eMedicine Specialties > Dermatology > Allergy & Immunology

Urticaria, Chronic

Daniel J Hogan, MD, Clinical Professor of Internal Medicine (Dermatology), NOVA Southeastern University; Investigator, Hill Top Research, Florida Research Center

Updated: Oct 23, 2009

Introduction

Background

Chronic urticaria, defined as urticaria that persists for longer than 6 weeks, is a frustrating condition for both patients and caregivers. Urticaria is not a single disease but a reaction pattern that represents cutaneous mast cell degranulation, resulting in extravasation of plasma into the dermis. Urticaria is characterized by hives or wheals, which are edematous pruritic papules or plaques. The variety of potential triggers of urticaria, especially for acute urticaria, can make the approach to diagnosis and treatment a challenge. Patients with chronic urticaria may not improve or may depend on medication for years to relieve symptoms.

The primary subgroups of chronic urticaria include physical urticaria (ie, symptomatic dermatographism, cholinergic urticaria, pressure urticaria), urticaria secondary to an underlying medical condition, and chronic idiopathic urticaria. Physical urticaria, which is reproducible with the appropriate stimuli, can be identified with a thorough history and challenge testing.

Pathophysiology

The mast cell is the primary agent in the pathogenesis of urticaria. Mast cell stimulation results in the release of both preformed (histamine) and newly formed (prostaglandins) mediators from cytoplasmic granules, which cause wheal formation, vasodilatation, and erythema. Mast cells also release chemoattractants for other cells (eg, neutrophils) that also are involved in wheal formation. A number of mediators may be involved in the pathogenesis of urticaria, which may explain why antihistamines are not always effective therapy.

After eliminating the physical urticarias and urticarial vasculitis, chronic urticaria can be divided into autoimmune chronic urticaria (45%) and idiopathic chronic urticaria (55%).² Immunoglobulin G autoantibodies to the alpha subunit of the Fc receptor of the immunoglobulin E (IgE) molecule (35-40%) or, less commonly, anti-IgE autoantibodies (5-10%), can activate basophils to release histamine. This response may be augmented by complement activation and production of C5a. Unlike pulmonary mast cells, cutaneous mast cells have C5a receptors. C5a not only brings about mast cell activation, but is also a neutrophil and eosinophil chemoattractant, leading to accumulation of these cells in lesional skin. 
 
Dermal mast cells secrete preformed mediators, including histamine (mainly the cause of pruritus.), proteases, interleukin 1, and tumor necrosis factor-alpha. The cytokines cause increased expression of adhesion molecules by endothelium of postcapillary venules.

Approximately one third of patients with chronic urticaria have either or both antithyroglobulin antibody and antimicrosomal antibody, and up to one fifth have abnormal thyroid function. A positive functional anti-FcεR test result supports an autoimmune basis. A positive test result does not indicate which autoantibody (anti-IgE, anti-FcεRI, or anti-FcεRII) is present. Affected patients may be categorized as having autoimmune chronic urticaria.

Other non–IgE-mediated mast cell degranulators include radiocontrast media, morphine, codeine, and vancomycin. Approximately one third of patients with chronic urticaria may develop angioedema after administration of aspirin or other nonsteroidal anti-inflammatory drugs.³

Approximately 85% of histamine receptors in the skin are of the H1 subtype, with the remaining 15% being H2 receptors. The addition of an H2 receptor antagonist to an H1 receptor antagonist augments the inhibition of a histamine-induced wheal-and-flare reaction once histamine-receptor blockade has been maximized. The combination of H2 receptor antagonists with an H1 receptor antagonist provides small additional benefit. Doxepin blocks both types of histamine receptors and is a much more potent inhibitor of H1 receptors than diphenhydramine or hydroxyzine.

Food allergy is rarely the basis of chronic urticaria.

Frequency

United States

Chronic urticaria is less common than acute urticaria. Urticaria affects 15-20% of the population at some point in their lives, but the urticaria persists daily or almost daily for more than 6 weeks in only approximately 1% of the population.

International

The incidence is the same as in the United States.

