Author and Editor Disclosure

Synonyms and related keywords: urticaria, hives, acute urticaria, chronic urticaria, chronic idiopathic urticaria, CIU, angioedema, welts, pruritus, dermographism, erythema, itching, delayed pressure urticaria, urticarial vasculitis, anaphylaxis

Background

Urticaria, or hives, is a common skin condition that affects 15-25% of the population at some point in their lives. Most cases of urticaria are self-limited and of short duration, but when urticaria becomes chronic, it can be a very problematic and frustrating condition, both for the patient and for the clinician.

Urticaria is classified as either acute or chronic. Acute urticaria is defined as urticaria that has been present for less than 6 weeks. Chronic urticaria is defined as urticaria that has been continuously or intermittently present for at least 6 weeks. The 6-week period is a guide and not an absolute demarcation.

When no underlying cause is found, chronic urticaria is referred to as chronic idiopathic urticaria (CIU).

Angioedema is a condition that involves swelling of the deep dermal and subcutaneous/submucosal tissues. Some patients can have both urticaria and angioedema, occurring simultaneously or separately. Approximately 50% of patients have both urticaria and angioedema, while 40% have urticaria alone, and 10% have angioedema alone. See Angioedema for more details.

Pathophysiology

Skin lesions and pruritus occur, caused by an allergic or nonallergic mechanism.

Histamine is thought to be the most important biochemical mediator in urticaria. It is known to cause the classic wheal-and-flare response that is observed with urticaria and with positive results on allergy skin tests. Studies have shown that histamine is present in fluid taken from urticarial wheals.

Mast cells are the major histamine-releasing cells of the skin. Some studies report increased numbers of mast cells in urticarial lesions. The mast cell possesses high-affinity receptors for immunoglobulin E (IgE). In allergic reactions, adjacent IgE molecules, which are bound to the surface of mast cells by the high-affinity IgE receptors, are cross-linked by allergens, leading to the release of histamine and other mediators.

Histamine and the other mediators can be released by other nonallergic mechanisms as well. For example, neuropeptides are known to cause mast cell degranulation by a nonallergic mechanism. Neuropeptides may well be involved in dermographism and in emotional exacerbation of urticaria. In addition to histamine, other mast cell mediators are also thought to play a role in urticaria.

Basophils also possess the high-affinity IgE receptor and may be involved in urticaria. Other inflammatory cells (ie, vide infra) are recruited into the lesional area in urticaria, particularly in chronic urticaria. These cells can release cytokines and chemokines that can cause histamine release or otherwise contribute to the pathology.

Histopathology

A lymphocytic infiltrate is commonly found in the lesions of both acute and chronic types of urticaria. Some urticarial lesions have a mixed cellular infiltrate, ie, a mixture of lymphocytes, polymorphonuclear leukocytes (PMNs), and other inflammatory cells. This mixed type of infiltrate seems to be particularly characteristic of certain refractory forms of chronic urticaria, such as autoimmune-mediated urticaria (see Causes).

The mixed infiltrate is similar to the histopathology of the allergic late-phase response. Some patients with particularly severe or atypical urticaria are found to have vasculitis on skin biopsy. Indeed, a spectrum in histopathology seems to exist, ranging from lymphocytic to vasculitic, that correlates approximately with disease severity, from mild to severe.

Frequency

International

Urticaria (chronic, acute, or both) affects 15-25% of the population at some time in their lives. CIU affects up to 3% of the population at some time in their lives. The incidence of acute urticaria is higher in people with atopy. The incidence of chronic urticaria is not increased in people with atopy.

Mortality/Morbidity

• Mortality is rare, unless the condition is accompanied by severe anaphylaxis or severe respiratory tract angioedema.
• Morbidity depends on the severity and duration of the condition. Of patients who have CIU, up to 20% can have symptoms for longer than 10 years. Some studies show chronic urticaria to be quite debilitating. One study finds that urticaria patients can have as much psychological, social, and occupational distress as patients who are awaiting triple coronary artery bypass surgery.

Sex

Chronic urticaria affects females more often than males (the female-to-male ratio is approximately 4:1).

Age

Acute urticaria occurs most commonly in children and young adults. CIU is more common in adults; middle-aged women seem to be most affected.

