Urticaria 

Updated: Jun 13, 2018
Author: Henry K Wong, MD, PhD; Chief Editor: Dirk M Elston, MD 

Overview

Practice Essentials

Urticaria appears as raised, well-circumscribed areas of erythema (redness) and edema (swelling) involving the dermis and epidermis that are very pruritic (itchy), as shown in the image below. Acute urticaria can be caused by allergic reactions to foods, drugs, cosmetics, or soaps; infections; insect bites, stings, or exposure; environmental factors; latex; undue skin pressure, cold, or heat; emotional stress; and exercise, among other factors. It may be acute (< 6 wk) or chronic (>6 wk). Urticaria may be confused with a variety of other dermatologic diseases that are similar in appearance and are also pruritic; usually, however, it can be distinguished from these diseases by an experienced clinician.[1] Urticaria is not contagious, unless the swollen hives themselves contain a pathogen.

Urticaria developed after bites from an imported f Urticaria developed after bites from an imported fire ant.

Signs and symptoms of urticaria

Information regarding history of previous urticaria and duration of rash and itching is useful for categorizing urticaria as acute, recurrent, or chronic. For chronic or recurrent urticaria, important considerations include previous causative factors and the effectiveness of various treatments, as follows[2] :

  • Precipitants, such as heat, cold, pressure, exercise, sunlight, emotional stress, or chronic medical conditions

  • Other medical conditions that can cause pruritus (usually without rash), such as diabetes mellitus, chronic renal insufficiency, primary biliary cirrhosis, or other nonurticarial dermatologic disorders

  • Family and personal medical history of angioedema - Characteristics of angioedema[1] include vasodilation and exudation of plasma into the deeper tissues more so than with simple urticaria; angioedema can occur with and without the wheals (hives) of simple urticaria and presents clinically as subcutaneous swelling that is generally nonpitting and nonpruritic; it can affect the mouth as well as the mucosal surfaces of the respiratory and GI tracts, manifesting as hoarseness and GI upset; it can be a feature of anaphylaxis if the throat is involved, leading to airway compromise

For acute urticaria, the main consideration involves possible precipitants, such as the following[1] :

  • Recent illness

  • Medication use

  • IV radiocontrast media

  • Travel

  • Foods

  • New perfumes, hair dyes, detergents, lotions, creams, or clothes

  • Exposure to new pets (dander), dust, mold, chemicals, or plants

  • Pregnancy (usually occurs in last trimester and typically resolves spontaneously soon after delivery)

  • Contact with nickel, rubber, latex, industrial chemicals, and nail polish

  • Sun or cold exposure

  • Exercise

  • Alcohol ingestion[3]

Physical urticaria is characterized by the following:

  • Blanchable, raised, palpable wheals, which can be linear, annular (circular), or arcuate (serpiginous); can occur on any skin area; are usually transient and migratory; and may coalesce rapidly to form large areas of erythematous, raised lesions that blanch with pressure

  • Dermographism or dermatographism (urticarial lesions resulting from light scratching)

The physical examination should focus on conditions that might precipitate urticaria or could be potentially life-threatening and include the following[1] :

  • Angioedema of the lips, tongue, or larynx

  • Individual urticarial lesions that are painful, long-lasting (>24 h), or ecchymotic or that leave residual hyperpigmentation or ecchymosis upon resolution are suggestive of urticarial vasculitis

  • Systemic signs or symptoms

  • Scleral icterus, hepatic enlargement, or tenderness

  • Thyromegaly

  • Pneumonia or bronchospasm (asthma)

  • Cutaneous evidence of bacterial or fungal infection

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies may be helpful, as follows:

  • Acute urticaria (< 6 wk) - Laboratory studies generally are not indicated

  • Chronic or recurrent urticaria (>6 wk) - Basic laboratory studies should include complete blood count (CBC), erythrocyte sedimentation rate (ESR), thyroid-stimulating hormone (TSH), and antinuclear antibody (ANA)[4]

Other studies that may be considered include the following:

  • Imaging studies - Generally not indicated unless suggested by a specific symptom or sign[4]

  • Punch biopsy - If urticarial vasculitis is suspected

See Workup for more detail.

Management

Acute urticaria may rarely progress to life-threatening angioedema or anaphylactic shock in a very short period, although anaphylactic shock is usually of rapid onset with no urticaria or angioedema.[5] Prehospital measures may include the following when there is concern for anaphylactic shock:

  • If associated angioedema is present, IM epinephrine

  • If associated bronchospasm is present, nebulized albuterol

  • Other measures may be appropriate, such as continuous ECG, blood pressure and pulse oximetry monitoring; administering intravenous crystalloids if the patient is hypotensive; and administering oxygen.

