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Urticaria, Angioedema, and Pruritus


Urticaria, also referred to as hives or wheals, is a common and distinctive cutaneous reaction pattern. Hives may occur at any age; up to 20% of the population will have at least one episode. Hives may be more common in atopic patients. Urticaria is classified as acute or chronic. The majority of cases are acute, lasting from hours to a few weeks. Angioedema frequently occurs with acute urticaria, which is more common in children and young adults. Chronic urticaria (CU; arbitrarily defined as episodes of urticaria lasting more than 6 weeks) is more common in middle-aged women.

Because most individuals can diagnose urticaria and realize that it is a self-limited condition, they do not seek medical attention.

The cause of acute urticaria is determined in many cases, but the cause of CU is determined in only 5% to 20% of cases. Patients with CU present a frustrating problem in diagnosis and management. History taking is crucial but tedious, and treatment is usually supportive rather than curative.

These patients are often subjected to detailed and expensive medical evaluations that usually prove unrewarding. Studies demonstrate the value of a complete history and physical examination followed by the judicious use of laboratory studies in evaluating the results of the history and physical examination.

Clinical Aspects

Definition

A hive or wheal is a circumscribed, erythematous or white, nonpitting, edematous, usually pruritic plaque that changes in size and shape by peripheral extension or regression during the few hours or days that the individual lesion exists. The edematous central area (wheal) can be pale in comparison to the erythematous surrounding area (flare).

The evolution of urticaria is a dynamic process. New lesions evolve as old ones resolve. Hives result from localized capillary vasodilation, followed by transudation of protein-rich fluid into the surrounding tissue; they resolve when the fluid is slowly reabsorbed. The edema in urticaria is found in the superficial dermis. Lesions of angioedema are less well demarcated. The edema in angioedema is found in the deep dermis or subcutaneous/submucosal locations. The differential diagnosis of hives is found in Box 6.1 and Fig. 6.1 .

Box 6.1
From Green JJ, Heymann WR. Urticaria and angioedema. Adv Dermatol 2001;17:141–82.
Differential Diagnosis of Urticaria

  • Bullous pemphigoid (urticarial stage)

  • Dermatitis herpetiformis

  • Drug eruptions

  • Erythema marginatum

  • Erythema multiforme

  • Papular urticaria

  • Pruritic urticarial papules and plaques of pregnancy

  • Still disease

  • Urticaria pigmentosa

  • Urticarial vasculitis

FIG 6.1, Phenotypic classification of urticaria and angioedema. This figure is intended to provide a framework for clinical use based on the author's and others’ experience that most presentations of urticaria and angioedema can be grouped in distinct categories that can predict prognosis and response to therapy. IgE, immunoglobulin E; NSAID, nonsteroidal antiinflammatory drug.

Clinical Presentation

Lesions vary in size from the 2- to 4-mm edematous papules of cholinergic urticaria to giant hives, a single lesion of which may cover an extremity. They may be round or oval; when confluent, they become polycyclic ( Figs. 6.2 to 6.9 ). A portion of the border either may not form or may be reabsorbed, giving the appearance of incomplete rings (see Fig. 6.4 ). Hives may be uniformly red or white, or the edematous border may be red and the remainder of the surface white. This variation in color is usually present in superficial hives; thicker plaques have a uniform color (see Figs. 6.2 to 6.7 ).

FIG 6.2, Hives. The most characteristic presentation is uniformly red edematous plaques surrounded by a faint white halo. These superficial lesions occur from transudation of fluid into the dermis.

FIG 6.3, Hives. Urticarial plaques in different stages of formation.

FIG 6.5, Hives. The entire palm is affected and is greatly swollen. The lesions resemble those of erythema multiforme.

FIG 6.6, Hives. Superficial hives vary in color.

FIG 6.7, Hives. Hives have become more extensive and confluent.

FIG 6.8, Hives. Angioedema is a deeper, larger hive than those shown in Figs. 6.2 to 6.4 . It is caused by transudation of fluid into the dermis and subcutaneous tissue. The lip is a common site.

FIG 6.9, Hives. Angioedema. Massive swelling of the entire central area of the back.