History

• Typical features
• • Typical lesions are described as edematous pink or red wheals of variable size and shape, with surrounding erythema. The lesions are often described as welts or hives.
  • The lesions are generally pruritic. A painful or burning sensation may be described (such lesions are often associated with angioedema). Pruritus of nonlesional skin may also occur.
  • Dermographism is often observed in conjunction with urticaria. Itching, erythema, and a raised wheal occur in areas that are scratched or stroked (see Image 1). Patients also may report pressure-induced hives, which can occur with elastic or tight clothing.
  • Individual lesions usually fade within 24 hours, but new lesions may be developing continuously. With delayed pressure urticaria, lesions may last as long as 48 hours. The lesions of urticarial vasculitis, which are palpable and purpuric, may last for several days or more and may lead to residual hyperpigmented changes.
• Questions asked to determine possible allergic and nonallergic causes
• • Are the hives associated with any foods? Have any new foods been added to the diet?
  • Is the patient taking any regular medications or have any new medicines been started? In particular, ask about aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, over-the-counter medications, herbs, and supplements.
  • Does the patient have any recent or chronic infections?
  • Are the hives caused by any physical stimuli (eg, heat, cold, pressure, vibration)?
  • Does the patient have any chronic medical conditions?
  • Is the urticaria associated with any substances that are inhaled or in contact with the skin (which may occur in an occupational setting)?
  • Is the urticaria associated with insect bites or stings?

Physical

• If any features of anaphylaxis (eg, hypotension, respiratory distress, stridor, gastrointestinal distress) are present, immediate medical intervention should occur.
• Look for typical skin lesions, which are edematous pink or red wheals of variable size and shape, with surrounding erythema. Also, look for any atypical skin lesions. Lesions that are purpuric, nonblanchable, and palpable are characteristic of urticarial vasculitis. These lesions may leave residual pigmented changes. Tiny pinpoint hives are characteristic of cholinergic urticaria.
• Examine for dermographism. The skin can be scratched with the end of a tongue blade or similar blunt object and observed over the next 5-15 minutes for the development of whealing with erythema (see Image 1).
• Look for any features of angioedema (deep tissue or submucosal edema).
• The remainder of the physical examination should be used to investigate any suspicions that were raised by the history.