Mortality/Morbidity

Unlike angioedema, which may affect the airway, urticaria is not a life-threatening disease; however, chronic urticaria has been shown to have a negative impact on the quality of life of affected patients.⁴ In a study by O'Donnell et al, the effects of chronic urticaria on the activities of daily living, social interactions, rest, and work were found to be similar to those experienced by patients with heart disease.⁵ These findings were confirmed by a more recent French/German study, which suggested that physicians discuss the emotional aspect of chronic urticaria with patients if time allows.⁶

Race

Urticaria affects persons of all races.

Sex

Both sexes are affected; however, urticaria is more common in women, especially in middle-aged women. Chronic idiopathic urticaria occurs twice as often in women as in men.

Age

Chronic urticaria is reported to be more common in adults, while acute urticaria is more common in children.

Clinical

History

An important historical characteristic of urticarial lesions is their transient nature. An individual wheal typically lasts for less than 24 hours. Pruritus is the most common associated symptom. If lesions last longer and are associated with pigmentary changes or symptoms (eg, pain or burning), consider performing a biopsy to exclude urticarial vasculitis.

Individual wheals last less than 1 hour in persons with physical urticaria, except for delayed pressure urticaria, in which individual wheals last at least 8-48 hours, especially on the palms and soles.

Physical

The typical lesion of urticaria is a pale-to-red, well-demarcated papule or plaque. Lesions may be round, oval, annular, arcuate, serpiginous, or generalized. They resolve without postinflammatory pigmentary changes or scaling.

• Primary lesion: They are edematous erythematous papules or plaques with a pale center (wheal) and surrounding erythema (flare).
• Distribution of lesions: Lesions can be localized or generalized.
• Color of lesions: Depending on background skin color, lesions may be pale to red.
• Differentiation: Stroking the skin firmly tests for symptomatic dermatographism. Exercise testing can confirm cholinergic urticaria. Application of an ice cube to the skin may test for cold urticaria.

Causes

A number of factors have been reported to cause chronic urticaria, and these include the following:

• Medications: Urticaria may be caused or exacerbated by a number of drugs. More common culprits include aspirin, other nonsteroidal anti-inflammatory drugs, opioids, ACE inhibitors, and alcohol.
• Contactants: Contact urticaria syndrome refers to the onset of urticaria within 30-60 minutes of contact with an inciting agent. The lesions may be localized or generalized. Precipitating factors include latex (especially in health care workers), plants, animals (eg, caterpillars, dander), medications, and food (eg, fish, garlic, onions, tomato).
• Foods and food additives: Some patients report the onset of acute urticaria associated with the consumption of certain foods, such as shellfish, eggs, nuts, strawberries, or certain baked goods.
• Arthropod assault: Arthropod assault is the most common cause of papular urticaria. Although patients who are bitten by mosquitoes are likely to be aware of the source of the problem, patients with scabies, bedbug bites, flea bites, or other similar problems may not be aware. Ask patients about exposure to animals, recent moves, hobbies, travel, or the presence of a similar skin condition in other members of the household.
• Infections: Urticaria has been reported to be associated with a number of infections; however, these associations are not strong and may be spurious. Infectious agents reported to cause urticaria include hepatitis B virus, Streptococcus and Mycoplasma species, Helicobacter pylori,^7,8 Mycobacterium tuberculosis, and herpes simplex virus.
• Autoimmune disease: Urticaria has been associated with a number of autoimmune diseases, including systemic lupus erythematosus, cryoglobulinemia, juvenile rheumatoid arthritis, and autoimmune thyroid disease, including Graves disease.^9,10 Patients may be euthyroid but respond to replacement therapy or may respond to treatment of hyperthyroidism with carbimazole.
• Autoinflammatory diseases: Urticaria is a feature of Muckle-Wells syndrome (amyloidosis, nerve deafness, and urticaria) and Schnitzler syndrome¹¹ (fever, joint/bone pain, monoclonal gammopathy, and urticaria).
• Malignancies: Little evidence exists to support the concern that chronic urticaria is a cutaneous sign of occult internal malignancy. In a study of 1155 patients with chronic urticaria in Sweden, Sigurgeirsson found no association with cancer, although acquired angioedema associated with C1 inhibitor depletion may be associated with malignancy.¹²
• Physical factors: Physical factors are the most commonly identified etiologies of chronic urticaria, accounting for approximately 20% of cases. The various types of physical urticaria are diagnosed by challenge testing. Several types exist, and finding that a single patient has more than 1 type is not uncommon. Below is a list of some types of physical urticaria and their causes. 
  • Dermatographism/dermographism - Firm stroking
  • Delayed pressure urticaria - Pressure
  • Cold urticaria - Cold
  • Aquagenic urticaria - Water exposure
  • Cholinergic urticaria - Heat, exercise, or stress
  • Solar urticaria - Sun exposure
  • Vibratory urticaria - Vibration
• Neurologic factors: An Italian study reported an association between chronic urticaria and fibromyalgia. The authors proposed that chronic urticaria is a consequence of fibromyalgia-neurogenic skin inflammation.¹³
• Emotional factors: Psychological factors are reported to play a role in a number of patients. Reports exist of improvement of symptoms using hypnotism; however, the role of emotional factors remains controversial.
• Genetic: Hereditary angioedema is characterized by recurrent attacks of angioedema (without urticaria) involving the skin, GI tract, respiratory tract, and mucous membranes in a patient with a positive family history. The disorder is autosomal dominant, and it is caused by a functional deficiency of the C1 inhibitor protein.