FIG 6.4, Hives. Polycyclic pattern.

Hives may be surrounded by a clear or red halo. Thicker plaques that result from massive transudation of fluid into the dermis and subcutaneous tissue are referred to as angioedema. These thick, firm plaques, like typical hives, may occur on any skin surface, but typically involve the lips, larynx (causing hoarseness or a sore throat), and mucosa of the gastrointestinal (GI) tract (causing abdominal pain) (see Figs. 6.8 and 6.9 ). Bullae or purpura may appear in areas of intense swelling. Purpura and scaling may result as urticaria clear. Hives usually have a haphazard distribution, but those elicited by physical stimuli have characteristic features and distribution.

Symptoms

Hives itch. The intensity varies, and some patients with a widespread eruption may experience little itching. Pruritus is milder in deep hives (angioedema) because the edema occurs in areas where there are fewer sensory nerve endings than there are near the surface of the skin.

Clinical Classification of Urticaria/Angioedema

The CU subtypes are found in Box 6.2 .

Box 6.2
Adapted from Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA 2 LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy 2014;69(7):868–87.
Chronic Urticaria Subtypes

Chronic Spontaneous Urticaria (CSU)

Spontaneous appearance of wheals, angioedema or both for >6 weeks due to known *

* For example, autoreactivity, i.e., the presence of mast cell–activating autoantibodies.

or unknown causes.

Inducible Urticaria

  • Symptomatic dermographism †

    † Also called urticaria factitia or dermographic urticaria.

  • Cold urticaria ‡

    ‡ Also called cold contact urticaria.

  • Delayed pressure urticaria §

    § Also called pressure urticaria.

  • Solar urticaria

  • Heat urticaria

    Also called heat contact urticaria.

  • Vibratory angioedema

  • Cholinergic urticaria

  • Contact urticaria

  • Aquagenic urticaria

Urticaria can be provoked by immunologic and nonimmunologic mechanisms, as well as physical stimuli, skin contact, or small vessel vasculitis. Physical and ordinary urticarias may coexist. Angioedema occurs with or without urticaria. Angioedema without urticaria may indicate a C1 esterase inhibitor deficiency. The duration of hives is also an important diagnostic feature ( Table 6.1 ).

TABLE 6.1
Duration of Hives
Type of Urticaria Duration
Ordinary and delayed pressure 4–36 hours
Physical (except delayed pressure) 30 min–2 hours
Contact (may have a delayed phase) 1–2 hours
Urticarial vasculitis 1–7 days

Pathophysiology

Histamine

Histamine is the most important mediator of urticaria. Histamine is produced and stored in mast cells. There are several mechanisms for histamine release via mast cell surface receptors. A variety of immunologic, nonimmunologic, physical, and chemical stimuli may be responsible for the degranulation of mast cell granules and the release of histamine into the surrounding tissue and circulation. About one third of patients with CU have circulating functional histamine-releasing immunoglobulin G (IgG) autoantibodies that bind to the high-affinity IgE receptor (Fc epsilon RI). Release of mast cell mediators can cause inflammation and accumulation and activation of other cells, including eosinophils, neutrophils, and possibly basophils. Histamine causes endothelial cell contraction, which allows vascular fluid to leak between the cells through the vessel wall, contributing to tissue edema and wheal formation.

When injected into skin, histamine produces the “triple response” of Lewis, the features of which are local erythema (vasodilation), the flare characterized by erythema beyond the border of the local erythema, and a wheal produced from leakage of fluid from the postcapillary venule. Histamine induces vascular changes by a number of mechanisms ( Fig. 6.10 ). Blood vessels contain two (and possibly more) receptors for histamine. The two most studied are designated H 1 and H 2 .

FIG 6.10, Physiology of histamine release.

H 1 Receptors

H 1 receptors, when stimulated by histamine, cause an axon reflex, vasodilation, and pruritus. Acting through H 1 receptors, histamine causes smooth muscle contraction in the respiratory and GI tracts and pruritus and sneezing by sensory nerve stimulation. H 1 receptors are blocked by the vast majority of clinically available antihistamines called H 1 antagonists (e.g., chlorpheniramine), which occupy the receptor site and prevent attachment of histamine.