  • Diphenhydramine or hydroxyzine, if available

Management of urticaria is focused on treating the symptoms and typically is not altered by underlying etiology. The mainstay is avoidance of further exposure to the antigen causing urticaria. Pharmacologic treatment options include the following:

  • Antihistamines, primarily those that block H1 receptors with low sedating activity, such as fexofenadine, loratadine, desloratadine, cetirizine, and levocetirizine are first-line therapy[6, 7] ; these are preferred over diphenhydramine and hydroxyzine; H2 antihistamines, such as cimetidine, famotidine, and ranitidine, may have a role when used in combination with H1 antihistamines, although the benefit is unclear[8]

  • Doxepin

  • Omalizumab

  • Glucocorticoids

  • Epinephrine (controversial in acute urticaria)

  • Methotrexate, colchicine, dapsone, indomethacin, and hydroxychloroquine (for urticarial vasculitis)[9]

  • Topical 5% doxepin cream or capsaicin (refractory cases)

Patients with chronic or recurrent urticaria should be referred to a dermatologist for further evaluation and management.

Consultation with or referral to a dermatologist, allergist, immunologist, or rheumatologist may be appropriate in selected cases, particularly in cases of complicated, recurrent, refractory, severe, or chronic urticaria. Dermatology referral is mandatory if urticarial vasculitis is suspected.

See Treatment and Medication for more detail.

Background

Urticaria is the most frequent dermatologic disorder seen in the emergency department (ED). A large variety of urticaria variants exist, including acute immunoglobulin E (IgE)–mediated urticaria, chemical-induced urticaria (non-IgE-mediated), autoimmune urticaria, cholinergic urticaria, cold urticaria, mastocytosis, periodic fever syndromes including Muckle-Wells syndrome, and many others.[2, 10] While acute urticaria is generally related to an exogenous allergen or acute infection, chronic urticaria is more likely to be associated with autoimmunity.[8, 11, 12]

Urticaria may be confused with a variety of other dermatologic diseases that are similar in appearance and are pruritic including atopic dermatitis (eczema), maculopapular drug eruptions, contact dermatitis, insect bites, erythema multiforme, pityriasis rosea, urticarial vasculitis, and others. Usually, however, the experienced clinician is able to distinguish urticaria from its mimickers owing to its distinctive appearance (see the images below), intensely pruritic nature, and complete blanching with pressure.[1]

Urticaria developed after bites from an imported f Urticaria developed after bites from an imported fire ant.
Urticaria associated with a drug reaction. Urticaria associated with a drug reaction.

Acute urticaria is most often a benign, self-limited skin disease. It usually occurs independently, but it may contribute to the more serious clinical manifestations of anaphylaxis: angioedema and anaphylactic shock. The etiologies of both acute and chronic urticaria are numerous (see Causes in Presentation). The etiologic agent is more likely to be identified in acute urticaria (40-60%) than in chronic urticaria (10-20%). The lesions of IgE-mediated urticaria usually last less than 24 hours and are often migratory, leaving no residual skin abnormalities. The lesions of urticarial vasculitis usually last longer, classically, but not always, longer than 24 hours.[8] They are both painful and itchy and often leave purpuric and hyperpigmented lesions.[9] Unlike simple urticaria, urticarial vasculitis demonstrates leukocytoclastic vasculitis on histology. Like urticaria, it may occur with or without angioedema. It may be associated with systemic symptoms such as arthralgias and GI symptoms, which are more common in patients with low complement levels. Although it is most often idiopathic, it is more often associated with autoimmune diseases such as lupus and Sjögren syndrome, as well as viral infections, medications, and malignancy, when compared with classic urticaria.[13] If urticarial vasculitis is suspected, an autoimmune screen, including complement levels, should be included in the workup. Initial treatment options include antihistamines and NSAIDs.

For more information, see Medscape's Allergy Resource Center.

Pathophysiology

Urticaria (hives) results from the release of histamine, bradykinin, leukotriene C4, prostaglandin D2, and other vasoactive substances from mast cells and basophils in the dermis. These substances cause extravasation of fluid into the dermis, leading to the urticarial lesion. The intense pruritus (itchiness) of urticaria is a result of histamine released into the dermis. Histamine is the ligand for two membrane-bound receptors, the H1 and H2 receptors, which are present on many cell types. The activation of the H1 histamine receptors on endothelial and smooth muscle cells leads to increased capillary permeability. The activation of the H2 histamine receptors leads to arteriolar and venule vasodilation.[14, 15]

This process is caused by several mechanisms. The type I allergic IgE response is initiated by antigen-mediated IgE immune complexes that bind and cross-link Fc receptors on the surface of mast cells and basophils, thus causing degranulation with histamine release. The type II allergic response is mediated by cytotoxic T cells, causing deposits of immunoglobulins, complement, and fibrin around blood vessels. This leads to urticarial vasculitis. The type III immune-complex disease is associated with systemic lupus erythematosus and other autoimmune diseases that cause urticaria.[15]  Some evidence suggests vitamin D levels have an inverse correlation with the severity of chronic urticaria.[16]

Complement-mediated urticarias include viral and bacterial infections, serum sickness, and transfusion reactions. Urticarial transfusion reactions occur when allergenic substances in the plasma of the donated blood product react with preexisting IgE antibodies in the recipient. Certain drugs (opioids, vecuronium, succinylcholine, vancomycin, and others) as well as radiocontrast agents cause urticaria due to mast cell degranulation through a non—IgE-mediated mechanism. Urticaria from nonsteroidal anti-inflammatory drugs may be IgE-mediated or due to mast cell degranulation, and there may be significant cross-reactivity among the nonsteroidal anti-inflammatory drugs (NSAIDs) in causing urticaria and anaphylaxis.[17]

