eMedicine Specialties > Allergy and Immunology > Urticaria and Angioedema

Urticaria

Javed Sheikh, MD, Assistant Professor of Medicine, Harvard Medical School; Clinical Director, Division of Allergy and Inflammation, Beth Israel Deaconess Medical Center; Clinical Director, Center for Eosinophilic Disorders, Beth Israel Deaconess Medical Center
Umer Najib, MD, Clinical Research Fellow, Department of Medicine, Division of Allergy and Inflammation, Beth Israel Deaconess Medical Center

Updated: Jun 5, 2009

Introduction

Background

Urticaria, or hives, is a common skin condition that affects 15-25% of the population at some point in their lives.¹ 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.¹ 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.² See eMedicine article 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.³ 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.⁴ Some studies report increased numbers of mast cells in urticarial lesions.¹ The mast cell possesses high-affinity receptors for immunoglobulin E (IgE).⁴ 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.⁵

Basophils also possess the high-affinity IgE receptor and may be involved in urticaria.⁶ Some patients with CIU may have underlying structural or functional defects in mast cells or basophils.^7,8,9,10 The clinical role of these varying mast cell or basophil phenotypes is not yet known. One group found increased expression of the cytoplasmic phosphatase SHIP-2 (Src homology domain 2–containing-5'-inositol phosphatase) as a possible explanation for decreased basophil responsiveness to stimulation with polyclonal anti-IgE,¹¹ but the role (if any) of this increased phosphatase expression in the pathophysiology of CIU is not yet known, and decreased responsiveness of basophils might be a consequence of having urticaria rather than its cause.¹²

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.¹³ 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.¹⁴ 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.¹ CIU affects up to 0.5-1.5% of the population at some time in their lives.¹⁵ The incidence of acute urticaria is higher in people with atopy.¹ 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 upper 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.¹⁶

Sex

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

Clinical

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.¹⁷ A painful or burning sensation may be described (such lesions are often associated with angioedema).¹⁸ 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.¹⁹ Patients also may report pressure-induced hives, which can occur with elastic or tight clothing.²⁰
    
    

    

    Photograph of dermographism.

    
    
  • Individual lesions usually fade within 24 hours or so, 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.¹⁴
• 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 (e.g. 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.²¹
• 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.
  
  

  

  Photograph of dermographism.

  
  
• Look for any features of angioedema (deep tissue or submucosal edema).²²
• 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.^12,23,24 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.
    
    

    

    Urticaria associated with a drug reaction.

    
    
  • Antibiotics, such as penicillin, have been implicated most frequently.²⁵ 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)
  
  

  

  Urticaria developed after bites from an imported fire ant.

  
  
  
  

  

  Local urticaria on a patient with latex allergy who was touched with a latex glove.

  
  
• 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.^{12,26,27,28,29}
  • 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. This may be hormonally mediated, but 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 antibodies³⁰ (ie, vide infra).
  • Lymphoreticular malignancies (eg, chronic lymphocytic leukemia)
• Physical causes (physical urticaria)
  • Cold
  • Pressure: In addition to being an isolated cause of urticaria, a delayed response to pressure (delayed pressure urticaria) occurs in up to 40% of patients with chronic idiopathic urticaria (CIU).
  • Vibration
  • Cholinergic (triggered by heat, exercise, or emotional stress)
  • Sunlight
  • Water
  • Dermographism (can occur as an isolated condition; can occur concomitantly with CIU in about 50% of cases)
  • Exercise
• Chronic idiopathic urticaria (CIU)
  • 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.¹³
  • These patients may have concomitant physical urticaria.
  • Idiopathic CIU can be separated into 2 categories, autoimmune and unknown.
  • Autoimmune component
    • Studies have shown that as many as 40-60% of cases of CIU have an autoimmune component.¹³ These studies found that sera from many of these patients, when injected intradermally, cause a wheal-and-flare reaction.^13,31 This is called an autologous serum skin test. Furthermore, these sera can cause a release of histamine from basophils in vitro.^7,31,32
    • Further studies have found that 25-60% of patients have autoantibodies directed against high-affinity IgE receptors.^33,34 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.^33,34 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 cause or association
    • 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.
    • As discussed previously, preliminary evidence has shown that some patients with CIU appear to have abnormal basophil signaling, with hyporesponsive basophils, but the pathophysiological role of this is still unknown.^{7,8,9,10,11,12}
    • A higher frequency of thyroid autoimmunity occurs in patients with chronic urticaria.³⁰ 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,³⁵ but other authors have not been able to reproduce this finding.³⁶ 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, but this finding is not absolute.³⁷
    • 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.