H 2 Receptors

When H 2 receptors are stimulated, vasodilation occurs. H 2 receptors are also present on the mast cell membrane surface and, when stimulated, further inhibit the production of histamine. Activation of H 2 receptors alone increases gastric acid secretion. Cimetidine, ranitidine, and famotidine are H 2 -blocking agents (antihistamines). H 2 receptors are present at other sites. Activation of both H 1 and H 2 receptors causes hypotension, tachycardia, flushing, and headache. The H 2 -blocking agents are used most often to suppress gastric acid secretion. They are used occasionally, usually in combination with an H 1 -blocking agent, to treat urticaria.

Initial Evaluation of All Patients With Urticaria

  • 1

    Determine by skin examination that the patient actually has urticaria and not bites.

  • 2

    Rule out the presence of physical urticaria to avoid an unnecessarily lengthy evaluation. Stroking the arm with the wood end of a cotton-tipped applicator will test for dermographism.

  • 3

    Determine whether hives are acute or chronic. The difference in duration has been arbitrarily set at 6 weeks. Acute urticaria involves episodes of urticaria persisting less than 6 weeks. Chronic urticaria consists of recurrent episodes of widespread urticaria present for longer than 6 weeks.

  • 4

    Review the known causes of urticaria listed in Box 6.3 (Etiologic Classification of Urticaria). Knowledge of the etiologic factors helps to direct the history and physical examination.

    Box 6.3
    From Geha R, Buckley CE, Greenberger P, et al. Aspartame is no more likely than placebo to cause urticaria/angioedema: results of a multicenter, randomized, double-blind, placebo-controlled, crossover study. J Allergy Clin Immunol 1993;92:513–20.
    Etiologic Classification of Urticaria

    Foods

    Fish, shellfish, nuts, eggs, chocolate, strawberries, tomatoes, pork, cow's milk, cheese, wheat, yeast

    Food Additives

    Salicylates, dyes such as tartrazine, benzoates, penicillin, aspartame (NutraSweet), *

    * Probably does not cause hives.

    sulfites

    Drugs

    Penicillin, aspirin, sulfonamides, and drugs that cause a nonimmunologic release of histamine (e.g., morphine, codeine, polymyxin, dextran, curare, quinine)

    Infections

    Chronic bacterial infections (e.g., sinus, dental, chest, gallbladder, urinary tract), Campylobacter enteritis, fungal infections (e.g., dermatophytosis, candidiasis), viral infections (e.g., hepatitis B prodromal reaction, infectious mononucleosis, coxsackie), protozoal and helminth infections (e.g., intestinal worms, malaria)

    Inhalants

    Pollens, mold spores, animal dander, house dust, aerosols, volatile chemicals

    Internal Disease

    Serum sickness, systemic lupus erythematosus, hyperthyroidism, autoimmune thyroid disease, carcinomas, lymphomas, juvenile rheumatoid arthritis (Still disease), leukocytoclastic vasculitis, polycythemia vera (acne urticaria: urticarial papule surmounted by a vesicle), rheumatic fever, some blood transfusion reactions

    Physical Stimuli (Physical Urticarias)

    Dermographism, pressure urticaria, cholinergic urticaria, exercise-induced anaphylactic syndrome, solar urticaria, cold urticaria, heat urticaria, vibratory urticaria, water (aquagenic) urticaria

    Nonimmunologic Contact Urticaria

    Plants (e.g., nettles), animals (e.g., caterpillars, jellyfish), medications (e.g., cinnamic aldehyde, compound 48/80, dimethyl sulfoxide)

    Immunologic or Uncertain Mechanism Contact Urticaria

    Ammonium persulfate used in hair bleaches, chemicals, foods, textiles, wood, saliva, cosmetics, perfumes, bacitracin

    Skin Diseases

    Urticaria pigmentosa (mastocytosis), dermatitis herpetiformis, pemphigoid, amyloidosis

    Hormones

    Pregnancy, premenstrual flare-ups (progesterone)