The physical urticarias in which some physical stimulus causes urticaria include immediate pressure urticaria, delayed pressure urticaria, cold urticaria, and cholinergic urticaria.[18, 19] For some urticarias, especially chronic urticarias, no cause can be found, despite exhaustive efforts—the so-called idiopathic urticarias, although most of these are chronic autoimmune urticaria as defined by a positive autologous serum skin test (ASST).[20] This test is not specific for autoantibodies against a specific antigen or diagnostic of a specific disease state.[21] To date, no reliable test exists to identify with certainty if chronic urticaria is autoimmune or nonautoimmune in the specific patient.[22, 23]

Etiology of Urticaria

The cause of acute generalized urticaria (hives) often is undetermined (some sources report that the cause is undetermined in more than 60% of cases). Known causes include the following:

  • Infections (eg, upper respiratory tract infections, pharyngitis, GI infections, genitourinary infections, respiratory infections, fungal infections [eg, dermatophytosis], malaria, amebiasis, hepatitis, mononucleosis, coxsackievirus, mycoplasmal infections, infestations [eg, scabies], HIV, parasitic infections [eg, ascariasis, strongyloidiasis, schistosomiasis, trichinosis]).

  • Caterpillars and moths[24]

  • Foods (particularly shellfish, fish, eggs, cheese, chocolate, nuts, berries, tomatoes; < 1% are associated with food.[13] )

  • Drugs (eg, penicillins, sulfonamides, salicylates, NSAIDs, codeine, antihistamines)

  • Environmental factors (eg, pollens, chemicals, plants, danders, dust, mold)

  • Exposure to latex

  • Exposure to undue skin pressure, cold, or heat

  • Emotional stress

  • Exercise

  • Pregnancy (ie, pruritic urticarial papules and plaques of pregnancy [PUPPP])

Chronic urticaria can be related to all of the above as well as to the following:

  • Autoimmune disorders (SLE, rheumatoid arthritis, polymyositis, thyroid autoimmunity, and other connective tissue diseases); probably up to 50% of chronic urticaria is autoimmune[20, 22, 25, 26]

  • Cholinergic urticaria induced by emotional stress, heat, or exercise; examine for other signs of cholinergic stimulation including lacrimation, salivation, and diarrhea.[18]

  • Chronic medical illness, such as hypothyroidism, hyperthyroidism, amyloidosis, polycythemia vera, malignant neoplasms, lupus, lymphoma, and many others[27]

  • Cold urticaria, cryoglobulinemia, cryofibrinogenemia, or syphilis[18]

  • Mastocytosis[28]

  • Inherited autoinflammatory syndromes[29]

  • The etiology of chronic urticaria is undetermined in at least 80-90% of patients.[30]

Urticaria pigmentosa (cutaneous mastocytosis) is a unique dermatologic disorder caused by infiltration of mast cells in the skin and has a pathology distinct from common urticaria but can present with urticarial lesions associated with blisters. Lesions are hyperpigmented (yellow, tan, or brown) and when lesions are stroked, a linear wheal (hive) is formed; this characteristic and diagnostic sign is known as the Darier sign.[31] Although these lesions can become urticarial upon stroking, urticaria pigmentosa is no longer considered a subtype of urticaria, owing to its distinct pathogenetic mechanism involving infiltration by mast cells.[32] Early-onset chronic urticaria is characteristic of autoinflammatory syndromes.[33] Nasal polyposis is associated with aspirin-induced urticaria.[34]

Recurrent urticaria can be related to the following:

  • Sun exposure - Solar urticaria occurs only on skin exposed to the sun[35]

  • Exercise (cholinergic urticaria)

  • Emotional or physical stress

  • Water (aquagenic urticaria)

Epidemiology

United States

Acute urticaria (hives) affects 15-20% of the general population at some time during their lifetime. Chronic urticaria affects 2-3% of individuals over their lifetime.[36]

International

The global frequency of urticaria is similar to that in the United States.

Race

No variation in race is noted.

Sex

Incidence rates for acute urticaria are similar for men and women; chronic urticaria occurs more frequently in women (60%).

Age

Urticaria can occur in any age group, although chronic urticaria is more common in the fourth and fifth decades.

Prognosis

Pruritus (itching) and rash are the primary manifestations of urticaria, and permanent hyperpigmentation or hypopigmentation is rare.

The prognosis in acute urticaria is excellent. Acute urticaria is usually self-limited, and individual lesions commonly resolve within 24 hours; however, episodes may recur for up to 6 weeks.

The prognosis in chronic urticaria is more guarded and depends on the comorbid disease causing the urticaria as well as the response to therapy. Chronic urticaria lasts more than 6 weeks.

Acute and chronic urticaria can result in severely impaired quality of life from pruritus and associated sleeplessness, as well as anxiety and depression. The depression can be severe enough to lead to suicide in rare cases. Additionally, many of the diseases associated with chronic urticaria may cause significant morbidity and mortality.

Patient Education

Education regarding avoidance of the suspected offending allergen is essential.

