Urticaria and Angioedema
PREVALENCE
Urticaria is a common disorder that has been described in the writings of Hippocrates, Pliny the Elder, and Celsus.1 The term urticaria was first used in the late 18th century; however, most of the research describing the different subtypes and pathophysiology has evolved over the last century or so.
Urticaria continues to be a prevalent skin disorder worldwide. Epidemiologic studies show that approximately 15% to 25% of the population experience at least one episode of urticaria in their lifetime.2,3 Hives affect 6% to 7% of preschool children and 17% of children with atopic dermatitis.4 In all age groups, 49% have a combination of urticaria and angioedema, 40% have urticaria only, and 11% have isolated angioedema.3
Urticaria and angioedema are considerable health care burdens in the United States. They are common causes of patient visits to physicians. Evaluation for the underlying cause can lead to extensive laboratory screening, on average more than 20 laboratory tests.5 Despite thorough evaluation, 80% of patients with chronic urticaria have no identifiable cause of hives, commonly called chronic idiopathic urticaria. Although hives rarely cause mortality, patients with chronic urticaria experience significant impairments in quality of life at home, school, and work from loss of sleep, loss of energy, social isolation, and altered emotional reactions.6,7
PATHOPHYSIOLOGY
Urticaria results from activation of cutaneous mast cells.8 Mast cell stimulation induces vasopermeation and vasodilation, leading to dermal edema and recruitment of cellular and humoral immune effectors. In many cases, the pathogenesis of mast cell activation is incompletely understood and still requires further elucidation. Three metabolic consequences occur with mast cell activation: degranulation (immediate release of mediators including histamine, serotonin, tumor necrosis factor [TNF]-α, proteases, and proteoglycans); cytokine and chemokine synthesis (leading to late-phase inflammation); and leukotriene and prostaglandin synthesis. Depending on the stimulus, mast cell activation can involve any or all three of the metabolic processes in the production and persistence of hives.9
Mast cell stimulation leading to acute and chronic urticaria can be caused by IgE-mediated reaction, autoimmunity, direct mast cell activation, arachidonic acid metabolism, infections, physical urticarias, and systemic diseases (Box 1).
Autoimmunity accounts for 30% to 50% of cases of chronic urticaria in adults and children.8,10 Autoantibodies against IgE and FcεRI (high-affinity receptor for IgE) have been shown to stimulate histamine release in vitro.11–14 Additionally, thyroid autoantibodies, such as antithyroglobulin and thyroid peroxidase antibodies, have been found to be significantly elevated in patients with chronic urticaria compared with the normal population (15%-24% versus 3%-6%, respectively).15–18 Although there is a significant correlation between the presence of thyroid antibodies and chronic urticaria, thyroid function does not necessarily correlate with severity of urticaria. Signs of thyroid autoimmunity in patients who are euthyroid appears to reflect an underlying tendency to develop autoantibodies.8,15,19
Arachidonic acid metabolism can be blocked by nonsteroidal anti-inflammatory medications (NSAIDs) that inhibit cyclooxygenase 1, such as aspirin. These medications can cause acute urticaria in susceptible persons and can also cause flares in patients with chronic urticaria.20 Aspirin-induced urticaria in patients with chronic idiopathic urticaria is reported to be between 21% and 30%.3,20,21
Infections have been implicated in both acute and chronic urticaria. Infections, especially those affecting the upper respiratory and gastrointestinal tracts, have been associated with up to 62% of cases of acute urticaria in the general population22,23 and 80% of cases in the pediatric population.24 Implicated viruses include cytomegalovirus, Coxsackievirus A and B, and infectious hepatitis.23,25 A large number of helminthic parasites have also been clearly associated with urticaria, although this is a rare cause in developed countries.25,26 Helicobacter pylori infection has been proposed as a cause of chronic urticaria; however, recent data indicate this association is more likely coincidental than causal.27,28
Physical urticarias are chronic urticarias triggered by physical stimulus.
