Published: August 2010
Urticaria, also known as hives, is defined as raised, erythematous skin lesions that are pruritic and evanescent. They typically last less than 24 hours without leaving residual marks or bruising. Urticaria can be divided into two categories. Acute urticaria is defined as outbreaks of urticarial lesions that do not persist beyond 6 weeks. Chronic urticaria is defined as the recurrence of hives on a near daily basis for more than 6 weeks.
Angioedema, deeper asymmetrical swelling of the lower dermal and subcutaneous or submucosal tissue, may be associated with or independent of hives.
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
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).
|Box 1 Mechanisms of Urticaria|
|Direct Mast Cell Activated|
|Arachidonic Acid Metabolism|
IgE, Immunoglobulin E; NSAID, nonsteroidal anti-inflammatory drug.
IgE-mediated reactions to foods, medications, stinging insects, aeroallergens, and contactants are common causes of acute urticaria.
Direct mast cell stimulation by medications, such as opioid narcotics, vancomycin, neuromuscular blocking agents, and radiocontrast media can cause urticaria and angioedema by a non-IgE-mediated process.
Autoimmunity accounts for 30% to 50% of cases of chronic urticaria in adults and children.8,10 Autoantibodies against IgE and FcɛRI (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.
Systemic diseases, such as autoimmune disorders, cryoglobulinemia, and neoplasia, have rarely been implicated in chronic urticaria.
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).
|Box 2 Differential Diagnosis of Urticaria|
|Erythema multiforme minor|
|Urticaria pigmentosa (mastocytosis)|
|Vasculitis (including urticarial vasculitis and Henoch-Schönlein purpura)|
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
Solar urticaria is caused by exposure to sunlight or certain wavelengths of artificial light. Other rare types of physical urticaria include aquagenic urticaria, local heat urticaria, and vibratory urticaria triggered by contact with water, a warm substance, or vibratory stimulus, respectively.
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.
Proper diagnosis of urticaria requires a detailed history and physical examination. Characteristics of the lesions are important for accurate diagnosis, especially if there is no evidence of rash at the time of evaluation. Questions regarding appearance (round or linear, raised, erythematous), duration (more or less than 24 hours), symptoms (pruritic, burning, or painful), and accompanying angioedema can help establish the 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.
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
A complete history for evidence of a physical stimulus eliciting a wheal-and-flare or angioedematous response is necessary for a diagnosis. Questions regarding causal relation to heat, exercise, stress, pressure, cold temperatures (air or water), or sun exposure are essential in diagnosing a physical urticaria. Dermatographism can be diagnosed by observing the skin after stroking it with a blunt object (e.g., tongue blade) or dermatographometer. Typically, these patients describe a history of scratching that precipitates linear hives and pruritus. Other specific provocation tests, such as an ice cube test (cold urticaria) or an intradermal injection of methacholine (cholinergic urticaria), may be completed when the history and physical examination suggest a physical urticaria.
Chronic urticaria has been uncommonly associated with systemic diseases such as collagen vascular disease or malignancy. In a meta-analysis by Kozel and colleagues, an underlying disease was considered to be the cause of chronic urticaria in only 1.6% of patients.5 For patients with chronic urticaria, screening laboratory tests may be completed to help detect underlying illness. These tests can include a complete blood count with differential, erythrocyte sedimentation rate, urinalysis, and liver function tests.29 Because thyroid autoimmunity has been associated with chronic urticaria, thyroid function tests including antimicrosomal and antithyroglobulin antibodies may be obtained.35 If a connective tissue disease is suspected, antinuclear antibody and other serologic tests may be warranted.35 A C4 level should be obtained in patients who experience angioedema without urticaria. If the C4 level is low, then C1 inhibitor level and function should be checked to evaluate further for possible hereditary or acquired angioedema.
Most often, chronic urticaria is not caused by an external trigger or an underlying illness and is classified as idiopathic. Chronic urticaria seems to be an autoimmune process in 40% to 50% of patients.11 These patients develop a localized wheal and pruritus after intradermal injection of autologous serum. Autoantibodies directed against the high-affinity IgE receptor or, less commonly, IgE itself have been identified in these patients.11
Palpable and purpuric lesions, the persistence of individual lesions for longer than 24 hours, or the presence of systemic symptoms such as fever or arthralgias, suggest possible urticarial vasculitis. A skin biopsy should be performed when urticarial vasculitis is suspected or when urticaria is particularly difficult to treat.29 Despite a thorough evaluation, 80% of patients with chronic urticaria have no identifiable underlying cause.