Differential Diagnoses

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

Other Problems to Be Considered

Workup

Laboratory Studies

• Skin tests or radioallergosorbent assay test (specific IgE)
  • Selected allergy tests can be performed if food allergy or stinging insect hypersensitivity is suspected. This may be helpful for some cases of acute urticaria but is rarely helpful in the evaluation of chronic urticaria.¹² 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.³⁸
  • Common screening laboratory tests that may be 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, although the clinical significance of finding positive titers in a euthyroid individual is still unclear.
  • Order 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 workup³⁹
    • 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/anti-FcεR1 and anti-IgE) have performed by some research centers, and can now be ordered through certain commercial laboratories.^40,41 Currently, 2 reference labs in the United States commercially offer such a test: IBT Reference Laboratory (with the test referred to as the “CU Index^TM ”) and Clinical Reference Laboratories at National Jewish Medical and Research Center (with the test referred to as the “Anti-FcεRI antibody”).^42,43 The role of a positive versus negative test finding on these assays is still unclear, as current evidence does not make clear whether a positive result should change management.
  • 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. These tests, however, are generally unnecessary in routine CIU.

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. With the exception of testing for dermographism, these tests are usually performed only by specialty centers.

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, such as those of vasculitis or cutaneous lymphoma, are present.¹⁴

Treatment

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,^44,45 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
  • Cyclosporin has been shown to be effective in two double-blind placebo-controlled studies. Intravenous gammaglobulin and plasmapheresis have been described as useful in a limited number of case studies.^46,47,48,49 They can be a consideration in severe urticaria, particularly of the autoimmune type that is unresponsive to medications, but such treatment is usually only initiated by specialists with considerable expertise in urticaria.
  • Colchicine and dapsone have also been reported to be useful for refractory urticaria and urticarial vasculitis,^50,51 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,^52,53 but extensive clinical trials have not been performed, so their usefulness is still questionable. Clinical trials might in the future support the theory that the antileukotriene agents can provide a synergistic response when used in conjunction with antihistamines.
  • Early case reports and a clinical trial of omalizumab (monoclonal antibody to IgE) in chronic urticaria appear promising, but considerable further study is needed.⁵⁴
  • 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 appear to be autoimmune, focused targeting of the autoimmune process may be a potential form of therapy if the autoimmune cause is further verified in clinical studies.

Consultations

A primary care provider 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.⁵⁵ 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.⁵⁵

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).

Medication

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.

H1 antagonists (antihistamines)

Primary agents used for urticaria.²⁵ 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).⁵⁶ Therefore, many specialists prefer the use of second-generation agents for chronic urticaria, with first-generation agents reserved for acute or refractory cases. The experimental evidence comparing the various possible regimens and rates of adverse effects in the long term is still minimal.

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 five are active in chronic urticaria. They have not been extensively compared with each other for this indication.

Loratadine (Claritin)

Tolerated very well, with a rate of sedation that is not significantly different from placebo. The once-daily dosing makes it convenient.

Dosing

Adult

10 mg PO qd

Pediatric

<6 years: Not established
>6 years: Administer as in adults

Interactions

Ketoconazole, erythromycin, procarbazine, and alcohol may increase loratadine levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Initiate therapy at lower dose in liver impairment; caution in pregnancy and lactation

Desloratadine (Clarinex)

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.

Dosing

Adult

5 mg PO qd

Pediatric

<12 years: Not established
>12 years: Administer as in adults

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

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Decrease dose in hepatic impairment; rarely causes pharyngitis or dry mouth

Fexofenadine (Allegra)

A second-generation agent that is effective in urticaria.⁵⁷ Tolerated very well, with a rate of sedation that is not significantly different from placebo.

Dosing

Adult

60 mg IR PO bid (maximum FDA-approved dose) or 180 mg SR PO qd

Pediatric

<6 years: Not established
6-12 years: 30 mg PO bid
>12 years: Administer as in adults

Interactions

Levels may increase with coadministration of erythromycin and ketoconazole

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adjust dose in renal impairment; caution in pregnancy and lactation

Levocetirizine (Xyzal)

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

Dosing

Adult

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

<6 years: Not established
6-12 years: 2.5 mg (half tab) PO qd in evening
>12 years: Administer as in adults

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%

Contraindications

Documented hypersensitivity; CrCl <10 mL/min or hemodialysis; children aged 6-11 y with renal impairment

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

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

Cetirizine (Zyrtec)

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.

Dosing

Adult

5-10 mg PO qd

Pediatric

<6 years: Not established
>6 years: 5-10 mg PO qd

Interactions

Increases CNS toxicity of depressants; theophylline decreases clearance of cetirizine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in hepatic or renal dysfunction; 10 mg/d may cause drowsiness in approximately 10% of patients

Diphenhydramine (Benadryl, Benylin)

A common first-generation agent that is available without a prescription in the United States.