For patient education resources, see the Allergies Center and Skin Conditions and Beauty Center. Also see the patient education article Hives and Angioedema.

 

Presentation

History

Urticarial wheals, commonly referred to as hives, are erythematous-to-pink swellings of various shapes and sizes, and classically have central pallor with an erythematous flare. Individual lesions come and go rapidly, although new lesions may develop simultaneously at other sites.[8, 13] In contrast, lesions of urticarial vasculitis last longer and leave pigmentary changes. Although lesions of urticarial vasculitis are historically described as lasting longer than 24 hours, more recent guidelines explain that lesions of urticarial vasculitis can sometimes be more evanescent and that the duration of lesions alone cannot be used to differentiate urticaria from urticarial vasculitis. Angioedema presents as ill-defined areas of nonpitting edema (swelling).[8]

Information regarding history of previous urticaria and duration of rash and itching is useful for categorizing urticaria as acute, recurrent, or chronic.

For chronic or recurrent urticaria, important considerations include previous causative factors and the effectiveness of various treatments.[2]

Ask about precipitants, such as heat, cold, pressure, exercise, sunlight, emotional stress, or chronic medical conditions (eg, hyperthyroidism, systemic lupus erythematosus [SLE], rheumatoid arthritis, polymyositis, amyloidosis, polycythemia vera, lymphoma and other malignant neoplasms).

Ask about other medical conditions that can cause pruritus (usually without rash), such as diabetes mellitus, chronic renal insufficiency, primary biliary cirrhosis, or other nonurticarial dermatologic disorders (eg, eczema, contact dermatitis).

Ask about family and personal medical history of angioedema, which is urticaria of the deeper tissues and can be life threatening if it involves the larynx and vocal cords. Causes specific to angioedema include hereditary angioedema (a deficiency in C1-inhibitors) and acquired angioedema (associated with angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers (ARBs). Hereditary angioedema is not associated with urticaria. Characteristics of angioedema include the following[1] :

  • Vasodilation and exudation of plasma into deeper tissues than is seen in simple urticaria

  • Swelling that is generally nonpitting and nonpruritic and usually occurs on the mucosal surfaces of the respiratory tract (lips, tongue, uvula, soft palate, and larynx) and GI tract (swelling of the intestine leading to severe abdominal pain)

  • Hoarseness, the earliest sign of laryngeal edema (Ask the patient if he or she has had a voice change.)

For acute urticaria, ask about possible precipitants, such as the following[1] :

  • Recent illness (eg, fever, sore throat, cough, rhinorrhea, vomiting, diarrhea, headache)

  • Medication use including penicillins, cephalosporins, sulfas, diuretics, aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), iodides, bromides, quinidine, chloroquine, vancomycin, isoniazid, antiepileptic agents, and other agents

  • Intravenous radiocontrast media

  • Travel (amebiasis, ascariasis, strongyloidiasis, trichinosis, malaria)

  • Foods (eg, shellfish, fish, eggs, cheese, chocolate, nuts, berries, tomatoes)

  • New perfumes, hair dyes, detergents, lotions, creams, or clothes

  • Exposure to new pets (dander), dust, mold, chemicals, or plants

  • Pregnancy (usually occurs in last trimester and typically resolves spontaneously soon after delivery)

  • Sun or cold exposure

  • Exercise

Physical Examination

Urticaria is characterized by blanching, raised, palpable wheals (hives), which can be linear, annular (circular), or arcuate (serpiginous). These lesions occur on any skin area and are usually transient and migratory. These lesions are often separated by normal skin, but may coalesce rapidly to form large areas of erythematous, raised lesions that blanch with pressure.

Dermographism may occur (urticarial lesions resulting from light scratching).

The physical examination should focus on conditions that might precipitate urticaria or could be potentially life threatening, such as the following[1] :

  • Angioedema of the lips, tongue, or larynx

  • Individual urticarial lesions that are painful, long lasting (longer than 36-48 h), or are ecchymotic; also, urticarial lesions that leave residual hyperpigmentation or ecchymosis upon resolution (suggesting urticarial vasculitis)

  • The presence of systemic signs or symptoms, particularly fever, arthralgias, arthritis, weight changes, bone pain, or lymphadenopathy

  • Scleral icterus, hepatic enlargement, or tenderness that suggests hepatitis or cholestatic liver disease

  • Thyromegaly suggesting autoimmune thyroid disease; joint examination for any evidence of connective tissue disease, rheumatoid arthritis, or systemic lupus erythematosus (SLE)

  • Lungs for pneumonia or bronchospasm (asthma)

  • Skin for evidence of bacterial or fungal infection

 

DDx

 

Workup

Approach Considerations

A thorough medical history, review of systems, and physical examination are warranted in order to exclude chronic autoimmune disease or underlying malignancy such as lymphoma.

Laboratory Studies

For acute urticaria, laboratory studies generally are not indicated. The patient's history and physical examination should direct any diagnostic studies.