    Genetic, Autosomal Dominant (All Rare)

    Hereditary angioedema, cholinergic urticaria with progressive nerve deafness, amyloidosis of the kidney, familial cold urticaria, vibratory urticaria

Acute Urticaria

If the urticaria has been present for less than 6 weeks, it is considered acute ( Fig. 6.11 ). The evaluation and management of acute urticaria are outlined in Box 6.4 . A history and physical examination should be performed, and laboratory studies are selected to investigate abnormalities. Histamine release that is induced by allergens (e.g., drugs, foods, or pollens) and mediated by IgE is a common cause of acute urticaria, and particular attention should be paid to these factors during the initial evaluation. There are no routine laboratory studies for the evaluation of acute urticaria. Once all possible causes are eliminated, the patient is treated with antihistamines to suppress the hives and stop the itching. Because urticaria clears spontaneously in most patients, an extensive workup is not advised during the early weeks of an urticarial eruption.

FIG 6.11, Acute urticaria. A–B, Wheals vary from a few millimeters to large, continuous plaques that may cover a large area. The plaques have smooth surfaces with curved or polycyclic borders. The degree of erythema varies. Central clearing occurs in expanding lesions.

Box 6.4
Acute Urticaria – Evaluation and Management

History and Physical Examination

  • 1

    Ask the patient if he or she knows what causes the hives. In many instances, the patient will have determined the cause.

  • 2

    Take a history. See Box 6.3 for specific etiologies. Drugs are common causes in adults. Viral respiratory tract infections and streptococcal infections are common causes in children.

  • 3

    Perform a physical examination.

  • 4

    Stroke the arm to test for dermographism.

If the etiology is not determined by history, physical examination, and stroking the arm, order laboratory tests.

Laboratory Tests

  • 1

    Order complete blood count (CBC) with differential, erythrocyte sedimentation rate (ESR), liver function tests (LFTs), and urinalysis.

  • 2

    The history and physical examination may provide evidence that warrants additional tests. Consider testing for hepatitis A, B, or C; infectious mononucleosis; thyroid function; thyroid antibodies; and antinuclear antibodies (ANAs).

Consider Allergen Testing

  • 1

    Skin tests: foods, drugs, aeroallergens, insect venom, natural rubber. Except for penicillin, antibiotics have a high false-positive rate with skin-prick testing.

  • 2

    Radioallergosorbent tests (RASTs) for penicillin, succinylcholine, natural rubber latex.

  • 3

    Food testing: food diaries and elimination diets.

  • 4

    Oral challenge testing for food and food additives.

Management

  • 1

    Avoid specific allergens.

  • 2

    Treat with oral H 1 antagonists.

  • 3

    Add H 2 antagonists for resistant cases.

  • 4

    Anaphylaxis – subcutaneous epinephrine with or without parenteral H 1 and H 2 antihistamines (e.g., 50 mg of diphenhydramine and 50 mg of ranitidine). Systemic corticosteroids are sometimes useful.

  • 5

    Intravenous contrast media reactions – pretreat with H 1 antagonists and corticosteroids.

  • 6

    Latex allergic patients – prophylactic administration of corticosteroids before surgery.

  • 7

    Insect venom reaction – desensitization, preloaded syringes of epinephrine.

Children With Hives

Food origin is important in the etiology of infantile urticaria. In one series it accounted for 62% of patients, more than drug etiology (22%), physical urticaria (8%), and contact urticaria (8%).

Etiology of Acute Urticaria

Acute urticaria is IgE-mediated, complement-mediated, or nonimmune-mediated. The cause of acute urticaria is unknown in 30% to 50% of cases. The most common causes are infections, drugs, and foods (see Box 6.3 ).

IgE-Mediated Reactions

Type I hypersensitivity reactions are probably responsible for most cases of acute urticaria. Circulating antigens such as foods, drugs, or inhalants interact with cell membrane–bound IgE to release histamine. Food allergies are present in 8% of children younger than 3 years of age and in 2% of adults. Food allergies are the most common cause of anaphylaxis. Yellow jackets are the most common cause of insect sting–induced urticaria/anaphylaxis in the United States. Latex-induced urticaria is an IgE-mediated reaction.

