with pale interiors and red margins.
Definition (MSH) A vascular reaction of the skin characterized by erythema and wheal formation due to localized increase of vascular permeability. The causative mechanism may be allergy, infection, or stress.
Definition (CSP) usually transient vascular reaction involving the upper dermis, representing local edema caused by dilation and increased permeability of the capilliaries and the development of wheals.
Concepts Disease or Syndrome (T047)
MSH D014581
ICD9 708.9, 708
ICD10 L50 , L50.9
SnomedCT 201272008, 267818006, 156427005, 267868003, 157756002, 269433002, 247472004, 126485001, 64305001
LNC LA20642-7
English Urticarias, Hives, Unspecified urticaria, Urticaria NOS, Urticaria, unspecified, urticaria, urticaria (diagnosis), Rash urticarial, Urticated rash, Urticarial, Urtication, Urticaria [Disease/Finding], hived, urticarias, nettle rash, urticaria nos, urticarial rash, urticarial, hives, nettles rash, rash nettle, hive, hiving, welt, Urticaria NOS (disorder), (Urticaria NOS) or (hives) (disorder), (Urticaria NOS) or (hives), URTICARIA, HIVES, Hive, Urticarial rash, Urticaria (disorder), Urticaria (morphologic abnormality), Hives NOS, Urticaria
French URTICAIRE, Rash urticarien, Urticarien, Eruptions urticariennes, Urticaire SAI, Urticaire, non précisé, Rash-urticaire, Urticaire non précisé, Urtication, ERUPTION ALLERGIQUE, Urticaires, Urticaire, Éruptions urticariennes
Portuguese URTICARIA, Urticária NE, Urticação, Urticáceo, Erupção urticariana, Exantema urticáceo, Urticária, Ardência, Urticárias
Spanish URTICARIA, Urticaria no especificada, Erupción urticante, Urticación, Erupción urticaria, Habón urticarial, Erupción urticarial, Urticaria NEOM, urticaria, SAI (trastorno), urticaria, SAI, erupción urticariana, pápula urticariana, urticaria (trastorno), urticaria, Urticarias, Urticaria, Escozor
Italian Orticarie, Orticarioide, Eruzione urticante, Urticazione, Orticaria NAS, Orticaria, non specificata, Esantema da orticaria, Eruzione orticarioide, Orticaria
Dutch urticaria, niet-gespecificeerd, urticaria NAO, niet-gespecificeerde urticaria, urticariële rash, rash urticaria, urticarieel, urticatie, galbulten, Urticaria, niet gespecificeerd, urticaria's, urticaria, Urticaria, Galbulten, Netelroos
German nesselartiger Ausschlag, Urtikaria NNB, Nesselausschlag, unspezifische Urtikaria, Urtikaria, unspezifisch, Quaddeln, Nessel-, NESSELAUSSCHLAG, URTICARIA, Urtikaria, nicht naeher bezeichnet, Urtikarielle Erscheinungen, Nesselauschlag, Nesselfieber, Nesselsucht, Urtikaria
Japanese 蕁麻疹形成, 詳細不明の蕁麻疹, 蕁麻疹様, 蕁麻疹ＮＯＳ, 蕁麻疹、詳細不明, 蕁麻疹様皮疹, ｼﾞﾝﾏｼﾝﾖｳﾋｼﾝ, ｼﾞﾝﾏｼﾝｼｮｳｻｲﾌﾒｲ, ｼﾞﾝﾏｼﾝﾖｳ, ｼﾞﾝﾏｼﾝ, ｼﾞﾝﾏｼﾝNOS, ｼｮｳｻｲﾌﾒｲﾉｼﾞﾝﾏｼﾝ, ｼﾞﾝﾏｼﾝｹｲｾｲ, じんましん, 蕁麻疹, じんま疹, じん麻疹
Swedish Nässelutslag
Czech kopřivka, urtikarie, Kopřivka, Blíže neurčená kopřivka, Tvorba kopřivkových pupenů, Kopřivkovitý výsev, Kopřivkový, Kopřivky, Kopřivková vyrážka, Kopřivka NOS, Kopřivkový výsev
Finnish Nokkosihottuma
Russian KRAPIVNITSA, URTICARIA, КРАПИВНИЦА
Korean 두드러기, 상세불명의 두드러기
Croatian URTIKARIJA
Polish Pokrzywka
Hungarian Urticaria k.m.n., Kiütés urticariás, Urticaria, nem meghatározott, Urticariaszerű kiütés, Nem meghatározott urticaria, Urticariás kiütés, Urticaria, Urticariás, Csalánkiütés kialakulása, Urticariák, Csalán
Norwegian Urticaria, Elveblest, Neller, Neslefeber
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Acute urticaria (C0234935)

Concepts Disease or Syndrome (T047)
SnomedCT 402408009
English URTICARIA ACUTE, Urticaria acute, acute urticaria, Acute urticaria, Acute urticaria (disorder)
Dutch acute urticaria, urticaria acuut
French Urticaire aiguë, Urticaire aigüe, URTICAIRE AIGUE
German akute Urtikaria, Urtikaria akut, URTICARIA AKUT
Italian Orticaria acuta
Portuguese Urticária aguda, URTICARIA AGUDA
Spanish Urticaria aguda, URTICARIA AGUDA, urticaria aguda (trastorno), urticaria aguda
Japanese 急性蕁麻疹, ｷｭｳｾｲｼﾞﾝﾏｼﾝ
Czech Akutní kopřivka
Hungarian Acut urticaria, acut urticaria
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Chronic urticaria (C0263338)

Concepts Disease or Syndrome (T047)
ICD10 L50.8
SnomedCT 51611005
Italian Orticaria cronica
Dutch chronische urticaria, chronisch; urticaria, periodiek recidiverend; urticaria, urticaria; chronisch, urticaria; periodiek recidiverend, urticaria chronisch
German chronische Urtikaria, Urtikaria chronisch
Japanese 慢性蕁麻疹, ﾏﾝｾｲｼﾞﾝﾏｼﾝ
English recurrent periodic urticaria (diagnosis), recurrent periodic urticaria, chronic urticaria, urticaria chronic, Urticaria chronic, Chronic urticaria, Recurrent periodic urticaria, Chronic urticaria (disorder), chronic; urticaria, recurrent periodic; urticaria, urticaria; chronic, urticaria; recurrent periodic, Urticaria, chronic, Urticaria, recurrent periodic
Czech Chronická kopřivka
Hungarian Idült csalánkiütés, Chronikus urticaria
Spanish urticaria crónica (trastorno), urticaria crónica, urticaria periódica recidivante, urticaria periódica recurrente, Urticaria crónica
Portuguese Urticária crónica
French Urticaire chronique
Derived from the NIH UMLS (Unified Medical Language System)

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