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Urticaria and Angioedema 101. Scot Laurie, MD Allergy and Asthma Center at NorthPark Assistant professor, University of Texas Southwestern Medical Center. Case Presentation.

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urticaria and angioedema 101

Urticaria and Angioedema 101

Scot Laurie, MD

Allergy and Asthma Center at NorthPark

Assistant professor, University of Texas Southwestern Medical Center

case presentation
Case Presentation
  • Jim S. is a 45 y/o who presented for evaluation of his urticaria. He has been suffering with hives for the past 4 months. He is unable to tell what triggers his hives.
  • His hives are generalized and an individual hive will last a few hours; he has had several episodes of lip swelling as well.
  • He might have had a similar episode 10 years ago and his doctor told him he was allergic to penicillin
case presentation3
Case presentation
  • He has visited his primary care physician who suggested he take Claritin
  • He returned when his hives persisted and the doctor told him that he was allergic to something and suggested an allergy evaluation.
case presentation4
Case presentation
  • Past medical history
    • Hypothyroidism
  • Medications
    • levothyroxine
    • Ibuprofen prn
  • Review of systems
    • Occasional headaches; otherwise negative
  • Physical exam
case presentation6
Case presentation
  • How would his hives be classified?
  • What is causing his hives?
  • Are his medical conditions or medications contributing to his hives?
  • What tests should be done to evaluate his hives?
  • How are his hives best treated?
urticaria angioedema
DESCRIPTION

Urticaria

Raised, erythematous, blanching

Pruritic

Lesions well-circumscribed; typically coalesce

Angioedema

Subcutaneous swelling

Predilection to areas of loose connective tissue, such as the face or mucus membranes involving the lips or the tongue

URTICARIA & ANGIOEDEMA
urticaria and angioedema
Urticaria and Angioedema
  • Clinical features: Urticaria
    • Repeated occurrence of short-lived cutaneous wheals accompanied by erythema and pruritus
      • Wheals range in size from a few millimeters to several centimeters
      • Wheals may coalesce to form larger lesions
      • Individual wheals typically last less than 24 hours
      • Urticaria may occur anywhere on the skin
        • Mucus membrane involvement is rare
      • Lesions should resolve without any residual marking
urticaria and angioedema12
Urticaria and Angioedema
  • Clinical features: Angioedema
    • Approximately 50% of patients with chronic urticaria have angioedema as well
    • Episodes of short-lived deep dermal and subcutaneous or submucosal edema
    • Like urticaria, symptoms generally last less than 24 hours
      • Larger swellings may take longer to resolve
    • Pruritus does not consistently accompany angioedema, and may not occur at all.
urticaria and angioedema14
Urticaria and Angioedema
  • Classification
    • Acute: < 6 weeks
      • Allergic
      • Infectious
      • Idiopathic
    • Recurrent acute
    • Chronic: > 6 weeks
      • Idiopathic
      • Autoimmune
      • Physical
urticaria classification
URTICARIA CLASSIFICATION
  • Acute: < 6 weeks
    • Affects as many as 10-20% of the population at some point in their lives
    • Etiology frequently identified
      • Food allergy
      • Drug allergy
      • Stings/venoms
      • Infection
        • Viral infection leading cause of urticaria in children
urticaria classification16
Urticaria Classification
  • Recurrent acute (intermittent)
    • Episodes of urticaria lasting days or weeks with intervals of days, weeks, or months in between episodes
  • Chronic: > 6 weeks
    • Idiopathic
    • Physical urticarias
urticaria etiologies
Common

Idiopathic

Medications

Stings

Foods

Infection

Physical urticarias

Rare Causes

Neoplasms

Collagen vascular disease

Endocrine

Urticarial vasculitis

URTICARIA ETIOLOGIES
urticaria etiologies18
Urticaria etiologies
  • Urticaria is rarely, if ever the presenting or sole symptom of an underlying disease
  • A complete Review of Systems will suggest or identify any systemic disease in which the urticaria occurs
urticaria etiologies19
URTICARIA ETIOLOGIES
  • Medications
    • Any drug has the potential to elicit an allergic reaction
      • Antibiotics in general, and penicillins specifically, are most often indicated
      • Aspirin/NSAID’s
          • Considered second most common cause of acute drug allergic reactions
          • Frequently exacerbate chronic urticaria and angioedema
urticaria etiologies20
URTICARIA ETIOLOGIES
  • Foods
      • Important cause of acute urticaria
        • Primary allergens are peanuts, tree nuts, shellfish, fish, eggs, milk
      • Chronic urticaria typically unrelated to food allergy
  • Infection
      • Common cause of acute urticaria
        • Viral infection most common cause in children
        • Episodes are self-limited
      • Rare cause of chronic urticaria
insect bites stings
Generalized urticaria/angioedema