Complement-Mediated, or Immune Complex–Mediated, Acute Urticaria

Complement-mediated acute urticaria can be precipitated by administration of whole blood, plasma, immunoglobulins, and drugs or by insect stings. Type III hypersensitivity reactions (Arthus reactions) occur with deposition of insoluble immune complexes in vessel walls. The complexes are composed of IgG or IgM with an antigen such as a drug. Urticaria occurs when the trapped complexes activate complement to cleave the anaphylatoxins C5a and C3a from C5 and C3. C5a and C3a are potent releasers of histamine from mast cells. Serum sickness (fevers, urticaria, lymphadenopathy, arthralgias, and myalgias), urticarial vasculitis, and systemic lupus erythematosus are diseases in which hives may occur as a result of immune complex deposition.

Nonimmunologic Release of Histamine

Pharmacologic mediators, such as acetylcholine, opiates, polymyxin B, and strawberries, react directly with cell membrane–bound mediators to release histamine. Aspirin/nonsteroidal antiinflammatory drugs (NSAIDs) cause a nonimmunologic release of histamine. Patients with aspirin/NSAID sensitivity may have a history of allergic rhinitis or asthma. Urticaria may be caused by histamine-containing foods. Fish of the Scombridae family accumulate histamine during spoilage. The mechanism of radiocontrast-related urticaria/anaphylaxis is unknown. Incidence varies from 3.1% with newer, lower osmolar agents to 12.7% with previously established, higher osmolar agents. Atopy is a risk factor for urticaria developing after radiocontrast exposure. The physical urticarias may be induced both by direct stimulation of cell membrane receptors and by immunologic mechanisms.

Chronic Urticaria

Patients who have a history of hives lasting for 6 or more weeks are classified as having CU. The etiology is often unclear. The morphology is similar to that of acute urticaria ( Fig. 6.12 ). CU is more common in middle-aged women and is infrequent in children. Individual lesions remain for less than 24 hours, and any skin surface can be affected. Itching is worse at night. Respiratory and GI complaints are rare. Angioedema occurs in 50% of cases. Angioedema with CU differs from hereditary angioedema (HAE) in that it rarely affects the larynx and HAE patients do not have urticaria. CU patients may experience physical urticaria. Symptoms continue for weeks, months, or years. Pressure urticaria, CU, and angioedema frequently occur in the same patient. In one study, delayed pressure urticaria was present in 37% of patients with CU. Aspirin/NSAIDs, penicillin, angiotensin-converting enzyme inhibitors (ACEIs), opiates, alcohol, febrile illnesses, and stress exacerbate urticaria.

FIG 6.12, Chronic urticaria. Wheals may have the same configuration and intensity as those seen in acute urticaria. This patient has red plaques with sharply defined round, oval, and annular borders. The central clearing is highly characteristic of urticaria.

Pathogenesis

Chronic urticaria results from the cutaneous mast cell release of histamine. In contrast to acute urticaria, exogenous triggers are not found in most cases. Chronic urticaria in many cases may be an immune-mediated inflammatory disease. Release can be induced by specific immunoglobulin E (IgE), components of complement activation and endogenous peptides, endorphins, and enkephalins. Greater than 30% of CU patients have autoimmune phenomena characterized by positive ASSTs, antibodies to the alpha subunit of the basophil IgE receptor and to IgE, and thyroid autoimmunity. The evaluation and management of CU is outlined in Box 6.5 .

Box 6.5
Chronic Urticaria – Evaluation and Management

  • 1

    CU is a diagnosis of exclusion

Determine that lesions are hives and not insect bites (see Table 6.2 for differential diagnosis). Individual bite lesion lasts longer than 24 hours. Hives last less than 24 hours. Most urticarial plaques are larger than 2 cm. Stroke the patient's arm to rule out dermographism.