Differential Diagnoses

Other Problems to Be Considered

Melkersson-Rosenthal syndrome

Workup

Laboratory Studies

Elicit a history and perform a physical examination and challenge testing for physical causes in patients with chronic urticaria. Direct the selection of laboratory tests using the information elicited from the history and physical examination.

• Complete blood cell count with differential: Patients with parasitic infections, especially in developing countries, or patients experiencing a drug reaction may have an elevated eosinophil count. The absence of blood eosinophilia may obviate the necessity for stool examination for ova.
• Erythrocyte sedimentation rate: It may be elevated in persons with urticarial vasculitis.
• Hepatitis B and C titers: Both hepatitis B and C may be associated with cryoglobulinemia, which is associated with some forms of cold-induced urticaria and urticarial vasculitis. In addition, an association has been reported between hepatitis C and chronic urticaria.¹⁴
• Antinuclear antibody titers: These are indicated in patients in whom urticarial vasculitis is suggested.
• Erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, and rheumatoid factor: Testing should be performed if an underlying rheumatologic disorder is suspected.
• Stool ova and parasites: Consider this test in patients with GI tract symptoms, an elevated eosinophil count, or a positive travel history.
• Serum cryoglobulins: Cryoglobulinemia is associated with some forms of cold-induced urticaria.
• Complement studies: C3 (associated with pulmonary involvement in a subset of patients with urticarial vasculitis), C4 (may be low in hereditary angioedema), and C1-esterase inhibitor (hereditary angioedema) functional assays may be performed.
• Thyroid function, antithyroid microsomal, and peroxidase antibody titers: Patients with urticaria unresponsive to antihistamines or steroids may have elevated titers, which may respond to thyroid hormone therapy.¹⁵ Patients may be euthyroid. Urticaria is also more common in patients with Hashimoto thyroiditis. If antithyroglobulin and antimicrosomal antibodies are present, this supports the diagnosis of chronic immunologic urticaria. The plasma level of thyrotropin helps screen for thyroid dysfunction.
• CU Index (Chronic Urticaria Index) is available from a few reference laboratories. Patients with a chronic form of urticaria with a positive functional anti-FcεR test result likely have an autoimmune basis for their disease. A positive result does not indicate which autoantibody (anti-IgE, anti-FcεRI, or anti-FcεRII) is present. This test is usually combined with thyroid function, antithyroid microsomal titers, and peroxidase antibody titers.

