Urticaria (Hives)

Urticaria is raised, well-circumscribed areas (wheals) of edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). 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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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Urticaria is a vascular reaction of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin noted as a transient appearance of slightly elevated patches (wheals) that are redder or paler than adjacent skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the 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 Penicillins Beta-lactam antibiotics contain a beta-lactam ring as a part of their chemical structure. Drugs in this class include penicillin G and V, penicillinase-sensitive and penicillinase-resistant penicillins, cephalosporins, carbapenems, and aztreonam. Penicillins, cephalosporins Cephalosporins Cephalosporins are a group of bactericidal beta-lactam antibiotics (similar to penicillins) that exert their effects by preventing bacteria from producing their cell walls, ultimately leading to cell death. Cephalosporins are categorized by generation and all drug names begin with "cef-" or "ceph-." 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 Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema results.
  • Angioedema that accompanies urticaria usually affects face, lips Lips The lips are the soft and movable most external parts of the oral cavity. The blood supply of the lips originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue, extremities, and genitalia.

Allergic IgE-mediated urticarias

  • Generally related to an exogenous allergen ( type I hypersensitivity reaction Type I hypersensitivity reaction Type I hypersensitivity reaction is an abnormal immune response triggered by exposure to specific antigens known as allergens. In this type of hypersensitivity reaction, the presentation of the antigen to the T-helper cells (Th cells) initiates a cascade of immunologic events leading to the production of antigen-specific IgE antibodies. 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 Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins 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 Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables 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 Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables size and shape
    • Wheal blanches with pressure.

Challenge tests

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

  • Pressure:
    • Stroke skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin.
  • Vibration: Apply a laboratory vortex to the forearm Forearm The forearm is the region of the upper limb between the elbow and the wrist. The term "forearm" is used in anatomy to distinguish this area from the arm, a term that is commonly used to describe the entire upper limb. The forearm consists of 2 long bones (the radius and the ulna), the interosseous membrane, and multiple arteries, nerves, and muscles. 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 Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins, and autologous serum skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the 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 Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines
      • Diphenhydramine
  • Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids:
    • Prominent angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema or persistent symptoms despite antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. 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 Atopic Dermatitis Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Atopic Dermatitis (Eczema) ( eczema Eczema Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Atopic Dermatitis (Eczema)): cutaneous disorder with intensely pruritic erythematous patches with papules and some scaling with a more prolonged course: Atopic dermatitis Atopic Dermatitis Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Atopic Dermatitis (Eczema) 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 Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines, and topical steroids.
  • Contact dermatitis: an erythematous, papular dermatitis, often with areas of vesiculation: Occurs due to direct skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the 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 Bullous pemphigoid Bullous pemphigoid and pemphigus vulgaris are two different blistering autoimmune diseases. In bullous pemphigoid, autoantibodies attack the hemidesmosomes, which connect epidermal keratinocytes to the basement membrane. This attack results in large, tense subepidermal blisters. Bullous Pemphigoid and Pemphigus Vulgaris: 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 Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins. 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 Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. 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 Erythema multiforme Erythema multiforme (EM) is an acute hypersensitivity reaction characterized by targetoid skin lesions with multiple rings and dusky centers. Lesions may be accompanied by systemic symptoms (e.g., fever) and mucosal lesions (e.g., bullae). 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the 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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