  • 2

    Take a history

    • Exact time of onset

    • Medication

    • Food and drink

    • Duration

    • Acute – days to a few weeks

    • Chronic – more than 6 weeks

    • Time of appearance

    • Time of day

    • Time of year

      • Constant – food, internal disease

      • Seasonal – inhalant allergy

    • Environment

    • Exposure to pollens, chemicals

      • Home – clear while at work or on vacation

      • Work – contact or inhalation of chemicals

    • Appearance after physical stimuli (physical urticaria)

    • Scratching, pressure, exercise, sun exposure, cold

    • Associated with arthralgia and fever

    • Juvenile rheumatoid arthritis, rheumatic fever, serum sickness, systemic lupus erythematosus, urticarial vasculitis, viral hepatitis

    • Duration of individual lesion

      • Less than 1 hour – physical urticarias, typical hives

      • Less than 24 hours – typical hives

      • More than 25 hours – urticarial vasculitis; scaling and purpura as lesions resolve

  • 3

    Physical examination

    • Stroke the arm to test for dermographism, and rule out other types of physical urticaria

    • Size

      • Papular – cholinergic urticaria, bites

      • Plaque – most cases

    • Thickness

      • Superficial – most cases

      • Deep – angioedema

    • Distribution

      • Generalized – ingestants, inhalants, internal disease

      • Localized – physical urticarias, contact urticaria

    • Sources of infection

      • Sinus and gum infections

      • Cystitis, vaginitis, prostatitis

      • Dental examination by dentist

      • Fix carious teeth

      • Treat periodontal disease

      • Internal disease, thyroid examination, gallbladder symptoms

If the etiology is not determined by history, physical examination, and stroking the arm, then consider ordering laboratory tests.

Laboratory Tests

  • 1

    Initial screening tests are complete blood count (CBC) with differential, erythrocyte sedimentation rate (ESR), liver function tests (LFTs), urinalysis, and studies to confirm findings of history and physical examination.

  • 2

    Order screening thyroid function tests and tests for thyroid autoimmunity (thyroid microsomal and thyroglobulin antibodies), especially in women or in those patients with a family history of thyroid disease or other autoimmune diseases.

  • 3

    Eosinophilia suggests drug, food, or parasitic causes.

  • 4

    Leukocytosis suggests chronic infection.

  • 5

    Order ANA and ESR for patients with connective tissue disease symptoms.

  • 6

    Sinus radiographs have been advocated.

  • 7

    Order oral challenge testing for food additives.

  • 8

    Food testing: use food diaries and elimination diets.

  • 9

    Perform lesion biopsy for hives lasting longer than 36 hours (rule out urticarial vasculitis), fever, arthralgias, elevated ESR, petechiae.

  • 10

    Order C4 only for patients with angioedema (not for patients with hives).

Management (See Also Table 6.3 )

  • 1

    Second-generation H 1 antihistamines: cetirizine (Zyrtec), loratadine (Claritin), fexofenadine (Allegra). Higher doses than suggested by the manufacturers may be required (e.g., 20 to 40 mg of cetirizine each day instead of 10 mg). Sedative side effects increase with higher dosages.

  • 2

    Add H 2 antagonists if H 1 agents do not provide effective control.

  • 3

    Hydroxyzine or doxepin is more sedating and can be added at nighttime. Doxepin can interact with other drugs that are metabolized by the cytochrome P-450 system (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin).

  • 4

    Systemic steroids (short courses) may be used to provide temporary relief.

  • 5

    Stop vitamins, laxatives, antacids, toothpaste, cigarettes, cosmetics and all toiletries, chewing gum, household cleaning solutions, aerosols.

  • 6

    Stop fruits, tomatoes, nuts, eggs, shellfish, chocolate, alcohol, milk, cheese, bread, diet drinks, junk food.

  • 7

    Consider a highly restricted diet such as lamb, rice, and salt (rarely effective).

  • 8

    Consider empiric treatment with antibiotics. Consider eradication of H. pylori in patients with infection.

  • 9

    Leukotriene receptor antagonists – zafirlukast (Accolate 10 mg, 20 mg) and montelukast (Singulair 10 mg/day) – may be effective, especially in combination with antihistamines. Leukotriene receptor antagonists may prevent the severe urticaria/angioedema exacerbations that follow the use of nonsteroidal antiinflammatory drugs (NSAIDs) in some patients with chronic urticaria.