Indicates systemic reaction

Requires allergist evaluation for possible immunotherapy

Urticaria in children does not require immunotherapy

Hymenoptera

bees, wasps, yellow jackets, hornets

Fire ants

INSECT BITES & STINGS
urticaria etiologies22
URTICARIA ETIOLOGIES
  • Aeroallergens
    • Rarely, if ever, cause urticaria
      • Animals may cause contact urticaria
      • Inhaled latex may result in systemic allergic reaction
      • ? seasonal pollens
  • Contact Urticaria
    • Nonimmunologic
      • cinnamic acid, benzoic acid
      • Diagnosed by open patch test
    • Immunologic (Allergic)
      • Latex, fruits, vegetables
      • Diagnosed by applying material to eczematous or scratched skin
urticaria etiologies23
Urticaria etiologies
  • Endocrine/autoimmune
    • Thyroid disease
      • Urticaria and angioedema has been associated with hypo- and hyperthyroidism
      • Possible association with the presence of thyroid autoantibodies (antithyroid peroxidase and antithyroglobulin)
        • Thyroid autoimmunity has been demonstrated in 12-26 % of subjects with chronic urticaria
        • Thyroid autoimmunity occurs in 3-6% of the population
urticaria etiologies24
URTICARIA ETIOLOGIES
  • Chronic urticaria
    • Most common etiology is idiopathic
    • 30-60% of patients exhibit a wheal-and-flare with autologous serum skin testing
      • Thought to be due to a complement-activating, histamine-releasing autoantibody (IgG) against the α-chain of the high-affinity IgE receptor (FcεRI)
        • These autoantibodies are able to trigger mast cell or basophil histamine release through direct crosslinking of adjacent receptors
        • Can cause histamine release in healthy subjects
      • Treatment implications: urticaria may be more difficult to control
slide25

Plasma of patients with chronic urticaria shows signs of thrombin generation, and its intradermal injection causes wheal-and-flare reactions more frequently than autologous serum

J Allergy Clin Immunol 2006;117:1113-7.

chronic urticaria etiologies
Chronic urticaria: etiologies
  • 51/96 (53%) patients had positive ASST
  • 61/71 (86%) patients had positive APST
  • Prothrombin fragment F(1+2) (marker of thrombin generation) was higher in patients than in controls
    • Levels directly related to severity of urticaria
chronic urticaria etiologies27
Chronic urticaria: etiologies
  • Conclusions
    • Suggests role of the activation of the extrinsic coagulation pathway with thrombin generation in chronic urticaria
      • Thrombin increases vascular permeability (edema)
      • May trigger mast cell degranulation
    • Possible therapeutic use of anticoagulants (heparin/warfarin)
natural history chronic urticaria
Natural history:Chronic Urticaria
  • Up to 50% patients resolve within 3-12 months
  • Another 20% of patients resolve in 12-36 months or 36-60 months
  • Up to 1.5% of patients persist for 20+ years
  • 50% of patients with chronic urticaria will have recurrences
  • Physical urticarias tend to last longer, as do more severe forms of chronic urticaria
physical urticarias
Symptomatic dermographism