Causes

• Food allergies
• • Food allergy should be considered in acute urticaria and urticaria in children.
  • Food allergy is unlikely to be a cause in adults with chronic urticaria, especially if it is not obvious by the history. It occurs in fewer than 2% of cases.
  • Food additives or preservatives have been reported to be a cause of chronic urticaria in 3-4% of cases. Data are scarce and questionable.
• Drug allergies
• • Allergic reactions to a wide variety of drugs can occur. Theoretically, almost any drug can cause an allergic reaction.
  • Antibiotics, such as penicillin, have been implicated most frequently. Urticarial reactions to penicillin can occur as long as 14 days after a course of treatment has stopped. In this situation, serum sickness may be present.
• Contact urticaria is an allergic reaction to a substance that comes into contact with the skin (eg, an occupational exposure).
• Papular urticaria is a variation of urticaria caused by insect bites; the lesions may last longer than 24 hours.
• Other immediate hypersensitivity allergic reaction to an ingested, inhaled, or percutaneously inoculated substance (eg, latex, stinging insects, occupational exposures)
• Nonallergic release of mediators
• • A number of drugs, such as aspirin, NSAIDs, opiates, succinylcholine, and certain antibiotics (eg, polymyxin, ciprofloxacin, rifampin, vancomycin, some beta-lactams) can cause urticaria by a nonallergic mechanism rather than by IgE-mediated hypersensitivity.
  • Certain foods or beverages, such as spoiled fish (scombroidosis), aged cheeses, or red wine: These foods can contain histidine, which is closely related to histamine. These foods often are listed as causes of urticaria in the literature, but experimental evidence is scarce.
  • Certain venoms
  • Radiocontrast media sensitivity is not related to iodine, fish, or shellfish allergy.
• Medical causes
• • Infectious causes
  • • Urticaria has been reported with certain viral infections, such as acute viral syndromes, hepatitis (A, B, and C), Epstein-Barr virus, and herpes simplex virus. Urticaria has also been reported with chronic parasitic infections.
    • Urticaria may possibly be caused by sinusitis, cutaneous fungal infections, Helicobacter pylori infection, or other occult infection. These causes have been reported in the literature, but data are not strongly supported.
  • Hormonal causes
  • • Endocrine tumors (rare)
    • Ovarian pathology (rare)
    • Oral contraceptive use or changes in the menstrual cycle: Patients commonly report worsening of hives with the menstrual cycle. Be sure to consider cyclical use of analgesics as a possible etiology.
  • Cryoglobulinemias (eg, associated with hepatitis C, chronic lymphocytic leukemia)
  • Serum sickness
  • Other immune complex–mediated inflammation
  • Systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, or other rheumatological diseases (these are rare causes of urticaria)
  • Urticaria has been reported with both hypothyroidism and hyperthyroidism and in euthyroid patients with antithyroid antibodies (ie, vide infra).
  • Lymphoreticular malignancies (eg, chronic lymphocytic leukemia
• Physical causes (physical urticaria)
• • Cold
  • Pressure: A delayed response to pressure (delayed pressure urticaria) occurs in up to 40% of patients with CIU.
  • Vibration
  • Cholinergic (triggered by heat, exercise, or emotional stress)
  • Sunlight
  • Water
  • Dermographism can occur concomitantly with CIU.
  • Exercise
• Chronic idiopathic urticaria
• • Urticaria is classified as idiopathic when no specific cause is identified by history, physical examination, or laboratory findings.
  • Eighty to 90% of cases of chronic urticaria can be classified as idiopathic.
  • These patients may have concomitant physical urticaria.
  • Causes are separated into 2 categories, autoimmune or unknown.
• • Autoimmune causes
  • • Studies have shown that as many as 40-60% of cases of CIU have an autoimmune component. These studies found that sera from many of these patients, when injected intradermally, cause a wheal-and-flare reaction. This is called an autologous serum skin test. Furthermore, these sera can cause a release of histamine from basophils in vitro.
    • Further studies have found that 25-60% of patients have autoantibodies directed against their high-affinity IgE receptors. The role of these autoantibodies is still unclear. They may bind to the high-affinity IgE receptors on mast cells and basophils, triggering the release of mediators, in a process that is thought to be complement-dependent.
    • Five to 10% of patients have autoantibodies directed against the IgE molecule. The role of these autoantibodies is still unclear. They may attach to IgE molecules that are bound to mast cells (or basophils), triggering the release of mediators.
  • Unknown causes
  • • In the remaining 40-60% of cases of CIU, the cause is unidentified. Numerous other possible causes have been suggested but have not been substantiated in the literature.
    • A higher frequency of thyroid autoimmunity occurs in patients with chronic urticaria. These patients have autoantibodies directed against thyroid proteins but may be euthyroid. Some authors have found that treatment of these euthyroid patients with thyroxine leads to an improvement in urticaria, but other authors have not been able to reproduce this finding. Some have speculated that the thyroid autoantibodies cause inflammation in the thyroid, leading to release of cytokines, which, in turn, decreases the threshold for mast cell mediator release. Others have suggested that the thyroid autoantibodies are merely markers for autoimmunity. For example, patients with thyroid autoantibodies are more likely to have other autoantibodies, such as the anti-IgE receptor and anti-IgE discussed above.
    • Occult infections and food additives have been reported to be causes of CIU in a small number of patients, but the data are scarce and questionable, as discussed previously.
    • Other histamine-releasing factors in the serum that cause a wheal-and-flare reaction independent of IgE or the high-affinity IgE receptor may be present. Experimental evidence for this is lacking.

Angioedema
Erythema Multiforme (Stevens-Johnson Syndrome)
Mastocytosis, Systemic

Other Problems to be Considered

Bullous pemphigoid
Dermatitis herpetiformis
Chronic pruritus (nonurticarial)
Hypersensitivity vasculitis and/or urticarial vasculitis
Urticaria pigmentosa or other mast cell releasability syndromes
Pruritic urticarial papules and plaques of pregnancy (PUPPP), also referred to as polymorphic eruption of pregnancy (PEP)