  • 10

    Cyclosporine – patients with severe, unremitting chronic urticaria that responded poorly to antihistamines responded to cyclosporine 4 mg/kg daily in combination with cetirizine 20 mg daily.

  • 11

    Omalizumab – patients 12 years and older with chronic idiopathic urticaria who fail H 1 antihistamines. Omalizumab is dosed subcutaneously 150 or 300 mg every 4 weeks.

The patient must understand that the course of this disease is unpredictable; it may last for months or years. During the evaluation, the patient should be assured that antihistamines will decrease discomfort. The patient should also be told that although the evaluation may be lengthy and is often unrewarding, in most cases the disease ends spontaneously. Patients who understand the nature of this disease do not become discouraged so easily, nor are they as apt to go from physician to physician seeking a cure.

There are many studies in the literature on CU. Most demonstrate that if the cause is not found after investigation of abnormalities elicited during the history and physical examination, there is little chance that it will be determined. It is tempting to order laboratory tests such as antinuclear antibody (ANA) levels and stool examinations for ova and parasites in an effort to be thorough, but results of studies do not support this approach. There are certain tests and procedures that might be considered when the initial evaluation has proved unrewarding.

Rule Out Physical Urticarias

Unrecognized physical urticarias (see p. 189 ) may account for approximately 10% of all cases of CU. In one large study physical urticarias were present in 71% of patients with CU: 22% had immediate dermographism, 37% had delayed pressure urticaria, 11% had cholinergic urticaria, and 2% had cold urticaria.

The presence of physical urticaria should be ruled out by history and appropriate tests before a lengthy evaluation and treatment program is undertaken. Dermographism is the most common type of physical urticaria; it begins suddenly following drug therapy or a viral illness, persists for months or years, and clears spontaneously. Wheals that appear after the patient's arm is stroked prove the diagnosis.

Thyroid Autoimmune Disease

There is a significant association between CU and autoimmune thyroid disease (Hashimoto thyroiditis, Graves disease, toxic multinodular goiter). Thyroid autoimmunity was found in 12% of 140 consecutively seen patients with CU in one series; 88% were women. Most patients with thyroid autoimmunity are asymptomatic and have thyroid function that is normal or only slightly abnormal. Guidelines for evaluation and treatment of thyroid-related urticaria are presented in Box 6.6 .

Box 6.6
From Heymann WR. Chronic urticaria and angioedema associated with thyroid autoimmunity: review and therapeutic implications. J Am Acad Dermatol 1999;40(2 Pt 1):229–32.
Guidelines of Evaluation and Treatment of Thyroid-Related Chronic Urticaria

  • 1

    Screen for thyroid autoimmunity by testing for thyroid microsomal and thyroglobulin antibodies, especially in women (female:male ratio was 7 : 1), or in those patients with a family history of thyroid disease or other autoimmune disorders.

  • 2

    The administration of thyroid hormone may alleviate chronic urticaria and/or angioedema in selected patients.

    If patients with documented thyroid autoimmunity have been unresponsive to standard therapy for chronic urticaria and/or angioedema, consider the use of levothyroxine if the patients are hypothyroid or euthyroid. An appropriate initial dose is 1.7 mcg/kg/day.

  • 3

    The level of thyroid-stimulating hormone should be monitored by weeks 4 to 6 after the initiation of therapy, being kept in the low–normal range, to ensure that the patient is not becoming hyperthyroid.

  • 4

    If there has been no response of the chronic urticaria and/or angioedema by week 8 of administration, levothyroxine should be discontinued.

  • 5

    After being in remission for at least 1 to 2 months, levothyroxine should be discontinued. Should the chronic urticaria and/or angioedema recur, the hormone may be readministered, with an expectation that most patients will again be responsive to treatment.

Differential Diagnosis

The differential diagnosis of CU includes diseases that have lesions that mimic urticaria ( Table 6.2 ). These often have fixed urticarial lesions that have some atypical features, such as duration greater than 24 hours, relative lack of itch, or presence of epithelial changes (e.g., hyperpigmentation or hypopigmentation, vesicles or blisters, or scaling).