Dosing

Adult

25-50 mg PO/IV/IM q4-6h

Pediatric

5 mg/kg/d PO/IV/IM divided tid/qid; not to exceed 300 mg/d

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

Contraindications

Documented hypersensitivity; MAOIs

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May exacerbate glaucoma, hyperthyroidism, peptic ulcer, or urinary tract obstruction; xerostomia may occur

Cyproheptadine (Periactin)

First-generation agent. Historically has been a drug of choice for prophylaxis of primary acquired cold-induced urticaria.

Dosing

Adult

2-4 mg PO tid

Pediatric

0.25 mg/kg/d PO divided bid/tid

Interactions

Potentiates effects of CNS depressants; MAOIs may prolong and intensify anticholinergic and sedative effects of antihistamines

Contraindications

Documented hypersensitivity; glaucoma; symptomatic prostatic hypertrophy; bladder neck obstruction; pyloroduodenal obstruction; severe lower respiratory tract symptoms

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

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

Chlorpheniramine (Chlor-Trimeton)

First-generation agent. One of the safest antihistamines to use during pregnancy.

Dosing

Adult

4 mg PO q4-6h
10-20 mg per dose IV/IM/SC; not to exceed 40 mg/d

Pediatric

<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

Interactions

CNS toxicity increases with coadministration of other CNS depressants, tricyclic antidepressants, MAOIs, and phenothiazines

Contraindications

Documented hypersensitivity; asthma attacks; narrow-angle glaucoma; symptomatic prostate hypertrophy; bladder neck obstruction; pyloroduodenal obstruction

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause significant confusional symptoms; not for administration to premature or full-term neonates

Hydroxyzine (Atarax, Vistaril, Vistazine)

Effective first-generation agent, but frequently produces sedation, particularly with higher doses. Historically has been considered a drug of choice for cholinergic urticaria. SC and IV are not recommended administration routes.

Dosing

Adult

10-100 mg PO/IM q6-8h

Pediatric

0.6 mg/kg/dose PO q6h
0.5-1 mg/kg/dose IM q4-6h

Interactions

CNS depression may increase with alcohol or other CNS depressants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

Doxepin (Sinequan)

A tricyclic antidepressant that has potent H1-blocking activity as well as H2 blocking activity, making it quite useful for urticaria.⁵⁸ 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.

Dosing

Adult

10-150 mg/d PO hs or divided bid/tid

Pediatric

<12 years: Not recommended
>12 years: 25-50 mg/d PO hs or bid/tid and increase gradually to 100 mg/d

Interactions

Decreases antihypertensive effects of clonidine but increases effects of sympathomimetics and benzodiazepines; antagonized by phenytoin, carbamazepine, and barbiturates

Contraindications

Documented hypersensitivity; urinary retention; acute recovery phase following myocardial infarction; glaucoma

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, hyperthyroidism, and patients receiving thyroid replacement therapy

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.⁵⁹ Any of the H2 blockers can be used. Two of the most commonly used agents are ranitidine and cimetidine.

Cimetidine (Tagamet)

If no response to H1 antagonist alone occurs, coadministration with this H2 antagonist can be useful to treat urticaria.

Dosing

Adult

300 mg PO qid or 400 mg PO bid

Pediatric

Infants: 10-20 mg/kg/d PO q6h
Children: 20-40 mg/kg/d PO in divided doses separated at least 6 h

Interactions

Can increase blood levels of theophylline, warfarin, tricyclic antidepressants, triamterene, phenytoin, quinidine, propranolol, metronidazole, procainamide, and lidocaine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

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

Ranitidine (Zantac)

H2 antagonist that, when combined with an H1 type, may be useful in treating urticaria when urticaria is not responsive to H1 antagonists alone.

Dosing

Adult

150 mg PO bid

Pediatric

1.5-2 mg/kg per dose PO bid

Interactions

May alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal function or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment

Corticosteroids

In some instances of acute or chronic urticaria, antihistamines may fail, even at high doses, or side effects may be problematic. 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.²

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.

Prednisolone (Pediapred, Prelone, Delta-Cortef)

Available in both tablet and liquid forms. Reduces capillary permeability.

Dosing

Adult

40-60 mg/d PO qd or divided bid

Pediatric

0.5-2 mg/kg/d PO divided bid/qid

Interactions

Decreases effects of toxoids (for immunizations); phenytoin, carbamazepine, barbiturates, and rifampin decrease effects of corticosteroids

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin diseases

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

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

Methylprednisolone (Medrol, Depo-Medrol, Solu-Medrol)

For treatment of severe urticaria reactions. Reverses increased capillary permeability.