Lab Studies

• Skin tests or radioallergosorbent assay test (specific IgE)
• • Selected allergy tests can be performed if food allergy or stinging insect hypersensitivity is suspected. Skin testing can be performed to detect hypersensitivity to a limited number of antibiotics. Testing for pollen or other inhalants is generally not helpful unless a severe allergy may be causing the urticaria, such as a severe allergy to pollens, cats, or latex (these may manifest as contact urticaria).
  • Routine allergy testing with a large battery of screening tests is not recommended.
  • A few research centers perform an autologous serum skin test, but it is not a well-established procedure currently.
• Screening laboratory studies
• • Which laboratory tests, if any, to order for routine screening is very controversial.
  • Many specialists order only a few select screening studies for patients who have chronic urticaria lasting at least 6 weeks with no apparent etiology.
  • Some choose to perform no testing at all. Laboratory testing for acute urticaria is not indicated, unless a particular medical condition is suspected.¹
  • Common screening laboratory tests that are ordered are as follows:
    • CBC with differential
    • Total eosinophil count
    • Sedimentation rate
    • Urinalysis
    • Liver function tests
  • Evaluation of the complement system, including total hemolytic complement (CH₅₀), C3, and C4 should be considered in patients with prominent angioedema and in patients with urticarial lesions lasting more than 24 hours. These tests are of no value in patients with classic chronic urticaria.
  • Thyroid studies, including thyroid autoantibody levels (antimicrosomal, antithyroglobulin) can be considered, particularly in women or in patients with a family history of thyroid disease or other autoimmune diseases.
  • Order other laboratory tests only if an abnormal result is found on the initial screening tests or if a specific medical condition is suspected. Evaluation for possible occult infection can be considered, but evidence that infections cause chronic urticaria is limited.
  • Other tests to consider if the history and physical examination findings are suggestive of specific problems include the following:
    • Chemistry panel
    • Stool analysis for ova and parasites
    • H pylori workup
    • Hepatitis B and C workup
    • Sinus radiography (if symptomatic)
    • Antinuclear antibody (ANA)
    • Rheumatoid factor
    • Cryoglobulin levels
    • Other imaging studies
  • Assays for serum histamine–releasing factors and evaluation for specific autoantibodies (anti-IgE receptor and anti-IgE) are performed by some research centers. These tests are not commercially available currently.
  • Patients with cold urticaria should be evaluated for cold agglutinins and cryoproteins because these are found in 5% of cases. The presence of a cryoglobulin suggests an underlying cause such chronic hepatitis (B or C) or lymphoreticular malignancy.

Other Tests

• Physical challenge tests can be performed if a physical urticaria is suspected. These include challenge with an ice cube, heat, pressure, light, scratching of the skin (dermographism), exercise, and vibration.

Procedures

• Skin biopsy is not indicated on a routine basis, but it should be considered if the urticaria does not respond to usual treatment or if any atypical features are present.

Medical Care

• Food/symptom diaries
• • For cases of acute urticaria (<6 wk) or to try to pinpoint a trigger, having the patient complete a food diary or symptom diary is sometimes helpful. For a preestablished duration (eg, 2 wk), the patient should record all foods that were eaten and all activities in which the patient was involved for 6-8 hours prior to the onset of an episode of urticaria.
  • In a small number of cases, a pattern may emerge, pinpointing the offending agent.
  • Excessive or prolonged use of a food or symptom diary is unlikely to be of benefit.
• Avoidance
• • If a trigger can be identified, avoidance is the most effective form of management. This would include any food, medication, physical agent, or other factor that triggers the urticaria.
  • Aspirin, NSAIDs, opiates, and alcohol have been reported to be nonspecific triggers of urticaria and might lower the threshold for urticaria in selected patients. Therefore, some specialists advise all patients with urticaria to avoid these agents. However, little experimental evidence is available to support this recommendation.
• Most cases of urticaria respond to pharmacotherapy (see Medication).
• Immunomodulatory and anti-inflammatory therapy
• • Intravenous gammaglobulin, plasmapheresis, and cyclosporin have been shown to be effective in urticaria in a limited number of studies. They can be a consideration in severe urticaria, particularly of the autoimmune type that is unresponsive to medications.
  • Colchicine and dapsone have also been reported to be useful for refractory urticaria and urticarial vasculitis, perhaps because of their ability to modulate PMN function. PMNs and a mixed infiltrate can be present in some urticarial lesions, particularly urticaria that is severe or refractory to antihistamine treatment.
  • Some reports describe the effectiveness of the antileukotriene agents in urticaria, but extensive clinical trials have not been performed, so their usefulness is still questionable. Clinical trials may support the theory that the antileukotriene agents can provide a synergistic response when used in conjunction with antihistamines.
  • Because the use of the aforementioned agents is not widespread, details of dosage and administration are not provided, but references are listed in the bibliography. The use of corticosteroids is more common and is discussed in Medication.
• Complementary and alternative medicine: Alternative therapies for urticaria have not been properly evaluated and, therefore, are not recommended.
• Potential therapies in the future: Because physicians now know that a large number of cases of CIU are actually autoimmune, targeting the autoimmune process may be a potential form of therapy.