Nonspecific triggers of urticaria including NSAIDs, alcohol, and overheating should be avoided.37 Angiotensin-converting enzyme (ACE) inhibitors can cause angioedema; therefore, this class of antihypertensive medications should be avoided, as feasible, in patients with angioedema.38 If a specific cause of the urticaria is identified, such as a food or medication, avoidance is crucial for treatment success. For physical urticarias, decreasing exposure to the provoking stimulus alleviates symptoms. For example, wearing warm and protective clothing outdoors during cold weather helps prevent exacerbations of cold urticaria.39
H1 antihistamines are the mainstay of treatment for urticaria.40 First-generation antihistamines, such as hydroxyzine and diphenhydramine, are effective but cause sedation and anticholinergic side effects (Table 1). The sedation can impair driving, increase the risk for occupational accidents, and adversely affect academic performance and workplace productivity.29 Anticholinergic effects include dry mouth, constipation, urinary retention, and blurred vision. Second-generation antihistamines—loratidine (Claritin), desloratidine (Clarinex), fexofenadine (Allegra), cetirizine (Zyrtec), and levocetirizine (Xyzal)—are generally preferred as first-line treatment (see Table 1). Loratidine, desloratidine, fexofenadine, and levocetirizine are relatively nonsedating when used at standard recommended doses. Cetirizine causes sedation in a minority of patients. The second-generation antihistamines have few or no anticholinergic side effects.
|First-Generation H1 Antihistamines|
|Chlorpheniramine||4 mg q4-6h prn, max 24 mg/day|
|Cyproheptadine (Periactin)||Start 4 mg tid, max 0.5 mg/kg/day|
|Diphenhydramine (Benadryl)||25 to 50 mg q6h prn|
|Hydroxyzine (Atarax, Vistaril)||10 to 100 mg q 6 h prn, max 600 mg/day|
|Second-Generation H1 Antihistamines|
|Cetirizine (Zyrtec)||5 to 10 mg daily|
|Desloratidine (Clarinex)||5 mg daily|
|Fexofenadine (Allegra)||180 mg daily or 60 mg bid|
|Loratidine (Claritin)||10 mg daily|
|Levocetirizine (Xyzal)||5 mg daily|
|Cimetidine (Tagamet)||400 mg bid or 400 to 800 mg qhs|
|Famotidine (Pepcid)||20 mg bid or 20 to 40 mg qhs|
|Nizatidine (Axid)||150 mg bid or 300 mg qhs|
|Ranitidine (Zantac)||150 mg bid or 300 mg qhs|
*Standard recommended doses for adults. Some physicians use higher doses when treating patients with severe urticaria.
Patients should be instructed to take antihistamines on a regular basis, not simply as needed, because treatment failure is more likely when a patient takes an antihistamine intermittently instead of continuously.41 If patients continue to experience symptoms despite regular use of a second-generation antihistamine, many physicians use a combination of first- and second-generation antihistamines. A commonly used regimen is a nonsedating antihistamine on awakening and a sedating antihistamine before going to bed.39
Although the majority of histamine receptors in the skin are of the H1 subtype, about 15% are of the H2 subtype.39 The use of a H2 receptor antagonist such as ranitidine (Zantac) or cimetidine (Tagamet) in conjunction with H1 antihistamines can provide additional clinical benefit for treatment of chronic urticaria (see Table 1).42 Doxepin, a tricyclic antidepressant, has potent H1 and H2 antihistamine activities and is effective for treating chronic urticaria.43 Side effects of this medication include sedation and increased appetite.