Cholinergic

Delayed pressure

Cold

Aquagenic

Solar

Vibratory

adrenergic

PHYSICAL URTICARIAS
physical urticarias30
PHYSICAL URTICARIAS
  • Dermographism
    • Very common- affects 2-5% of population
      • Small fraction of these patients will seek treatment
    • Stroking of the skin results in linear wheals which may persist as long as 30 minutes
      • patients may complain of generalized pruritus or “skin crawling”
physical urticarias32
PHYSICAL URTICARIAS
  • Cholinergic urticaria
    • Likely the most common of the physical urticarias- 30% of the physical urticarias
    • Occurs primarily in teenagers and young adults
    • Pruritic, small macules and papules occur in response to heat, exercise, or emotional stress
      • May occur with wheezing
      • May occur without visible skin lesions (cholinergic pruritus)
physical urticarias34
Physical urticarias
  • Cold urticaria
    • Characterized by the rapid onset of pruritus, erythema, and swelling after exposure to a cold stimulus
      • Holding cold objects: hand swelling
      • Eating cold items: lip swelling/ oropharyngeal edema
      • Swimming, with total body immersion, can result in massive mediator release, resulting in hypotension
        • Risk factor: oral symptoms with ingestion of cold items
urticaria evaluation
URTICARIA EVALUATION
  • Acute urticaria and angioedema
    • History to ascertain for possible triggers: food, drug, sting, infection
    • Exam to confirm diagnosis
    • May refer to board-certified allergist for select skin testing/challenge tests to suspected agents
urticaria evaluation38
Urticaria evaluation
  • Chronic urticaria
    • History and physical exam
      • Confirm diagnosis of urticaria/angioedema
    • Laboratory studies
      • Usually none required
        • No relationship has been found between the number of identified diagnoses and the number of laboratory tests performed
      • Consider thyroid evaluation (TSH, thyroid autoantibodies) in patients who fail initial therapy
      • If urticarial vasculitis suspected:
        • ANA, complement levels
        • Referral for skin biopsy
skin biopsy
Skin biopsy
  • Indications
    • Individual urticarial lesion persists for >48 hours
    • Urticaria are less than moderately pruritic
    • Lack of significant response to “maximum” doses of antihistamines
urticaria management
URTICARIA MANAGEMENT
  • Goals
    • control symptoms & keep patient comfortable
      • search for and treat underlying etiologies
      • exclude serious diseases
  • Avoidance
    • causative factor if identified
    • NSAID’s & ASA
    • excessive heat
  • Supportive therapy
    • Reassurance
    • Patient education is most important
urticaria management41
Urticaria management
  • Chronic idiopathic urticaria
    • Because there is no one specific causative agent that can be withdrawn, the hives cannot be “cured”.
    • Treatment is considered palliative, until the condition resolves on its own
      • Goal is to maintain a patient’s quality of life, despite condition
initial urticaria pharmacotherapy
INITIAL URTICARIA PHARMACOTHERAPY
  • Antihistamines: H1 receptor antagonists
    • Second generation (“Non-sedating”)
      • equal in efficacy to first generation without as many side effects
        • cetirizine, levocetirizine, desloratadine, fexofenadine, loratadine
    • First generation
      • Generally administered on a daily basis for preventative therapy
        • hydroxyzine, diphenhydramine, chlorpheniramine, etc.
        • dose at qhs initially to reduce daytime somnolence
        • May be used on a prn basis
secondary urticaria pharmacotherapy
SECONDARY URTICARIA PHARMACOTHERAPY
  • H2 antagonists
    • 15% of histamine receptors in the skin are H2
    • May use in combination with H1 antagonists
    • Inhibits metabolism of hydroxyzine, resulting in higher plasma concentration of hydroxyzine
  • Doxepin
    • Very potent H1 antagonist
    • H2 antagonist as well
    • May be very sedating- generally use at night
  • Leukotriene antagonists
    • Zafirlukast and montelukast superior to placebo in the treatment of chronic urticaria
urticaria management44
Urticaria management
  • Antihistamine “cocktail”
    • Begin with 2nd generation antihistamine once a day; if response unsatisfactory,
    • Double the dose (either split-dose twice daily, or full dose once daily); if response unsatisfactory, ADD
    • Doxepin 10-50 qhs (titrate over time to reduce sedation)

Levocetirizine/cetirizine>fexofenadine>desloratadine/

loratadine

secondary urticaria pharmacotherapy45
SECONDARY URTICARIA PHARMACOTHERAPY
  • Oral corticosteroids
    • Role of systemic steroids in the treatment of chronic urticaria is limited
    • Short-term use in special situations (e.g. control of symptoms prior to an important event.)
    • Prolonged treatment complicated by severe side effects along with worsening of urticaria upon withdrawal
alternative agents for refractory chronic urticaria
Alternative agents for refractory chronic urticaria

Drug Level of evidence

Leukotriene modifiers Ib

Dapsone IIb

Sulfasalazine III

Hydroxychloroquine Ib

Colchicine III

Calcineurin inhibitors Ib

Mycophenolate IIb

Omalizumab III

secondary urticaria pharmacotherapy47
SECONDARY URTICARIA PHARMACOTHERAPY
  • Immunomodulatory agents
    • Limited studies demonstrate efficacy of cyclosporine in improving urticaria along with decreasing dependence on prednisone.
      • Suppressive effect on basophil and mast cell activation
      • Requires monitoring of a patient’s blood pressure and renal function
cyclosporine
Cyclosporine
  • Patients with chronic, severe urticaria with positive autologous skin test
    • 3-month course of treatment resulted in 80% totally or almost clearing their symptoms
    • Upon medication withdrawal at 3 months:
      • 1/3 remained clear
      • 1/3 relapsed mildly
      • 1/3 relapsed to baseline

Br J Dermatol 2000;143:368.

urticaria and angioedema49
Urticaria and angioedema
  • Pearls
    • Urticaria and angioedema frequently is not an allergic condition
    • Urticaria does not respond to topical treatment
    • Urticaria in the setting of antibiotics use might be due to the infection, rather than the antibiotic
    • Almost all urticaria is responsive to antihistamines; if your initial dose does not work, use more
    • When all else fails, refer to your favorite fellowship-trained allergy and immunology specialist
    • Treatment references: N Engl J Med 2002;346:175-9

or Allergy and Asthma Proc 2004;25:143-149.