Consultations

A primary care physician can manage most cases of acute urticaria, as well as uncomplicated cases of chronic urticaria.

If a trigger is easily identified and avoidance leads to resolution, then referral is not necessary. If an allergic trigger is suspected but not easily identified, then referral to an allergy specialist is warranted. Similarly, if avoidance of a trigger does not lead to resolution or if the patient does not respond well to antihistamines, then referral to an allergist or dermatologist is warranted.

Diet

Dietary modification is only necessary if food allergy or food additive hypersensitivity has been established. Food additives or preservatives have been reported to cause chronic urticaria in 3-4% of cases, but the data are scarce and questionable (see Causes).

Most cases of acute and chronic urticaria respond to pharmacotherapy. Use of antihistamines is the mainstay of therapy. In acute cases, a short course of steroids can be very effective. Long-term treatment with steroids should be avoided, if possible, but may be necessary in severe cases. A number of other classes of medicines have been found to be effective, mostly on an experimental basis. If urticaria does not respond to antihistamine treatment (with the possible addition of a short course of steroids), then referral to a specialist is indicated.

Drug Category: H1 antagonists (antihistamines)

Primary agents used for urticaria.² The older, first-generation H1 antagonists (eg, diphenhydramine, hydroxyzine) are effective in reducing the lesions and pruritus but can produce a number of adverse effects, such as drowsiness and anticholinergic effects.

They can be used as primary treatment of acute episodes, but the adverse effects may limit their usefulness for chronic urticaria. Some patients seem to develop a tolerance to the adverse effects with prolonged use, but they may still experience cognitive impairment, and their driving skills may still be affected.

The first-generation agents can sometimes be useful if administered at bedtime because the sedative effects can help with sleep, but the sedation and cognitive effects may continue until the next day. The newer second-generation antihistamines are nonsedating in most patients, with very few side effects reported (cetirizine can cause drowsiness in up to 10% of patients). Therefore, many specialists prefer the use of second-generation agents for chronic urticaria, with first-generation agents reserved for acute or refractory cases.

Any patient who is taking a medication that has potential sedative effects should be cautioned about driving and operating heavy machinery. Commonly used first-generation agents include diphenhydramine, hydroxyzine, doxepin, chlorpheniramine, and cyproheptadine. The second-generation agents that are currently available in the United States are cetirizine, levocetirizine, desloratadine, loratadine, and fexofenadine. All 4 are active in chronic urticaria. They have not been extensively compared with each other for this indication.

Drug Name	Diphenhydramine (Benadryl, Benylin)
Description	A common first-generation agent that is available without a prescription in the United States.
Adult Dose	25-50 mg PO/IV/IM q4-6h
Pediatric Dose	5 mg/kg/d PO/IV/IM divided tid/qid; not to exceed 300 mg/d
Contraindications	Documented hypersensitivity; MAOIs
Interactions	Potentiates effect of CNS depressants; due to alcohol content, do not administer syrup dosage form to patient taking medications that can cause disulfiramlike reactions
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May exacerbate glaucoma, hyperthyroidism, peptic ulcer, or urinary tract obstruction; xerostomia may occur

Drug Name	Hydroxyzine (Atarax, Vistaril, Vistazine)
Description	Effective first-generation agent, but frequently produces sedation. Considerable sedation may occur with higher doses. A drug of choice for primary acquired cold urticaria. SC and IV are not recommended administration routes.
Adult Dose	10-100 mg PO/IM q6-8h
Pediatric Dose	0.6 mg/kg/dose PO q6h 0.5-1 mg/kg/dose IM q4-6h
Contraindications	Documented hypersensitivity
Interactions	CNS depression may increase with alcohol or other CNS depressants
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Associated with clinical exacerbations of porphyria (may not be safe for porphyric patients); ECG abnormalities (alterations in T waves) may occur; may cause drowsiness

