URTICARIA

URTICARIA - Weily Soong, MD
BASICS
DESCRIPTION
A rapid eruption of polymorphic-shaped cutaneous wheals with central swelling, erythema, and blanching; size ranges from a few millimeters to several centimeters; single or multiple superficial papules and plaques; associated with itching or burning; subsides within 24 hours with no scars or change in pigmentation; may be recurrent; often associated with angioedema (swelling of the lower dermis and subcutis); also known as hives.
• Spontaneous urticaria
- Acute: Persists 6 weeks
 Vast number of possible triggers, e.g., foods, medications, insect stings/bites, infections, physical stimuli, and occupational exposures
 Etiology is usually obvious to the patient and physician.
- Chronic: Persists >6 weeks
 Can be either continuous (daily symptoms) or recurrent (periods with flares and periods with no symptoms)
 The longer the urticaria persists, the more difficult to find the etiology
 Usually not IgE mediated
 Most likely idiopathic (~80% of cases), but reported associations with psychological stress, pseudoallergenic foods/additives, autoimmunity, chronic indolent infections, or malignancy
• Physical urticaria
- Dermatographism: Linear, itchy, red wheal and flare from scratching or rubbing the skin
- Cold urticaria: From exposure to cold; usually idiopathic but can be due to infections, neoplasia, or autoimmune diseases. The familial form, called Familial Cold Autoinflammatory Syndrome, is characterized by recurrent bouts of fever, urticaria, and joint pain triggered by cold, and is caused by mutations in the Cryopyrin gene resulting in the release of interleukin 1.
- Delayed pressure urticaria: Deeper and more painful urticaria; occurs 2-6 hours after pressure to skin (e.g., from elastic or shoes)
- Solar urticaria: From exposure to sunlight of different wavelengths, usually ultraviolet light; onset in minutes; subsides within 2 hours
- Heat urticaria: From direct contact with warm objects or air; rare
- Vibratory urticaria/angioedema: From strong vibrating mechanical forces; rare
• Special forms of urticaria
- Cholinergic urticaria: Due to brief increase of core body temperature; small pin-sized (5-10 mm) wheals surrounded by an erythema but can also have larger wheals; from physical exercise, stress, and hot showers
- Adrenergic urticaria: Caused by stress; extremely rare; has pinpoint-sized red wheals with a white halo
- Contact urticaria: Wheals at sites where chemical substances contact with the skin
- Aquagenic urticaria: Small wheals after contact with water at any temperature; rare
- Urticarial vasculitis: A leukocytoclastic vasculitis looking like urticaria and tending to last >24 hours; more painful than puritic; maybe palpable and purpuric
GENERAL PREVENTION
• Acute, physical, and special forms of urticaria: Avoidance of the potential trigger
• Chronic urticaria: Usually unable to prevent
EPIDEMIOLOGY
• Predominant in all ages: Acute form mainly in children; chronic form mainly in adults
• Predominant sex: Male = Female
• 50% of patients have urticaria with angioedema, 40% with urticaria only, 10% with angioedema only
• 20% of chronic urticaria have known causes.
Prevalence
• Affects 15-25% of population during lifetime
• In the US population: 1 in 1000
ALERT
Pediatric Considerations
• Acute isolated incidents are more frequent; affects 6-7% of preschool children; 17% of children have a history of atopic dermatitis
• In childhood acute urticaria, infection (especially respiratory and urinary tract) is the most frequently documented cause (49%), followed by drug (5%) and food allergies (3%)
RISK FACTORS
History of atopic diseases: Allergic rhinitis, asthma, atopic dermatitis, food and drug allergies
Genetics
No consistent pattern known
PATHOPHYSIOLOGY
• Caused by a degranulation of mast cells which triggers a release of inflammatory mediators (e.g., histamine and leukotrienes) to cause local vasodilatation, cellular infiltration (lymphocytes, eosinophils, mast cells, basophils, neutrophils), vascular permeability, and edema of the dermis of the skin (urticaria) or of subcutaneous skin tissue (angioedema)
• May be immune-mediated (IgE-mediated), complement-mediated, nonimmune-mediated (e.g., degranulation of mast cells by physical stimuli), autoimmune-mediated, or idiopathic
ETIOLOGY
• Spontaneous urticaria
- Acute
 Viral infections: Upper respiratory tract (most common cause, especially in children), mononucleosis, viral hepatitis
 Bacterial infections: Strep throat, sinusitis, dental caries, otitis, urinary tract
 Foods, especially in children: Most common are peanut, tree nuts, seafood, milk, soy, fish, wheat, and eggs. Tend to be IgE mediated. Allergies to food preservatives and additives are possible but not common.