Dosing

Adult

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

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

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

Contraindications

Documented hypersensitivity; viral, fungal or tubercular infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

Prednisone (Deltasone, Orasone, Meticorten)

A commonly used oral agent. Must be metabolized to the active metabolite prednisolone for effect. Conversion may be impaired in liver disease.

Dosing

Adult

40-60 mg/d PO divided 1-2 doses/d

Pediatric

0.5-2 mg/kg/d PO divided 1-4 doses/d

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

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; active peptic gastrointestinal bleeding

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

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.

Epinephrine (Adrenalin, Sus-Phrine, Epi-Pen, Ana-Guard, Twinject)

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. Intramuscular administration of epinephrine is preferred over subcutaneous.

Dosing

Adult

0.2-0.5 mg IM/SC single dose; can be repeated in 15- to 20-min intervals prn
Most single-dose autoinjectors administer a dose of 0.3 mg
IM administration has been associated with a faster time of onset than SC when studied in pediatric and adult populations

Pediatric

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

Interactions

Increases toxicity of beta- and alpha-blocking agents and that of halogenated inhalational anesthetics

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)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in elderly patients and patients with diabetes mellitus, cardiovascular diseases, hyperthyroidism, cerebral arteriosclerosis, Parkinson disease, and pregnancy

Follow-up

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.

Miscellaneous

Medicolegal 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.

Multimedia

Media file 1: Photograph of dermographism.

Media file 2: Urticaria associated with a drug reaction.

Media file 3: Urticaria developed after bites from an imported fire ant.

Media file 4: Local urticaria on a patient with latex allergy who was touched with a latex glove.

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Keywords

urticaria, hives, acute urticaria, chronic urticaria, chronic idiopathic urticaria, CIU, angioedema, welts, pruritus, dermographism, erythema, itching, delayed pressure urticaria, urticarial vasculitis, anaphylaxis

Contributor Information and Disclosures

Author

Javed Sheikh, MD, Assistant Professor of Medicine, Harvard Medical School; Clinical Director, Division of Allergy and Inflammation, Beth Israel Deaconess Medical Center; Clinical Director, Center for Eosinophilic Disorders, Beth Israel Deaconess Medical Center
Javed Sheikh, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology and American College of Allergy, Asthma and Immunology
Disclosure: UCB Honoraria Speaking and teaching; Sanofi-Aventis Honoraria Speaking and teaching; GlaxoSmithKline Grant/research funds Clinical Trial funding; GlaxoSmithKline Consulting fee Review panel membership; Novartis Honoraria Speaking and teaching; Genentech Honoraria Speaking and teaching; MedPointe Pharmaceuticals  Speaking and teaching

Coauthor(s)

Umer Najib, MD, Clinical Research Fellow, Department of Medicine, Division of Allergy and Inflammation, Beth Israel Deaconess Medical Center
Disclosure: Nothing to disclose.

Medical Editor

Stephen C Dreskin, MD, PhD, Director of Allergy, Asthma, and Immunology Practice, Professor of Medicine, Departments of Internal Medicine and Immunology, University of Colorado Health Sciences Center
Stephen C Dreskin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association for the Advancement of Science, American Association of Immunologists, American Association of Neuropathologists, American Association of Ophthalmic Pathologists, American Association of Oral and Maxillofacial Surgeons, American College of Allergy, Asthma and Immunology, Clinical Immunology Society, and Joint Council of Allergy, Asthma and Immunology
Disclosure: Genentech Consulting fee Consulting

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Stephen C Dreskin, MD, PhD, Director of Allergy, Asthma, and Immunology Practice, Professor of Medicine, Departments of Internal Medicine and Immunology, University of Colorado Health Sciences Center
Stephen C Dreskin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association for the Advancement of Science, American Association of Immunologists, American Association of Neuropathologists, American Association of Ophthalmic Pathologists, American Association of Oral and Maxillofacial Surgeons, American College of Allergy, Asthma and Immunology, Clinical Immunology Society, and Joint Council of Allergy, Asthma and Immunology
Disclosure: Genentech Consulting fee Consulting

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Michael A Kaliner, MD, Clinical Professor of Medicine, George Washington University School of Medicine; Chief, Section of Allergy and Immunology, Washington Hospital Center; Medical Director, Institute for Asthma and Allergy
Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, and Association of American Physicians
Disclosure: Abbott Consulting fee Consulting; Alcon Consulting fee Consulting; Glaxo Consulting fee Consulting; Greer Consulting fee Consulting; Sanofi Consulting fee Consulting; Schering Consulting fee Consulting; Teva  Consulting; Meda Honoraria Speaking and teaching

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