Drug Name	Doxepin (Sinequan)
Description	A tricyclic antidepressant that has potent H1-blocking activity, making it quite useful for urticaria. However, it has very potent sedative and anticholinergic effects. Can be quite effective if used at bedtime, because the sedative effects can help an itching patient sleep. Can be helpful for cold-induced urticaria.
Adult Dose	10-150 mg/d PO hs or divided bid/tid
Pediatric Dose	<12 years: Not recommended >12 years: 25-50 mg/d PO hs or bid/tid and increase gradually to 100 mg/d
Contraindications	Documented hypersensitivity; urinary retention; acute recovery phase following myocardial infarction; glaucoma
Interactions	Decreases antihypertensive effects of clonidine but increases effects of sympathomimetics and benzodiazepines; antagonized by phenytoin, carbamazepine, and barbiturates
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, hyperthyroidism, and patients receiving thyroid replacement therapy

Drug Name	Chlorpheniramine (Chlor-Trimeton)
Description	First-generation agent. One of the safest antihistamines to use during pregnancy.
Adult Dose	4 mg PO q4-6h 10-20 mg per dose IV/IM/SC; not to exceed 40 mg/d
Pediatric Dose	<2 years: Not established 2-6 years: 1 mg PO q4-6h; not to exceed 4 mg/d 6-12 years: 2 mg PO q4-6h; not to exceed 12 mg/d >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; asthma attacks; narrow-angle glaucoma; symptomatic prostate hypertrophy; bladder neck obstruction; pyloroduodenal obstruction
Interactions	CNS toxicity increases with coadministration of other CNS depressants, tricyclic antidepressants, MAOIs, and phenothiazines
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May cause significant confusional symptoms; not for administration to premature or full-term neonates

Drug Name	Cyproheptadine (Periactin)
Description	First-generation agent. A drug of choice for prophylaxis of primary acquired cold-induced urticaria.
Adult Dose	2-4 mg PO tid
Pediatric Dose	0.25 mg/kg/d PO divided bid/tid
Contraindications	Documented hypersensitivity; glaucoma; symptomatic prostatic hypertrophy; bladder neck obstruction; pyloroduodenal obstruction; severe lower respiratory tract symptoms
Interactions	Potentiates effects of CNS depressants; MAOIs may prolong and intensify anticholinergic and sedative effects of antihistamines
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in patients with a predisposition to urinary retention, poorly controlled asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease, or hypertension; may thicken bronchial secretions caused by anticholinergic properties and may inhibit expectoration and sinus drainage

Drug Name	Cetirizine (Zyrtec)
Description	Second-generation agent that is frequently used in urticaria. Once-daily dosing makes it convenient. Sedation occurs in approximately 10% of patients. Dosing qhs may be useful if sedation is a problem. Although the standard dose is 5-10 mg qd, some specialists increase this to 10 mg bid for chronic urticaria that is not responding to the usual FDA-approved maximum dose.
Adult Dose	5-10 mg PO qd
Pediatric Dose	<6 years: Not established >6 years: 5-10 mg PO qd
Contraindications	Documented hypersensitivity
Interactions	Increases CNS toxicity of depressants; theophylline decreases clearance of cetirizine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in hepatic or renal dysfunction; 10 mg/d may cause drowsiness in approximately 10% of patients

Drug Name	Levocetirizine (Xyzal)
Description	Histamine1-receptor antagonist. Active enantiomer of cetirizine. Peak plasma levels reached within 1 h and half-life is about 8 h. Available as a 5-mg breakable (scored) tab. Indicated for uncomplicated skin manifestations of chronic idiopathic urticaria
Adult Dose	5 mg PO qd in evening CrCl 50-80 mL/min: 2.5 mg (half tab) PO qd in evening CrCl 30-49 mL/min: 2.5 mg PO qod CrCl 10-29 mL/min: 2.5 mg PO 2 times/wk
Pediatric Dose	<6 years: Not established 6-11 years: 2.5 mg (half tab) PO qd in evening >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; CrCl <10 mL/min or hemodialysis; children aged 6-11 y with renal impairment
Interactions	Coadministration with CNS depressants (eg, alcohol, sedative-hypnotics) may increase somnolence; ritonavir increased plasma AUC of measurable cetirizine by 42% and half-life by 53%
Pregnancy	B - Usually safe but benefits must outweigh the risks
Precautions	Common adverse effects include somnolence, nasopharyngitis, fatigue, xerostomia, and pharyngitis in adults and children >12 y; pyrexia, somnolence, cough, and epistaxis commonly observed in children 6-12 y; caution with activities requiring mental alertness