For chronic or recurrent urticaria, basic laboratory studies should be prompted by signs and symptoms but may include a CBC count, erythrocyte sedimentation rate, thyroid-stimulating hormone value, and an antinuclear antibody level looking for possible causes of the urticaria.[4]

Imaging Studies

Imaging studies generally are not indicated unless a specific finding on clinical examination or history suggests an underlying etiology that may warrant further diagnostic studies.[4]

Procedures

Biopsy is generally not required for the diagnosis of classic urticaria (hives). However, if urticarial vasculitis is suspected (urticaria lasting >24 h with residual dyspigmentation; significant pain as well as pruritus), a punch biopsy of the lesion should be performed and sent to the pathology laboratory to look for leukocytoclastic vasculitis.[9]

 

Treatment

Approach Considerations

Individual wheals (hives) typically clear within 24 hours without treatment; however, angioedema may take up to 72 hours to resolve.[37] Typically, the hives (urticarial lesions) do not remain after the symptoms resolve. Excoriation may be present due to scratching of the lesions. With acute urticaria, wheals can recur for up to 6 weeks, depending on the cause. For chronic urticaria, urticarial flare-ups reoccur more days than not, for more than 6 weeks.

Timely transport to the ED for any patient with signs or symptoms of a life-threatening allergic reaction, including urticaria (hives), angioedema, or anaphylactic shock is essential. Acute urticaria may progress to life-threatening angioedema and/or anaphylactic shock in a very short period, although anaphylaxis usually presents as rapid-onset shock with no urticaria or angioedema.[5] See Anaphylaxis.

If associated angioedema is present, especially if laryngeal angioedema (eg, hoarseness, stridor) is suspected, prehospital administration of 0.3-0.5 mg of intramuscular epinephrine may be warranted.

If associated bronchospasm is present, prehospital nebulized albuterol may be warranted.

Other measures may be appropriate, such as continuous ECG, blood pressure and pulse oximetry monitoring; administering intravenous crystalloids if the patient is hypotensive; and administering oxygen.

Diphenhydramine (25 mg IV or 50 mg IM or PO) or hydroxyzine (50 mg IM or PO) should be administered if they are available.[6]

The management of urticaria is straightforward and typically is not altered by underlying etiology, but guidelines are in evolution with some variation in different parts of the world.[38, 39, 40]

Antihistamines are first-line therapy for urticaria. The older sedating antihistamines (first-generation antihistamines) that block the H1 receptors were previously first-line therapy for urticaria.[6, 7] Diphenhydramine and hydroxyzine are the most commonly used in this class. They act more rapidly than the minimally sedating H1-blocking antihistamines and are effective in relieving the pruritus (itchiness) and rash in most cases. However, because these medications are often sedating with the potential for other anticholinergic adverse effects, second-generation antihistamines are now considered first line.[8, 32, 41, 42]

Newer H1-blocking, minimally sedating, second-generation antihistamines are now available and include fexofenadine, loratadine, desloratadine, cetirizine, and levocetirizine. These are now considered first line and are used in the management of both acute and chronic urticaria.[42, 43] If symptoms are uncontrolled, the dose can be increased up to four-fold. In fact, up-dosing has been shown to increase the response rate without increasing the adverse effect profile.[32] If symptoms are still uncontrolled, a first-generation antihistamine can be added.

H2 antihistamines, such as cimetidine, famotidine, and ranitidine, may have a role when used in combination with H1 antihistamines in urticaria. H1 and H2 antihistamines are thought to have a synergistic effect that may result in a more rapid and complete resolution of urticaria than H1 antihistamines alone.[44] Cimetidine, in particular, is thought to effect cytochrome P450 enzymes involved in the metabolism of first-generation antihistamines, thus increasing their plasma concentrations.[32] Because of this, H2 antihistamines are often added in combination with H1 antihistamines in the treatment of acute and chronic urticaria. However, the evidence supporting the use of H2 antihistamines in combination with H1 antihistamines is weak and does not seem to show any advantage over use of H1 antihistamines alone. Thus, their addition is often physician dependent.[36, 32, 42, 45]

Doxepin is an antidepressant and an antihistamine that blocks both H1 and H2 receptors and may be effective in refractory cases of urticaria in doses of 25-50 mg at bedtime or 10-25 mg 3-4 times a day.[46]

Glucocorticoids stabilize mast cell membranes and inhibit further histamine release. They also reduce the inflammatory effect of histamine and other mediators. Oral glucocorticoids are effective in acute urticaria but are not suitable for long-term use. In one study, acute urticaria improved more quickly in the group treated with prednisone than in the group treated with placebo.[47] In adults, 40-60 mg daily of prednisone for 5 days is a reasonable therapeutic regimen. In children, the treatment is 1 mg/kg/d for 5 days. Tapering of the corticosteroid dose is not necessary in most cases of acute urticaria.[1]

If urticaria is present with angioedema and systemic symptoms such as coughing or wheezing are present, raising concern for anaphylaxis,[8] 0.3-0.5 mg of epinephrine should be administered intramuscularly. Remember that ACE-inhibitor–induced angioedema usually does not respond to epinephrine or most other common therapies, since it is not an IgE-mediated process.[48]

The use of methotrexate, colchicine, dapsone, indomethacin, and hydroxychloroquine may be effective in the management of urticarial vasculitis.[9]

Control of chronic urticaria may be achieved with omalizumab, although anaphylaxis and angioedema are potential risks.[49, 50, 51]

Topical therapy with 5% doxepin cream (Zonalon) or capsaicin may also be used in refractory cases.