 Drugs: Can be IgE-mediated (e.g., penicillin), nonIgE-mediated (e.g., aspirin and NSAIDs), or idiosyncratic
 Inhalant, contact, ingestion, or occupational exposure
 Insect bite or sting
 Transfusion reaction
- Chronic: >80% of cases idiopathic; usually nonIgE-mediated
 Chronic indolent infections: Helicobacter pylori, vaginitis, fungal or tinea, parasitic, chronic sinusitis, dental cavities, and chronic viral infections (hepatitis)
 Collagen vascular disease (cutaneous vasculitis, serum sickness, lupus)
 Thyroid autoimmunity
 Autoimmune antibodies to the IgE receptor on mast cells and to the IgE antibody causing mast cell degranulation
 Malignancy; rare
 Emotional stress (little supporting evidence)
• Physical and special forms of urticaria: Nonimmune- mediated mast cell degranulation caused by a specific physical stimuli, body temperature changes, stress, chemical substances, and water
ASSOCIATED CONDITIONS
• Angioedema
• Anaphylaxis


DIAGNOSIS
SIGNS AND SYMPTOMS
• Seen alone or with angioedema
• Urticaria may be an initial symptom of a generalized anaphylactic reaction, potentially fatal.
• Single or multiple raised, blanched, central wheals surrounded by red flare anywhere on body
• Intensely pruritic
• Variably sized, 1-2 mm to 15-20 cm or larger; sometimes confluent
• Fast onset, resolves spontaneously in 48 hours
History
The most important: A detailed history and review of symptoms, including the timing/duration of the symptoms, potential triggers, and history of atopic diseases and autoimmune diseases
Physical Exam
A complete physical exam to detect any associated conditions (autoimmune; malignancy; and viral, bacterial, and fungal/tinea infections)
TESTS
Lab
• Acute urticaria: Testing depends on the history and the potential triggers.
- Allergy skin tests and radioallergosorbent test (RAST) for inhaled allergens, insects, drugs, or foods and for assessing other atopic conditions
- Infection: Pharyngeal culture, liver function tests, mononucleosis test, urine analysis
- Food and drug reactions: Elimination of or challenges with suspected agents
• Chronic urticaria: Depending on diagnostic suspicions
- CBC with differential
- Tests for H. pylori (e.g., antibodies)
- Thyroid function tests and anti-thyroid antibodies (anti-thyroperoxidase and anti-thyroglobulin)
- Autoimmune: ESR, antinuclear antibody (ANA), rheumatoid factor, complement (such as CH50), cryoglobulins
- Stool for ova and parasites
- Urine analysis
- Autologous serum skin testing
- Food and drug reactions: Elimination of or challenges with suspected agents
- Maligancy work-up, including serum protein electrophoresis and immunofixation assay
• Physical and special forms of urticaria
- Dermatographism: Scratch skin with a tongue blade, observe for surrounding uricaria.
- Cold urticaria: Ice cube testplace ice cube on skin 5 minutes, observe 10-15 minutes
- Cholinergic: Exercise challenge
- Solar: Expose skin to wavelengths of light.
- Delayed pressure: Apply 5-10-lb sandbag for 3 hours, observe
- Aquagenic: Apply water at various temperatures.
- Vibratory: Apply vibration 4-5 minutes with a lab mixing device, observe.
Imaging
Any imaging necessary to rule out chronic indolent infections (e.g., sinus CT) or malignancy
Diagnostic Procedures/Surgery
• Skin biopsy to rule out urticarial vasculitis
• Routine dental care to rule out dental caries
DIFFERENTIAL DIAGNOSIS
• Anaphylaxis (a potentially fatal generalized systemic allergic disorder with urticaria, angioedema, respiratory distress, abdominal pain, hypotension; may present initially with urticaria)
• Insect bites
• Morbilliform drug eruptions
• Erythema multiforme
• Systemic lupus erythematosus
• Vasculitis and polyarteritis
• Angioedema without urticaria (related to complement and bradykinin disorders, such as familial hereditary angioedema, angiotensin converting enzyme (ACE) inhbitor angioedema, complement deficiencies)
• Urticaria pigmentosa (mastocytosis). Pink lesions urticate when scratched (Darier sign).