Other Tests

• Challenge testing: Challenge testing may be required to exclude a physical urticaria.
• Skin biopsy: Histologic examination is not necessary for the diagnosis urticaria. A biopsy is necessary for the diagnosis of urticarial vasculitis or a neutrophil-predominant pattern of urticaria that may not respond well to antihistamines. A skin biopsy is indicated when individual urticarial lesions persist for more than 24 hours or have associated petechiae or purpura and in patients with systemic symptoms such as fever, arthralgia, or arthritis. Histological evidence of leukocytoclasia (neutrophilic infiltration with fragmentation of nuclei) is a characteristic feature of urticarial vasculitis. The presence of neutrophils may indicate potential benefit from treatment with dapsone or colchicine.
• Prick or radioallergosorbent assay testing: This might be useful if contact urticaria is suggested.
• Skin prick testing: Results may help identify a food allergy, which is a rare cause of chronic urticaria.

Histologic Findings

Dermal edema, blood vessel dilatation, and mild perivascular infiltrate predominantly consisting of monocytes and CD4⁺ lymphocytes are characteristic findings; some forms exist in which neutrophils predominate.

Treatment

Medical Care

Avoidance of mental stress, overtiredness, alcohol, nonsteroidal anti-inflammatory drugs, and tight-fitting garments is recommended. Nocturnal pruritus may be reduced by lukewarm bathing and keeping the ambient temperature of the bedroom cool. Application of lotions with menthol and phenol (Sarna) provide prompt relief of pruritus for some patients.
 
Nonsedating antihistamines remain the mainstay of treatment. Many patients find pruritus less troublesome during the daytime, with pruritus maximized at night when there are fewer distractions. An additional nocturnal dose of a sedative antihistamine such as hydroxyzine or doxepin may be added to the morning dose of a low-sedation anti-H1 antihistamine. Doxepin should not be used in patients with glaucoma and should be used with extreme caution in elderly patients or those with heart disease. Doubling the labeled dose of low-sedating antihistamines may benefit some patients, and increasing the dose of these antihistamines is often the safest therapeutic approach for patients who do not have an adequate response to the conventional dose of these medications.

Patients who respond poorly to antihistamine therapy or who are known to have urticaria in which the inflammatory infiltrate is neutrophil predominant may require the addition of colchicine (0.6 mg twice daily) or dapsone (50-150 mg once daily) to the treatment regimen (except patients with glucose-6-phosphate dehydrogenase [G-6-PD] deficiency). Patients with autoimmune urticaria may benefit from methotrexate or cyclosporine.^16,17,18

Also see a clinical guideline summary from the British Association of Dermatologists, Guidelines for evaluation and management of urticaria in adults and children.¹⁹

Consultations

A consultation with an allergist is recommended when the eliciting factor seems to be food sensitivity. The following clinical guideline summaries from the American College of Allergy, Asthma, & Immunology may be helpful:

• Consultation and referral guidelines citing the evidence: how the allergist-immunologist can help²⁰
• Food allergy: a practice parameter²¹

Diet

Advise patients to avoid foods containing salicylate if they are allergic to salicylic acid Additionally, advise patients with known food allergies to avoid those foods.

Medication

Antihistamines^22,23
 
The mainstay of pharmacotherapy for chronic urticaria is low-sedation anti-H1 antihistamines, which have a low incidence of adverse effects. Quality of life appears to be improved more by daily therapy than therapy administered on an “as needed” basis.²⁴ . Low-sedating antihistamines such as loratadine, cetirizine, levocetirizine, and fexofenadine decrease the intensity of hives and pruritus in patients with mild, chronic urticaria and are considered first-line therapy. Crossover studies comparing the suppression of skin papule and erythema formation induced by intradermal histamine injection following a single antihistamine dose suggest the following order of inhibitory effect: (1) levocetirizine, (2) cetirizine, (3) terfenadine, (4) fexofenadine, and (5) loratadine.

Skin concentration—not plasma concentration—correlates to drug potency in inhibiting wheal and erythema formation response to intradermal histamine injection. Sedation and impairment of performance are concerns when using sedating antihistamines, yet these adverse effects may diminish after 1-2 weeks of therapy.
 