Patients with chronic or recurrent urticaria should be referred to a dermatologist or allergist for further evaluation and management.

Inpatient care

In general, patients with urticaria (hives) can be cared for on an outpatient basis unless their urticaria is severe and does not respond to antihistamine therapy or if they progress to laryngeal angioedema and/or anaphylactic shock, or have comorbidities that require inpatient therapy.

Consultations

Consultation with or referral to a dermatologist, allergist, immunologist, or rheumatologist may be appropriate in selected cases, particularly in cases of complicated, recurrent, refractory, severe, or chronic urticaria. Dermatology referral is mandatory if urticarial vasculitis is suspected.

Prevention of Urticaria

Patients with acute urticaria should avoid any medication, food, or other allergen that has precipitated urticaria (hives) or other serious allergic reaction previously. Chronic urticaria is seldom related to food allergens, and complicated elimination diets are seldom of benefit.[52] Urticaria is not contagious, unless the swollen hives themselves contain a pathogen.

Long-Term Monitoring

Most patients with urticaria can be treated at home with first- or second-generation H1 antihistamines alone or in combination with one another (ie, cetirizine uptitrated to 20 mg twice daily, diphenhydramine 50 mg q6h or hydroxyzine 50 mg q6h for 24-48 h) In refractory cases, oral glucocorticoids can be added. Additional therapies likely warrant referral to a specialist.

If the patient has angioedema that is treated successfully in the ED, the patient should be sent home with an EpiPen prescription and told to keep it with him or her at all times and to use it if swelling of the lips, tongue, face develops or if his or her voice acutely become hoarse.

Consultation with or referral to a dermatologist, allergist, immunologist, or rheumatologist may be appropriate in cases of suspected urticarial vasculitis and in cases of chronic or recurrent urticaria.

 

Medication

Medication Summary

Most cases of simple acute urticaria (hives) can be treated with H1 antihistamine agents.[53] In cases of severe or persistent urticaria, H2 antihistamines may be added and may be given simultaneously orally or intravenously.[44] If the patient with chronic urticaria is refractory to nonsedating antihistamines, doses up to 4 times the recommended maximal dose may be effective.[6] If maximum doses of nonsedating antihistamines are not effective, other therapies should be tried.[54, 55]

In patients with urticaria resistant to the standard dosage of cetirizine or fexofenadine, doubling the daily dose may be effective. In a study of 51 patients treated with cetirizine at a dosage of 10 mg once daily, 18 patients had an inadequate response and were randomized to further treatment with either cetirizine 20 mg once daily or olopatadine 5 mg twice daily. Patients in the increased cetirizine dose group showed significant improvements in the severity of wheal and itching and in quality of life.[56]

Omalizumab (Xolair) was approved by the FDA in March 2014 for chronic idiopathic urticaria (CIU) in adults and children aged 12 years or older who remain symptomatic despite H1 antihistamine treatment. It was originally approved for asthma in 2003. It is a monoclonal antibody that selectively binds to IgE and inhibits binding to IgE receptors on the surface of mast cells and basophils. The efficacy and safety of omalizumab for CIU was demonstrated in two clinical studies that showed omalizumab significantly improved the mean weekly Itch Severity Score (ISS) from baseline by 9.4-9.6 in the 300-mg treatment arm (P< .001-0.0001), 6.4-6.7 in the 150-mg treatment arm (P = .001-0.0012), and 5.9-6.5 in the 75-mg treatment arm (P = .001), compared with a 3.6-5.1 improvement in patients on placebo.[15, 57] Omalizumab treatment is associated with improved quality of life.[58, 59]

Omalizumab is administered as a monthly injection and is effective in approximately 80% of individuals.[36] It is generally very well tolerated and the rate of adverse events is low, but major risk factors include anaphylaxis, among others; thus, it must be administered in a physician’s office.[8, 42] The dosing for use in asthma is based on weight and IgE levels, but omalizumab can be administered in 150- or 300-mg doses and, unfortunately, there are no clinical markers that can predict whether or not it will be effective. Although the evidence supporting its efficacy in treating urticaria is of high quality, the cost of the drug may preclude its use in many patients.[8]

Refractory cases of chronic urticaria may improve with glucocorticoids, but the complications of long-term use generally outweigh the benefits.[8]

Chronic urticaria may benefit from doxepin, a tricyclic antidepressant with potent antihistamine properties. Because of its significant sedative properties, it should be given at bedtime.

Topical therapy with 5% doxepin cream (Zonalon) or capsaicin may also be used in refractory cases.