Drug Name	Loratadine (Claritin)
Description	Tolerated very well, with a rate of sedation that is not significantly different from placebo. The once daily dosing makes it convenient.
Adult Dose	10 mg PO qd
Pediatric Dose	<6 years: Not established >6 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Ketoconazole, erythromycin, procarbazine, and alcohol may increase loratadine levels
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Initiate therapy at lower dose in liver impairment; caution in pregnancy and lactation

Drug Name	Desloratadine (Clarinex)
Description	Long-acting tricyclic histamine antagonist selective for H1 receptor. Is a major metabolite of loratadine, which, after ingestion, is metabolized extensively to active metabolite 3-hydroxydesloratadine.
Adult Dose	5 mg PO qd
Pediatric Dose	<12 years: Not established >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Limited data exist; erythromycin and ketoconazole increase desloratadine and 3-hydroxydesloratadine plasma concentrations, but no increase in clinically relevant adverse effects, including QTc, was observed
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Decrease dose in hepatic impairment; rarely causes pharyngitis or dry mouth

Drug Name	Fexofenadine (Allegra)
Description	A second-generation agent that is effective in urticaria. Tolerated very well, with a rate of sedation that is not significantly different from placebo.
Adult Dose	60 mg IR PO bid (maximum FDA-approved dose) or 180 mg SR PO qd
Pediatric Dose	<6 years: Not established 6-11 years: 30 mg PO bid >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Levels may increase with coadministration of erythromycin and ketoconazole
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adjust dose in renal impairment; caution in pregnancy and lactation

Drug Category: H2 antagonists (antihistamines)

These drugs are usually used to decrease gastric acid secretion. When used as a single agent for urticaria, they are not effective. However, the combination of an H1 antagonist with an H2 antagonist has been shown to be more effective than an H1 antagonist alone. Any of the H2 blockers can be used. Two of the most commonly used agents are ranitidine and cimetidine.

Drug Name	Cimetidine (Tagamet)
Description	If no response to H1 antagonist alone occurs, coadministration with this H2 antagonist can be useful to treat urticaria.
Adult Dose	300 mg PO qid or 400 mg PO bid
Pediatric Dose	Infants: 10-20 mg/kg/d PO q6h Children: 20-40 mg/kg/d PO in divided doses separated at least 6 h
Contraindications	Documented hypersensitivity
Interactions	Can increase blood levels of theophylline, warfarin, tricyclic antidepressants, triamterene, phenytoin, quinidine, propranolol, metronidazole, procainamide, and lidocaine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Elderly patients may experience confusional states; may cause impotence and gynecomastia in young males; may increase levels of many drugs; adjust dose or discontinue treatment if changes in renal function occur

Drug Name	Ranitidine (Zantac)
Description	H2 antagonist that, when combined with an H1 type, may be useful in treating urticaria when urticaria is not responsive to H1 antagonists alone.
Adult Dose	150 mg PO bid
Pediatric Dose	1.5-2 mg/kg per dose PO bid
Contraindications	Documented hypersensitivity
Interactions	May alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal function or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment

Drug Category: Corticosteroids

In some instances of acute or chronic urticaria, antihistamines may fail. Mediators other than histamine may be involved. In such situations, urticaria should respond to corticosteroids. If not, then consider the possibility of another disease process (eg, malignancy, mastocytosis, vasculitis). Corticosteroids may also be used in urticarial vasculitis, which usually does not respond to antihistamines.

A short course of an oral corticosteroid (administered daily for 5-7 d, with or without a taper) or a single dose of a long-acting injectable steroid is not usually associated with long-term sequelae and can be helpful when used for an acute episode of urticaria nonresponsive to antihistamines.

Because of adverse effects of chronic or recurrent use of systemic corticosteroids, the long-term use of these agents should be avoided in chronic urticaria, when possible. If urticaria is severe and cannot be safely controlled with other medications, low-dose therapy and/or alternate day therapy can be considered.

A large number of preparations are available. Representative examples are prednisone, prednisolone, methylprednisolone, and triamcinolone.