Pregnancy
 
Cetirizine and loratadine are category B; nevertheless, a first-generation antihistamine, such as chlorpheniramine, may be considered the drug of choice because the cumulative experience of use of this agent in pregnant women is greater.
 
Kidney or liver impairment

For cetirizine, 60% is eliminated via the kidneys. For levocetirizine, the figure is 85%. Most H1 or H2 antihistamines undergo presystemic metabolism in the liver via cytochrome P-450. A reduction in dose of low-sedating antihistamines is advised in patients with liver or renal failure. 

Children
 
Cetirizine and fexofenadine are approved by the US Food and Drug Administration for chronic urticaria in children aged 6 months and older. Desloratadine is approved for chronic urticaria in children aged 1 year and older. Loratadine is approved for chronic urticaria in children aged 2 years and older. Levocetirizine is approved for chronic urticaria in children aged 6 years and older. Hydroxyzine has been used to alleviate pruritus in children with atopic dermatitis and is an appropriate second-line agent in children with chronic urticaria refractory to low-sedating antihistamines.

Antileukotrienes^25,26

Leukotriene antagonists have been shown to be superior to placebo in the treatment of patients with chronic urticaria but are considered less effective than nonsedating antihistamines; however, the agents can be combined. Montelukast at 10 mg/d may be particularly helpful for patients experiencing flare-ups due to aspirin or other nonsteroidal anti-inflammatory drugs. Montelukast is approved for perennial allergic rhinitis in children aged 6 months and older.

Cyclosporine

Cyclosporine at 4-6 mg/kg/d has been shown in randomized double-blind studies to be effective for chronic urticaria. Cyclosporine therapy should be limited to 3 months or less for chronic urticaria. A sustained remission is observed in approximately one third of patients treated with his medication.

Systemic corticosteroids

Systemic corticosteroids are usually effective when antihistamines are not adequate. In the rare situation when systemic corticosteroid treatment is needed to treat chronic urticaria, a low dose daily or alternate-day dosing of corticosteroids is advised, and the dose should be titrated to the lowest effective level. Patients receiving long-term corticosteroid therapy should be routinely monitored for bone density changes and adverse ocular effects.

Levothyroxine

Some patients with chronic urticaria and antithyroid antibodies have been shown to benefit from levothyroxine treatment, perhaps by suppression of thyroid activity and, possibly, the autoimmune process. The goal of treatment is to maximally suppress thyrotropin without rendering the patient clinically hyperthyroid. The urticaria may respond within 2 weeks of initiation of adequate treatment. Some patients may maintain a sustained remission after 3-6 months of treatment, at which point the levothyroxine can be tapered and then discontinued.

Antihistamines, first generation

Compete with histamine at tissue receptor level, preventing it from carrying out its mediator functions in urticaria.

Diphenhydramine (Benadryl)

For symptomatic relief of symptoms caused by release of histamine in allergic reactions.

Dosing

Adult

25-50 mg PO q6-8h prn; may administer as single dose of 25-50 mg qhs if somnolence occurs; not to exceed 400 mg/d
10-50 mg IV/IM q6-8h prn; not to exceed 400 mg/d

Pediatric

>10 lb: 12.5-25 mg PO tid/qid or 5 mg/kg/d or 150 mg/m²/d divided tid/qid; not to exceed 300 mg/d
5 mg/kg/d IV/IM or 150 mg/m²/d divided qid; not to exceed 300 mg/d

Interactions

Potentiates effect of CNS depressants; because of alcohol content, do not administer syr to patient taking medications that can cause disulfiramlike reactions

Contraindications

Documented hypersensitivity; MAOIs; newborns and premature infants

Precautions

Pregnancy

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

Precautions

May exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer disease, and urinary tract obstruction; may cause sedation; anticholinergic adverse effects (eg, xerostomia, urinary retention, orthostatic hypotension) may occur, especially in elderly patients; avoid in patients with asthma, increased intraocular pressure, narrow-angle glaucoma, hyperthyroidism, cardiovascular disease, and hypertension; avoid in peptic ulcer disease, symptomatic benign prostatic hypertrophy, or bladder-neck obstruction

Hydroxyzine (Atarax, Vistaril)

Antagonizes H1 receptors in periphery. May suppress histamine activity in subcortical region of CNS.
For patients who have difficulty swallowing, a 25-mg/5-mL oral susp is available.