Cyproheptadine may be useful to suppress recurrent cold urticaria. One study showed that the combination of a leukotriene receptor antagonist and a nonsedating antihistamine was superior to the antihistamine alone in treating chronic idiopathic urticaria.[60]

Cyclosporine has been shown to be effective in cases of refractory chronic urticaria.[61, 62]

Mycophenolate mofetil (CellCept) has also been shown to be effective.[8]

A 2017 literature review concluded that the best current evidence for nonantihistamine/nonbiologic agents is for montelukast and cyclosporine, followed by ultraviolet (UV) light therapy, dapsone, and intravenous immunoglobulin (IVIG).[63, 64]

H1-receptor antagonist antihistamines

Class Summary

These agents block the histamine response in sensory nerve endings and blood vessels. They act by competitive inhibition of histamine at the H1 receptor, which mediates wheal and flare reactions, bronchial constriction, mucus secretion, smooth muscle contraction, and edema (swelling). Because they have significant anticholinergic activity, especially the older sedating antihistamines, they may cause hypotension, CNS depression, urinary retention, and cardiac arrhythmias, especially in higher therapeutic doses or overdoses.

Hydroxyzine hydrochloride (Atarax, Vistaril)

Hydroxyzine is a sedating peripheral H1 receptor antagonist. It is very effective in urticaria. Hydroxyzine also may suppress histamine activity in the subcortical region of the CNS.

Diphenhydramine (Benadryl, Benylin, Diphen)

Diphenhydramine is a sedating peripheral H1 receptor antagonist. It is used for symptomatic relief of allergic symptoms caused by histamine released in response to allergens.

Cyproheptadine (Periactin)

Cyproheptadine is a sedating H1 antihistamine for symptomatic relief of allergic symptoms caused by histamine released in response to allergens and skin manifestations.

Cetirizine (Zyrtec)

Cetirizine selectively inhibits peripheral histamine H1-receptors and is minimally sedating.

Levocetirizine (Xyzal)

Levocetirizine is a histamine1-receptor antagonist. It is an active enantiomer of cetirizine. Peak plasma levels are reached within 1 hour and the half-life is about 8 hours. Levocetirizine is available as a 5-mg breakable (scored) tablet. It is indicated for seasonal and perennial allergic rhinitis.

Fexofenadine (Allegra)

Fexofenadine selectively inhibits peripheral histamine H1-receptors and is minimally sedating.

Loratadine (Claritin, Alavert)

Loratadine selectively inhibits peripheral histamine H1-receptors and is minimally sedating.

Desloratadine (Clarinex)

Desloratadine is a long-acting tricyclic histamine antagonist selective for H1-receptors. It is a major metabolite of loratadine, which, after ingestion, is extensively metabolized to the active metabolite 3-hydroxydesloratadine.

Tricyclic antidepressants (TCAs)

Class Summary

These agents are a complex group of drugs that have central and peripheral anticholinergic effects, as well as sedative effects, and block the active reuptake of norepinephrine and serotonin. Some TCAs (eg, doxepin) have antihistamine effects, blocking both the H1 and H2 receptors and have been used in the treatment of allergic reactions, especially urticaria.

Doxepin (Sinequan, Adapin, Zonalon)

Doxepin inhibits histamine and acetylcholine activity and has proven useful in the treatment of allergic dermatologic disorders.

Glucocorticoids

Class Summary

These agents decrease the inflammation associated with urticaria resistant to H1- and H2-receptor antihistamine therapy. They do not inhibit mast cell degranulation. They are often used to treat flares of chronic urticaria or as treatment of histamine-resistant acute urticaria or when angioedema is present. Long-term use is discouraged owing to long-term adverse effects.

Prednisone (Deltasone, Orasone, Meticorten)

Prednisone is used in the treatment of various allergic and inflammatory diseases. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

H2-receptor antagonists

Class Summary

These are reversible, competitive blockers of histamine at H2 receptors, particularly those in gastric parietal cells. The H2 antagonists are highly selective, do not affect H1 receptors, and are not anticholinergic agents. They block the vasodilation mediated by the H2 receptors in blood vessels, possibly leading to less edema formation in urticaria.

The combination of H1 and H2 antagonists may be useful in acute urticaria as well as chronic idiopathic urticaria not responding to H1 antagonists alone. This combination in IV form also may be useful for itching and flushing in anaphylaxis, pruritus, urticaria, and contact dermatitis.

Famotidine (Pepcid)

Famotidine is an H2 antagonist that, when combined with an H1 type, may be useful in treating allergic reactions that do not respond to H1 antagonists alone.

Ranitidine (Zantac)

Ranitidine is an H2 antagonist that, when combined with an H1 type, may be useful in treating allergic reactions that do not respond to H1 antagonists alone.

Cimetidine (Tagamet)

Cimetidine is an H2 antagonist that, when combined with an H1 type, may be useful in treating allergic reactions that do not respond to H1 antagonists alone.

Monoclonal Antibody

Class Summary

Monoclonal antibodies directed to IgE binding may reduce release of mediators that provoke an allergic response. These agents may be considered when H1-anagonists are ineffective.

Omalizumab (Xolair)

Omalizumab is a recombinant humanized monoclonal antibody administered by subcutaneous injection every 4 weeks. It selectively binds to IgE and inhibits binding to IgE receptors on the surface of mast cells and basophils. It is indicated for chronic idiopathic urticaria in adults and children aged 12 years or older who remain symptomatic despite H1 antihistamine treatment.

Topical Skin Products

Doxepin cream (Prudoxin, Xepin, Zonalon)

Doxepin is a TCA that has potent H1-blocking activity, making it quite useful for urticaria. However, it has very potent sedative and anticholinergic effects. It can be quite effective if used at bedtime because the sedative effects can help a patient with pruritus sleep. Widespread use produces sedation, as does use in areas of high percutaneous absorption (eg, genitals). Many individuals develop an allergy to topical doxepin.