• Bullous pemphigoid (urticarial stage)
TREATMENT
GENERAL MEASURES
Avoidance or elimination of the eliciting stimulus
Diet
If a particular food is implicated, avoidance of the food or a trial of avoiding the food for 2-3 weeks
Activity
Depends on the urticarial trigger
• Cold and heat urticaria: Avoid sudden changes in temperature (e.g., slowly getting into a cold swimming pool).
• Dermatographic and delayed-pressure urticaria: Spread out the amount of force per area applied to the skin.
• Solar urticaria: Avoid the sun; use sunscreen.
• Cholinergic urticaria: Avoid sudden changes in body temperature (e.g., slow warm-ups and cooldowns during exercise).
Complementary and Alternative Medicine
• Avoid use of alternative medicine drugs. Herbal and vitamin supplements may make the urticaria worse, because trace contaminants in the supplements might be allergenic.
• Beware of certain "experts" in alternative medicine who might place chronic urticarial patients on severe food and activity restrictions based on lab tests that have little scientific basis.
MEDICATION (DRUGS)
First Line
• 1st-generation antihistaminesmainly for short, intermittent attacks of urticaria; use is limited by its sedation and short half-life) (1,2)[A]
- Older children and adults: Hydroxyzine or diphenhydramine 25-50 mg q6h
- Children 6 years old: Diphenhydramine 12.5 mg (elixir) q6-8h (5 mg/kg/d) or hydroxyzine elixir (10 mg/5 mL) 2 mg/kg/d divided q6-8h
• 2nd-generation H1-blockersmore expensive; effectiveness like older antihistamines but less sedating; a longer half-life. (1,2)[A]
- Fexofenadine (Allegra): 180 mg/d
- Loratadine (Claritin): 10 mg/d
- Desloratadine (Clarinex): 5 mg/d
- Cetirizine (Zyrtec): 10 mg/d
• May need higher doses of antihistamines or a combination of multiple antihistamines for control
• Precautions
- Drowsiness and dry mouth and eyes
- Should be used with caution in the elderly and during pregnancy
Second Line
• Doxepin (Sinequan): Tricyclic antidepressant with strong H1- and H2-blocking properties; 10-25 mg at bedtime; sedation limits usefulness (2)[C]
• H2-blockers: mildly helpful (1,2)[C]
• Corticosteroids: For unresponsive cases, e.g., prednisone 40 mg/d for 5-7 days, taper as antihistamines are introduced; avoid chronic use due to the severe side effects which might be worse than the effects of the urticaria (2)[C]
• Cyproheptadine: Antihistamine and antiserotonergic agent (2)[C]
• Cyclosporine: Best-studied immunosuppressive therapy; effective (2.5-5 mg/kg/d) and steroid sparing (3)[C]
• Leukotriene antagonists: Safe and worth trying in chronic, unresponsive cases (2)[C]
• Intravenous immune globulin, plasmapheresis, sulfasalazine, dapsone, danazol, and hydroxychloroquine require further study. (3)
• Administering thyroid hormone may alleviate chronic urticaria in hypothyroid patients with autoantibodies. (3)[C]
FOLLOW-UP
DISPOSITION
Admission Criteria
If urticaria and angioedema progress into anaphylaxis or threaten the airway. Will need to be discharged with an EpiPen
Issues for Referral
• Referral to an allergist and immunologist for elucidating and testing of potential triggers, life-threatening reactions, and complex management
• Referral to a dermatologist for skin biopsy
• Referral to a rheumatologist for treatment of autoimmune causes of urticaria
PROGNOSIS
• 70% of acute symptoms are better in 72 hours.
• 30% of the patients are chronic.
• >50% of chronic idiopathic urticaria resolve in 3-5 years but are at risk for a reoccurrence many years later.
PATIENT MONITORING
If symptoms persist or recur, patient may need to keep a daily diary of potential triggers (foods, activities, etc.). Pictures of the urticarial lesions are helpful.
REFERENCES
1. Baxi S, Dinakar C. Urticaria and angioedema. Immunol Allergy Clin N Am. 2005;25:353-367.
2. Zuberbier T. Urticaria. Allergy. 2003;58:1224-1234.
3. Kaplan AP. Chronic urticaria: Pathogenesis and treatment. J Allergy Clin Immunol. 2004;114:465-474.
4. Joint Task Force on Practice Parameters. The diagnosis and management of urticaria: A practice parameter. Ann Allergy Asthma Immunol. 2000;85:521-544.
5. Wedi B, Raap U, Kapp A. Chronic urticaria and infections. Curr Opin Allergy Clin Immunol. 2004;4:387-396.
MISCELLANEOUS
See also: Anaphylaxis; Angioedema