Urticaria (Hives)

Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation resulting in the release of histamine and other vasoactive substances from mast cells and basophils in the dermis resulting in extravasation of plasma into the dermis. Urticaria can be caused by myriad inciting events, such as allergic reactions, infections, exposure, and many others. The diagnosis is made clinically. H1-antagonists are used as 1st-line treatment.

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Overview

Definition

Urticaria is a vascular reaction of the skin noted as a transient appearance of slightly elevated patches (wheals) that are redder or paler than adjacent skin and often accompanied by significant itching.

Epidemiology

  • Urticaria is the most common dermatologic disorder seen in the ED.
  • About 15%–20% of the general population experience acute urticaria during their lifetime.
  • Lifetime incidence of chronic urticaria: 2%–3%.
  • Urticaria can occur in any age group.
  • Categories:
    • Acute urticaria:
      • Duration < 6 weeks
      • Similar for men and women
    • Chronic urticaria:
      • Signs and symptoms appearing 2–3 days per week
      • Duration > 6 weeks
      • More frequent in females (60%)
      • Chronic urticaria is more common between 40 and 60 years of age.

Etiology

IgE-mediated urticarias (type I hypersensitivity, release of histamine from mast cells) are often due to exposure to certain allergens:

  • Foods: fish, shellfish, eggs, tree nuts, peanuts, milk, soy 
  • Drugs: penicillins, cephalosporins
  • Insect venom: bee stings
  • Inhalants: dust mites, pollens, molds, animal danders
  • Blood products
  • Latex
  • Skin pressure, cold, or heat
  • Emotional stress
  • Exercise
  • Occurs within minutes to 2 hours after exposure

Non–IgE-mediated urticaria (histamine release secondary to):

  • Narcotics
  • Muscle relaxants:
    • Atracurium
    • Vecuronium
    • Succinylcholine
    • Curare
  • Vancomycin
  • Radiocontrast media
  • Pseudoallergens (certain foods):
    • Tomatoes
    • Strawberries
  • NSAIDs
  • Autoimmune complex–mediated reactions (type III hypersensitivity)

Physical urticarias:

  • Occur as both acute and chronic forms
  • Wheals develop within minutes after exposure to physical factors:
    • Cold temperature
    • Heat
    • Vibration (vibratory urticaria) 
    • Pressure (pressure urticaria)
    • Water (aquagenic urticaria)
    • Sunlight (solar urticaria)

Pathophysiology

Pathogenesis

  • Urticaria is mediated by cutaneous mast cells.
  • These mast cells release multiple mediators (histamine and other substances) in the superficial dermis.
  • When mast cells release vasoactive mediators in deeper dermis and subcutaneous tissues, angioedema results.
  • Angioedema that accompanies urticaria usually affects face, lips, extremities, and genitalia.

Allergic IgE-mediated urticarias

  • Generally related to an exogenous allergen (type I hypersensitivity reaction) or acute infection
  • Usually acute onset:
    • Immediate development (within minutes) of edematous, erythematous wheal-and-flare lesion
    • Evolve and dissipate in < 24 hours
  • Allergens bind to IgE antibodies on mast Fc receptors → release of vasoactive substances with extravasation of plasma into the dermis
  • Histamine: 
    • Most important vasoactive substance
    • Stimulation of H1-receptors:
      •  Endothelial and smooth muscle sites
      •  Increased capillary permeability
    • Stimulation of H2-receptors:
      •  Dilation of arterioles and venules
      •  Extravasation of fluid in the dermis
  • Other vasoactive substances:
    • Bradykinin
    • Leukotriene C4
    • Prostaglandin D2
Mechanism of type 1 hypersensitivity reaction involved in IgE mediated urticarias

Mechanism of type 1 hypersensitivity reaction involved in IgE-mediated urticarias (IgE-mediated mast cell degranulation)

Image by Lecturio.