Capsaicin topical (Axsain, Capzasin P, Capzasin-HP)

Capsaicin is a natural chemical derived from plants of the Solanaceae family. It penetrates deep for temporary relief of minor aches and pains of muscles and joints associated with inflammatory reactions. Capsaicin may render skin and joints insensitive to pain by depleting substance P in peripheral sensory neurons. It has demonstrated effectiveness in several studies of diabetic neuropathic pain and in other types of neuropathic pain.

 

Questions & Answers

Overview

What is urticaria (hives) and how is it characterized?

How is urticaria (hives) categorized?

What are possible precipitants of acute urticaria (hives)?

How is physical urticaria (hives) characterized?

What should be the focus of the physical exam for urticaria (hives)?

What studies are performed in the evaluation of urticaria (hives)?

What prehospital care should be given for urticaria (hives) if anaphylactic shock is suspected?

What are the treatment options for urticaria (hives)?

What consultations may be helpful for the treatment of urticaria (hives)?

What is urticaria (hives) and what other conditions does it resemble?

How is acute urticaria (hives) characterized?

What is the pathophysiology of urticaria (hives)?

Which mechanisms activate histamine in the pathophysiology of urticaria (hives)?

What is the role of physical stimulus in the pathophysiology of urticaria (hives)?

What are causes of acute generalized urticaria (hives)?

What are the causes of chronic urticaria (hives)?

What is urticaria pigmentosa (cutaneous mastocytosis), and how is it differentiated from common urticaria (hives)?

What causes recurrent urticaria (hives)?

What is the prevalence of urticaria (hives) in the US?

What is the global prevalence of urticaria (hives)?

How does the prevalence of urticaria (hives) vary by race?

How does the incidence of urticaria (hives) vary by sex?

How does the incidence of urticaria (hives) vary by age?

What are the primary manifestations of urticaria (hives)?

What is the prognosis of acute and chronic urticaria (hives)?

What information about urticaria (hives) should patients receive?

Presentation

What are the signs and symptoms of urticaria (hives)?

What history is helpful in categorizing urticaria (hives)?

What is the focus of history for chronic or recurrent urticaria (hives)?

What should be the focus of history for acute urticaria (hives)?

Which physical findings are characteristic of urticaria (hives)?

What should be the focus of the physical exam for urticaria (hives)?

DDX

What are the differential diagnoses for Urticaria?

Workup

How are chronic autoimmune disease or underlying malignancy excluded during the evaluation of urticaria (hives)?

What is the role of lab testing in the evaluation of urticaria (hives)?

What is the role of imaging studies in the evaluation of urticaria (hives)?

What is the role of biopsy in the evaluation of urticaria (hives)?

Treatment

When is emergency department (ED) treatment of urticaria (hives) indicated?

When is epinephrine indicated in the treatment of urticaria (hives)?

How should hypotension be treated in a patient with urticaria (hives)?

What is the first-line therapy for urticaria (hives)?

What is the role of H2 antihistamines in the treatment of urticaria (hives)?

What is the role of doxepin in the treatment of urticaria (hives)?

What is the role of glucocorticoids in the treatment of urticaria (hives)?

What is the treatment for angioedema in patients with urticaria (hives)?

How is urticarial vasculitis managed?

What is the treatment for chronic urticaria (hives)?

When is hospitalization indicated for the treatment of urticaria (hives)?

Which specialist consultations may be helpful in the treatment of urticaria (hives)?

How is urticaria (hives) prevented?

What is the outpatient treatment for urticaria (hives)?

What long-term monitoring is needed following treatment of angioedema and urticaria (hives)?

Which specialist consultations may be needed for suspected urticarial vasculitis, chronic or recurrent urticaria (hives)?

Medications

How are most cases of urticaria (hives) treated?

What is the treatment regimen for urticaria (hives) resistant to the standard dosage of cetirizine or fexofenadine?

What is the role of omalizumab (Xolair) in the treatment of chronic idiopathic urticaria (hives) (CIU)?

What is the role of glucocorticoids in the treatment of refractory chronic urticaria (hives)?

What is the role of doxepin in the treatment of chronic urticaria (hives)?

What are topical treatment options for refractory urticaria (hives)?

What is the role of cyproheptadine in the treatment of urticaria (hives)?

What is the role of cyclosporine in the treatment of refractory chronic urticaria (hives)?

Which nonantihistamine or nonbiologic agents are effective in the treatment of urticaria (hives)?

Which medications in the drug class Monoclonal Antibody are used in the treatment of Urticaria?

Which medications in the drug class H2-receptor antagonists are used in the treatment of Urticaria?

Which medications in the drug class Glucocorticoids are used in the treatment of Urticaria?

Which medications in the drug class Tricyclic antidepressants (TCAs) are used in the treatment of Urticaria?

Which medications in the drug class H1-receptor antagonist antihistamines are used in the treatment of Urticaria?

Which medications in the drug class Topical Skin Products are used in the treatment of Urticaria?