SIGNS AND SYMPTOMS
Urticaria is characterized by the appearance of wheals that have three typical features: central swelling, pruritus, and evanescent nature. The combination of pruritus and transient lesions are more specific for urticaria than the other conditions in the differential diagnosis (Box 2). The skin lesions often involve the trunk and extremities but can occur anywhere on the body.29 Pruritus is almost always present with urticaria, although some patients complain of pain, tenderness, or burning instead of pruritus.30 Individual urticarial lesions resolve within 24 hours without residual bruising or hyperpigmentation of the skin. As lesions resolve, others might appear.31 Although the lesions of acute and chronic urticaria are virtually identical, individual wheals can persist longer in patients with chronic urticaria (4-36 hours).
Physical Urticarias
The physical urticarias are common causes of chronic urticaria. With the exception of delayed pressure urticaria, the lesions of the physical urticarias typically occur within minutes of exposure to the appropriate stimulus and fade within 1 to 2 hours.30 The physical urticarias are described here in decreasing order of frequency.
The most common physical urticaria is cholinergic urticaria, which is characterized by small pinpoint hives associated with exercise, hot showers, sweating, or stress. It occurs in up to 11.2% of young adults (16-35 years of age) and is often unnoticed in milder forms.26,32
Dermatographism is diagnosed by the development of a wheal-and-flare response after stroking or scratching the skin. About 10% of patients with chronic idiopathic urticaria have symptomatic dermatographism.33
Delayed pressure urticaria develops 4 to 12 hours after a significant amount of pressure has been applied to the skin.34 The lesions of delayed pressure urticaria are often more painful than pruritic. This form of urticaria is invariably associated with chronic idiopathic urticaria.32,33
In cold urticaria, symptoms occur after exposure to a cold stimulus including air or water. Fatalities have been reported due to anaphylactoid reactions in extremely cold-sensitive patients swimming in lakes or oceans.25,32
Angioedema
Patients with acute or chronic urticaria can also experience angioedema. Angioedema typically affects areas of loose connective tissue, such as the periorbital region, lips, extremities, and genitals (e.g., scrotum). Occasionally, the tongue and pharynx are involved.35 Angioedema involving the oropharynx can cause life-threatening airway obstruction. The edema of subcutaneous tissue may be more painful than pruritic. Swelling can take up to 72 hours to resolve. Isolated angioedema, especially laryngeal edema, requires consideration for hereditary or acquired C1-inhibitor deficiency.
DIAGNOSIS
A detailed history is important for identifying potential causes of urticaria (see Box 1). Key components of the history include current and recent medication use, including herbals, over-the-counter medications, and hormone replacement; food exposures associated with the onset of symptoms; physical triggers such as pressure, physical exertion, or cold temperatures; symptoms of a concurrent infection, such as hepatitis, mononucleosis, or an upper respiratory infection; contact or inhalant exposure to allergens, including occupational exposures; and recent insect sting or bite.29 A complete review of systems is necessary to screen for symptoms of systemic diseases, such as collagen vascular disease or malignancy.
Immunoglobulin E
The history might suggest an underlying cause of acute urticaria. A temporal history of an insect sting or bite, contactant, or food exposure followed by the development of urticaria suggests possible IgE-mediated hypersensitivity. Cutaneous testing or serum radioallergosorbent testing (RAST), usually overseen by a specialist in allergy and immunology, may be performed to identify a cause. Foods are a common cause of acute urticaria but a rare cause of chronic urticaria. The most frequently implicated foods eliciting generalized urticaria in children include milk, soy, wheat, eggs, peanuts, tree nuts, shellfish, and fish. Peanuts, tree nuts, shellfish, and fish are common causes in adults. Occasionally, foods cause hives through a non–IgE-mediated reaction. For example, scombroidosis, which occurs after ingesting contaminated scombroid fish such as tuna or mackerel, can cause urticaria with flushing, nausea, and vomiting.36
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