Drug Name	Prednisolone (Pediapred, Prelone, Delta-Cortef)
Description	Available in both tablet and liquid forms. Reduces capillary permeability.
Adult Dose	40-60 mg/d PO divided 1-2 doses/d
Pediatric Dose	0.5-2 mg/kg/d PO divided 2-4 doses/d
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin diseases
Interactions	Decreases effects of toxoids (for immunizations); phenytoin, carbamazepine, barbiturates, and rifampin decrease effects of corticosteroids
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, and infections may occur with glucocorticoid use

Drug Name	Methylprednisolone (Medrol, Depo-Medrol, Solu-Medrol)
Description	For treatment of severe urticaria reactions. Reverses increased capillary permeability.
Adult Dose	4-48 mg/d PO Acetate/Depo-Medrol: 40-120 mg IM single dose; should not be repeated because knowing whether urticaria has resolved due to the prolonged effect of this medication is difficult Sodium succinate/Solu-Medrol: 10-60 mg/dose IV/IM; this drug is most often used for acute urticaria associated with an allergic emergency and is not used for chronic urticaria
Pediatric Dose	0.16-0.8 mg/kg/d PO divided bid/qid Sodium succinate/Solu-Medrol: 0.5-2 mg/kg per dose IV/IM repeated at intervals depending on clinical response; this drug is most often used for acute urticaria associated with an allergic emergency and is not used for chronic urticaria
Contraindications	Documented hypersensitivity; viral, fungal or tubercular infections
Interactions	Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

Drug Name	Prednisone (Deltasone, Orasone, Meticorten)
Description	A commonly used oral agent. Must be metabolized to the active metabolite prednisolone for effect. Conversion may be impaired in liver disease.
Adult Dose	40-60 mg/d PO divided 1-2 doses per d
Pediatric Dose	0.5-2 mg/kg/d PO divided 1-4 doses per d
Contraindications	Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; active peptic gastrointestinal bleeding
Interactions	Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Category: Adrenergic agents

For use if urticaria is accompanied by a potentially life-threatening condition, such as anaphylactic shock, respiratory tract angioedema (which may manifest as stridor), or significant wheezing.

Drug Name	Epinephrine (Adrenalin, Sus-Phrine, Epi-Pen, Ana-Guard)
Description	Not indicated in uncomplicated urticaria. Any patient who has had a potentially life-threatening allergic reaction should have injectable epinephrine available for use at all times (eg, portable Epi-Pen). Any use of epinephrine necessitates an immediate evaluation in the nearest emergency department.
Adult Dose	0.2-0.5 mg IM/SC single dose; can be repeated in 15- to 20-min intervals prn IM administration has been associated with a faster time of onset than SC when studied in pediatric and adult populations
Pediatric Dose	0.01 mg/kg, up to 0.5 mg, IM/SC single dose; can be repeated in 15- to 20-min intervals prn IM administration has been associated with a faster time of onset than SC when studied in pediatric and adult populations
Contraindications	Documented hypersensitivity; coronary insufficiency; cardiac arrhythmias; glaucoma; local anesthesia in areas such as fingers or toes because vasoconstriction may produce sloughing of tissue; use with caution during labor (may delay second stage of labor)
Interactions	Increases toxicity of beta- and alpha-blocking agents and that of halogenated inhalational anesthetics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in elderly patients and patients with diabetes mellitus, cardiovascular diseases, hyperthyroidism, cerebral arteriosclerosis, Parkinson disease, and pregnancy

Prognosis

• Acute urticaria usually resolves with only symptomatic treatment. If a known triggering factor is present, the urticaria should resolve with appropriate avoidance. If a patient continues to be exposed to a known trigger, the condition may become chronic.
• The prognosis of patients with chronic urticaria is highly variable. Episodes can last for days, weeks, months, or even years at a time. Some patients may only have one episode and never have urticaria again. Others have recurrences after months or years. Recurrences are more likely to occur during periods of stress and illness. As many as 20% of patients with chronic urticaria have symptoms for more than 10 years. In many of these patients, the condition can become quite debilitating and psychologically distressing.

Patient Education

• For excellent patient education resources, visit eMedicine's Allergy Center and Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Hives and Angioedema.

Medical/Legal Pitfalls

• The major potential pitfall is failure to recognize when urticaria is accompanied by life-threatening angioedema or anaphylaxis. Discuss a detailed management plan with patients who have had previous life-threatening events or who are at risk for life-threatening angioedema or anaphylaxis, and prescribe injectable epinephrine.
• Another potential pitfall is failure to diagnose one of the related medical conditions noted in Differentials.