Dosing

Adult

25-100 mg PO qd/qid or single dose of 25-50 mg qhs if somnolence occurs

Pediatric

<6 years: 50 mg/d PO in divided doses
>6 years: 50-100 mg/d in divided doses

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 patients with porphyria); ECG abnormalities (alterations in T waves) may occur; may cause drowsiness

Doxepin (Sinequan, Zonalon)

Inhibits histamine and acetylcholine activity.

Dosing

Adult

10-50 mg PO qhs

Pediatric

Not recommended in children <12 years

Interactions

Decreases antihypertensive effects of clonidine but increases effects of sympathomimetics and benzodiazepines; effects increase with phenytoin, carbamazepine, and barbiturates

Contraindications

Documented hypersensitivity; urinary retention; acute recovery phase following MI; 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

Anti-inflammatory agents

Modify the immune response to diverse stimuli.

Prednisone (Deltasone, Orasone, Meticorten, Sterapred)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Dosing

Adult

0.5-2 mg/kg/d PO; taper as condition improves; single morning dose is safer for long-term use, but divided doses have more anti-inflammatory effect

Pediatric

Not established

Interactions

Coadministration with estrogens may decrease 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 infection; fungal or tubercular skin infection; GI tract disease

Precautions

Pregnancy

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

Precautions

Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur

Colchicine

Decreases leukocyte motility and phagocytosis in inflammatory responses.

Dosing

Adult

0.6 mg PO bid

Pediatric

Not established

Interactions

Sympathomimetic agent toxicity and effect of CNS depressants are increased significantly with colchicine

Contraindications

Documented hypersensitivity; severe renal, hepatic, GI, or cardiac disorders; blood dyscrasias

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

Risk of renal failure, hepatic failure, permanent hair loss, bone marrow suppression, numbness or tingling in hands and feet, disseminated intravascular coagulopathy, and decreased sperm count

Sulfones

May reduce inflammation.

Dapsone (Avlosulfon)

Mechanism of action is similar to that of sulfonamides, in which competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth. Effects in inflammatory reactions unknown.

Dosing

Adult

50-150 mg PO qd

Pediatric

Not established

Interactions

May inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists, eg, pyrimethamine (monitor for agranulocytosis during second and third months of therapy); probenecid increases toxicity; trimethoprim with dapsone may increase toxicity of both; levels may decrease significantly when administered concurrently with rifampin because of increased renal clearance

Contraindications

Documented hypersensitivity; G-6-PD deficiency

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

Check serum G-6-PD levels prior to initiating therapy; perform weekly blood cell counts (first month), then perform WBC counts monthly (6 mo), then semiannually; discontinue if significant reduction in platelets or leukocytes occurs or if hematopoiesis is observed; caution in methemoglobin reductase deficiency, G-6-PD deficiency (patients receiving >200 mg/d), or hemoglobin M because of high risk for hemolysis and Heinz body formation; caution in patients exposed to other agents or conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; peripheral neuropathy can occur (rare); phototoxicity may occur when exposed to UV light

Antihistamines, second generation

Also known as less-sedating antihistamines, these drugs produce less sedation than traditional H1 blockers because they are less lipid soluble and only cross the blood-brain barrier in small amounts. Also have longer half-lives, allowing for less-frequent dosing.

Cetirizine (Zyrtec)

Forms complex with histamine for H1-receptor sites in blood vessels, GI tract, and respiratory tract.
Available as 5- or 10-mg tab and as 1-mg/mL syr; each teaspoonful (5 mL) contains 5 mg.