Nonallergic urticaria

  • Non–IgE-mediated histamine release: secondary to exposure to specific substances
  • More likely to be associated with autoimmune disorders

Clinical Presentation

Onset

  • Acute:
    • Develops within minutes to 2 hours after exposure
    • Edematous and erythematous wheal formation:
      • Central pallor with surrounding red flare
      • Single or multiple lesions
      • Variable size and shape
      • Typically blanch with pressure
    • Pruritus (severe) is common.
    • Duration < 6 weeks
  • Chronic:
    • Duration > 6 weeks
    • 2 or more episodes per week
    • Appearance is identical to that of the acute form.
    • Pruritus, sometimes severe, is common.
    • Many potential triggers
    • Idiopathic etiology common

Clinical observations

  • Wheals classically exhibit:
    • Edema
    • Erythema
    • Well-demarcated edges
    • Central pallor
    • Surrounding red flare
    • Can be localized or generalized
  • Wheals dissipate rapidly (< 24 hours).
  • Pruritus: most common associated symptom
  • Angioedema is simultaneously present in half the patients with urticaria.

Diagnosis

History

  • Wheals:
    • Rapid onset
    • Dissipate rapidly (< 24 hours)
    • Not normally painful
  • Pruritus
  • Duration: 
    • Acute: < 6 weeks
    • Chronic: 
      • > 6 weeks
      • Several episodes per week
  • History of exposure to triggering agents:
    • Foods
    • Drugs
    • Insect bites/stings
    • Infections (upper respiratory)
    • Blood products
    • Latex
    • Skin pressure
    • Emotional stress
    • Exercise
    • Radiocontrast media
  • Comorbid autoimmune disease
  • Family history:
    • Autoimmune disease
    • Urticaria

Physical exam

  • Wheals may or may not be present at the time of the exam.
  • Skin wheal appearance:
    • Central pallor 
    • Surrounding red flare
    • Edema
    • Erythema
    • Well-demarcated edges
    • Single or multiple lesions
    • Variable size and shape
    • Wheal blanches with pressure.

Challenge tests

Challenge tests can be used to elicit symptoms of physical urticaria.

  • Pressure:
    • Stroke skin with blunt object; development of wheals within minutes (dermographism)
  • Delayed pressure:
    • Application of sustained pressure with hanging weight or calibrated dermographometer at 100 g/mm²
    • Development of urticaria within 24 hours
  • Core temperature:
    • Increase body temperature by 1.0°C.
    • Rapid development of wheals
  • Surface temperature:
    • Cold: Apply ice bag for up to 20 minutes.
    • Heat: Apply heated object for 2–5 minutes.
  • Solar: development of wheals within minutes after sunlight exposure
  • Water: Apply water to skin.
  • Vibration: Apply a laboratory vortex to the forearm for 1–5 minutes.

Laboratory studies

  • More commonly done with chronic urticaria
  • Usually done to evaluate for the underlying disease process:
    • CBC with differential
    • ESR
    • CRP
    • Thyroid function tests 
    • ANAs
    • Serum cryoglobulins (cold urticaria)
    • Allergy evaluation
    • Anti-IgE, anti-FcεRI antibodies, and autologous serum skin test (ASST) for autoimmune urticaria
    • Punch biopsy (suspected urticarial vasculitis)

Management

Supportive/prophylactic measures

  • About ⅔ of acute new-onset urticarias will resolve spontaneously and do not require medications.
  • Avoidance of triggers
  • Application of topical cooling moisturizing to reduce itching
  • Repeated controlled exposure to physical factors to induce tolerance

Medications

  • H1-antagonists:
    • Nonsedating:
      • 1st-line treatment
      • Loratadine
    • Moderately sedating:
      • 2nd-line treatment: cetirizine
    • Sedating: 
      • 1st-generation antihistamines
      • Diphenhydramine
  • Glucocorticoids:
    • Prominent angioedema or persistent symptoms despite antihistamines
    • Prednisone
    • Prednisolone
  • Leukotriene-receptor antagonists:
    • Montelukast
    • Zafirlukast
  • Omalizumab: monoclonal antibody against IgE
  • Immunosuppressant drugs:
    • Cyclosporin
    • Mycophenolate mofetil
  • Antiinflammatory agents:
    • Dapsone
    • Sulfasalazine
    • Hydroxychloroquine