Systemic corticosteroids are efficacious for treating urticaria, but use should be limited because of potential side effects.40 In treating acute urticaria, a short course of oral steroids has been shown to provide symptomatic relief earlier than loratidine.22 In chronic urticaria, corticosteroids should be used only in highly selective situations, such as during a significant exacerbation of symptoms or in severe cases refractory to other treatments.40 Side effects of systemic corticosteroids include osteoporosis, edema, hypertension, peptic ulcers, glaucoma, and cataracts. Some patients experience a significant flare of urticaria after tapering or discontinuing steroids.39 Corticosteroids should be prescribed at the lowest effective dose and therapy should be tapered and discontinued as soon as possible to minimize potential side effects.40
Epinephrine can be lifesaving for patients who experience laryngeal edema or anaphylaxis.37 The proper dose for adults is 0.3 mL to 0.5 mL of intramuscular epinephrine in 1 : 1000 concentration. Pediatric dosing is 0.01 mL/kg of intramuscular epinephrine in 1 : 1000 concentration, up to 0.3 mL. The lateral thigh is the preferred injection site.44 The dose may be repeated if necessary. Epinephrine should be used with caution in patients with hypertension or ischemic heart disease.37 Patients with a history of laryngeal edema or anaphylaxis, and patients with a history of food allergy, stinging insect hypersensitivity, or latex allergy should have self-injectable epinephrine (Epipen, Twinject) available at all times.29 The patient should be instructed on the proper use of this medication and told to seek emergency medical care immediately after use, because symptoms can recur or worsen as the medication wears off. Patients should also be instructed to wear a medical alert bracelet.
The antileukotriene drugs, montelukast (Singulair), zafirlukast (Accolate), and zileuton (Zyflo), although not FDA approved for this indication, can provide clinical benefit in treating chronic urticaria.45,46 These medications appear to be more effective when used in combination with antihistamines rather than as monotherapy.47
Mast cell-stabilizing agents have been used to treat urticaria. Nifedipine, a calcium-channel blocker, has been effective for treating chronic urticaria when used as an adjunct to antihistamines.48 Oral sympathomimetic agents such as terbutaline occasionally provide relief, but the overall efficacy is low. Side effects of terbutaline include tachycardia and insomnia.35
Other interventions have been used to treat refractory urticaria. Thyroxine treatment can lead to remission of symptoms in patients with chronic urticaria and evidence of thyroid autoimmunity.19 Dapsone and hydroxychloroquine (Plaquenil) have been used to treat severe cases of urticaria.38,49 Cyclosporine, an immunosuppressant used in organ transplant recipients, has been effective at a low dose for treatment of urticaria.50 Cyclosporine is contraindicated in patients with a history of malignancy or impaired renal function.38 Plasmapheresis and intravenous immunoglobulin have been used to treat small numbers of patients.51,52 Other agents used include colchicine, sulfasalazine, warfarin, and methotrexate.39
Treatment of hereditary and acquired angioedema differs from treatment of idiopathic urticaria and angioedema and is typically supervised by a specialist in allergy and immunology. Danazol, an attenuated androgen, has been used to treat hereditary angioedema. Danazol appears to work by upregulating hepatic synthesis of C1 inhibitor. Abnormal liver function, lipid abnormalities, weight gain, amenorrhea, and hirsutism are side effects of danazol.53 Antifibrinolytic agents, such as tranexamic acid and ɛ-amino caproic acid, have also been used to treat hereditary and acquired angioedema. Clinical trials are investigating the use of recombinant C1 inhibitor to treat hereditary angioedema.54
Specialist referral should be considered if urticaria might be caused by an IgE-mediated reaction; if the lesions last longer than 6 weeks; if there is evidence of urticarial vasculitis; if the hives respond poorly, there is an impairment on quality of life, or there is increased absenteeism from work or school despite an adequate regimen of antihistamine therapy; if there is evidence of angioedema involving the oral-pharyngeal region; or if there is isolated angioedema (without a history of ACE inhibitor use).
In a study by Aoki and colleagues regarding the natural course of acute urticaria, 86% experienced remission of symptoms within 2 weeks, and 6% experienced remission between 2 weeks and 1 month. Symptoms persisted for longer than 6 weeks in 8% of the patients.23 In those with chronic urticaria, symptoms resolve for 50% of patients within 1 year and for an additional 20% within 1 to 5 years. Symptoms persist for 20 years for 10% to 20% of patients.3 Physical urticarias tend to persist longer than chronic idiopathic urticaria.3 Patients who have had one episode of chronic urticaria might experience a later recurrence of symptoms.39