Dosing

Adult

5-20 mg PO qd; reduce to 5 mg qd in patients with renal and hepatic impairment

Pediatric

<2 years: Not established
2-5 years: 2.5 mg PO qd; can increase to 5 mg/d and administer as qd or bid dose; do not use in renal or hepatic impairment
>5 years: 5-10 mg PO qd depending on severity (halve dose with renal impairment)

Interactions

Increases CNS toxicity of depressants

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; doses >10 mg/d may cause drowsiness; sedation less frequent than with traditional H1 blockers; anticholinergic adverse effects may occur (eg dry mouth, urinary retention, orthostatic hypotension)

Fexofenadine (Allegra)

Competes with histamine for H1 receptors in GI tract, blood vessels, and respiratory tract, reducing hypersensitivity reactions. Does not sedate.

Dosing

Adult

60 mg PO bid

Pediatric

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

Interactions

Toxicity increases 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

No data available in breastfeeding

Loratadine (Claritin)

Selectively inhibits peripheral histamine H1 receptors.
Available as 10-mg tab or 10-mg RediTabs (rapidly disintegrating tab). Syr available in 1-mg/mL concentration.

Dosing

Adult

10 mg PO qd; qod in patients with renal or hepatic impairment

Pediatric

<2 years: Not established
2-6 years: 5 mg/d PO
>6 years: Administer as in adults

Interactions

Ketoconazole, erythromycin, procarbazine, and alcohol may increase 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

Desloratadine (Clarinex)

Long-acting tricyclic histamine antagonist selective for H1 receptor. Relieves nasal congestion and systemic effects of seasonal allergy. 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

Data limited; erythromycin and ketoconazole increase desloratadine and 3-hydroxydesloratadine plasma concentrations, but no increase in clinically relevant adverse effects, including QTc, 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

Follow-up

Deterrence/Prevention

If a precipitating factor is identified, patients should be advised to avoid it. Certain medications, such as aspirin and nonsteroidal anti-inflammatory drugs, are reported to exacerbate urticaria in patients with chronic urticaria resulting from other causes.

Complications

Lesions of urticaria should resolve without complication; however, patients with severe pruritus may develop scratch purpura and excoriations that may become secondarily infected. Additionally, antihistamine use may cause somnolence and dry mouth. Finally, patients with severe disease may be impacted by quality-of-life issues.

Prognosis

Most patients with chronic idiopathic urticaria have resolution of symptoms within 3 years from the onset of symptoms; 86% are symptom free at 5 years. The presence of anti–immunoglobulin G or antithyroid antibodies may worsen the prognosis. Chronic urticaria impairs quality of life to the extent experienced by persons with severe coronary artery disease. Chronic urticaria can lead to significant psychological stress, and the converse is also recognized. A possible mechanism is through stress-induced release of corticotrophin-releasing hormone (CRH), which is known to be expressed in the skin. Up-regulation occurs of the CRH-R1 receptor that mediates CRH-dependent cutaneous mast cell degranulation in chronic urticaria.²⁷

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

A potential pitfall is the failure to consider a diagnosis of urticarial vasculitis in patients with lesions lasting longer than 24 hours, in patients with lesions associated with pain more than with itching, and in patients with lesions resolving with pigmentary changes or scaling.

References

1. Tong LJ, Balakrishnan G, Kochan JP, Kinet JP, Kaplan AP. Assessment of autoimmunity in patients with chronic urticaria. J Allergy Clin Immunol. Apr 1997;99(4):461-5. [Medline].

2. Kaplan AP, Greaves M. Pathogenesis of chronic urticaria. Clin Exp Allergy. Jun 2009;39(6):777-87. [Medline].

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Keywords

chronic urticaria, hives, wheals, allergy, allergic reaction, anaphylaxis, anaphylactoid reaction, angioedema

Contributor Information and Disclosures

Author

Daniel J Hogan, MD, Clinical Professor of Internal Medicine (Dermatology), NOVA Southeastern University; Investigator, Hill Top Research, Florida Research Center
Daniel J Hogan, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Contact Dermatitis Society, and Canadian Dermatology Association
Disclosure: Nothing to disclose.

Medical Editor

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey
Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Catherine M Quirk, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania
Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Dr Dina Strachan, to the development and writing of this article. The authors and editors of eMedicine would also like to gratefully acknowledge the contributions of previous Chief Editor, William D. James, MD, to the development and writing of this article.

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