Association with anaphylaxis

If associated with anaphylaxis:

  • Emergency management required
  • Airway protection (intubation/tracheostomy)
  • Epinephrine

Differential Diagnosis

  • Atopic dermatitis (eczema): cutaneous disorder with intensely pruritic erythematous patches with papules and some scaling with a more prolonged course: Atopic dermatitis is often associated with elevated serum levels of IgE and a personal or family history of atopy. Most frequently appears in children. Treatment includes avoidance of triggers and use of emollients and moisturizers, topical antiinflammatory agents, antihistamines, and topical steroids.
  • Contact dermatitis: an erythematous, papular dermatitis, often with areas of vesiculation: Occurs due to direct skin exposure to an offending irritant with a direct cytotoxic effect. Diagnosis is made by history and physical exam findings. Treatment includes avoidance of offending irritants and adoption of protective measures, as well as the use of emollients and moisturizers. Topical steroids are the 1st-line intervention.
  • Bullous pemphigoid: a blistering autoimmune disease: Autoantibodies attack the hemidesmosomes, which connect epidermal keratinocytes to the basement membrane. This results in large, tense subepidermal blisters. Diagnosis is made with biopsy and immunofluorescent staining to identify and localize the antibodies. Management involves immunosuppression with corticosteroids and other steroid-sparing immunomodulatory agents.
  • Viral exanthems: generally not pruritic and usually consist of erythematous maculopapular eruptions that persist for days: Fever is often present. The macules are relatively fixed, with new lesions appearing as older lesions resolve. More common in children. Diagnosed clinically. Treatment is symptomatic.
  • Erythema multiforme minor: a syndrome characterized by erythematous, iris-shaped macules and vesiculobullous lesions with a target appearance: these lesions may be painful or pruritic and have a symmetrical distribution on the extensor surfaces of the extremities, especially on the palms and soles, and last for days, potentially with accompanying fever and malaise. The clinical course is usually self-limited without significant sequelae. Diagnosis is made clinically, and skin biopsy is sometimes required. Treatment is usually symptomatic.

References

  1. Asero R. (2020). New-onset urticaria. In Saini S, Callen J. (Eds.), UpToDate. Retrieved March 14, 2021, from https://www.uptodate.com/contents/new-onset-urticaria
  2. Khan D. (2020). Chronic spontaneous urticaria: standard management and patient education. In Saini S, Callen J. (Eds.), UpToDate. Retrieved March 14, 2021, from https://www.uptodate.com/contents/chronic-spontaneous-urticaria-standard-management-and-patient-education
  3. Saini S. (2021).  Chronic spontaneous urticaria: clinical manifestations, diagnosis, pathogenesis, and natural history.  In Callen J. (Ed.), UpToDate.  Retrieved March 14, 2021, from https://www.uptodate.com/contents/chronic-spontaneous-urticaria-clinical-manifestations-diagnosis-pathogenesis-and-natural-history
  4. Wong H. (2020). Urticaria. In Elston D. (Ed.), Medscape. Retrieved March 14, 2021, from https://reference.medscape.com/article/762917-overview
  5. Schwartz R. (2021). Cholinergic urticaria. In Elston D. (Ed.), Medscape.  Retrieved March 14, 2021, from https://reference.medscape.com/article/1049978-overview
  6. Diakow, M., (2018). Chronic Urticaria. In James, W. (Ed.), Medscape.  Retrieved March 14, 2021, from https://reference.medscape.com/article/1050052-overview
  7. Frigas E, Park MA. (2009). Acute urticaria and angioedema: diagnostic and treatment considerations. Am J Clin Dermatol 10(4):239–50.

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