TABLE 6.2
Differential Diagnosis of Chronic Urticaria
Cutaneous lupus erythematosus Subacute cutaneous lupus erythematosus can present with urticarial-like lesions that burn rather than itch.
Urticarial vasculitis A small- to medium-vessel leukocytoclastic vasculitis, urticarial wheals; up to 40% have angioedema. Lesions are painful or burn, last several days, heal with dyspigmentation or purpura. Urticarial vasculitis is a harbinger of more active disease.
Urticaria pigmentosa Orange to deep brown pigmentation overlying the wheal. Urtication produced by stroking the skin; spares face, scalp, palms, and soles.
Sweet syndrome Women 30 to 50 years of age, acute fever, leukocytosis, urticarial-like plaques that may resemble urticaria, but are more persistent. Some lesions are studded with papules.
Fixed drug eruption Lesions occur in the same spot (or spots) with each exposure to offending agent. Red macule becomes edematous and develops hyperpigmentation.
Bullous pemphigoid In this autoimmune, subepidermal blistering disease, blisters appear on urticarial plaques.
Muckle–Wells syndrome (urticaria–deafness– amyloidosis syndrome) Symptoms include recurrent urticarial lesions, fever, arthralgia, arthritis, malaise, conjunctivitis, sensorineural hearing loss, secondary amyloidosis.
Chronic infantile neurologic cutaneous articular syndrome (neonatal-onset multisystemic inflammatory disease) Characteristics include (1) neonatal onset of cutaneous symptoms, (2) chronic meningitis, and (3) joint manifestations with recurrent fever and inflammation.
Schnitzler syndrome Symptoms include chronic, nonpruritic urticaria, fever, arthralgias or arthritis, bone pain, lymphadenopathy, immunoglobulin G (IgG) gammopathy.

Change of Environment

Because the environment consists of numerous antigens, patients should consider a trial period of 1 or 2 weeks of separation from home and work, preferably with a geographic change.

Highly Restricted Diet

A highly restricted diet may be attempted. Patients are fed lamb, rice, sugar, salt, and water for 5 days. The occurrence of new hives after 3 days suggests that foods have no role. If hives disappear, a new food is reintroduced every other day until hives appear.

Treatment of Occult Infections

Patients occasionally respond to antibiotics even in the absence of clinical infection. Consider eradication of Helicobacter pylori in patients with infection.

Skin Biopsy

Urticarial reactions display a wide spectrum of changes, ranging from a mild, mixed dermal inflammatory response to true vasculitis. Patients with hives that are characteristic of urticarial vasculitis should have a biopsy taken of the urticarial plaque. These hives burn rather than itch and last longer than 24 hours.

Dermal edema and dilated lymphatic and vascular capillaries occur. Increased numbers of neutrophils and eosinophils occur in patients with acute urticaria and in those with delayed pressure urticaria. Mast cell numbers are higher in the dermis of lesional and uninvolved skin of all patients with urticaria. Mononuclear infiltrates are more pronounced in cold urticaria and CU, when compared with other forms of CU.

Treatment of Urticaria

Table 6.3 lists the medications used to treat urticaria.

TABLE 6.3
Medications for Urticaria
Drug Initial Dose (Adult) Maximum Dose * (Adult) Liquid Formulation Tablet Formulation
H 1 -RECEPTOR ANTAGONISTS
Nonsedating *
Fexofenadine (Allegra) 180 mg daily 180 mg bid – 30, 60, 180 mg
Desloratadine (Clarinex) 5 mg daily 10 mg daily 5 mg
Loratadine (Claritin) 10 mg daily 20 mg bid 5 mg/5 mL 10 mg
Cetirizine (Zyrtec) 10 mg daily 10 mg bid 5 mg/5 mL 5, 10 mg
Carbinoxamine (Palgic) 4 mg daily 4–8 mg three to four times/day
Not for children <3 years of age		 4 mg/5 mL 4 mg
Levocetirizine (Xyzal) 5 mg daily 5 mg 2.5 mg/5 mL 5 mg
Sedating
Hydroxyzine (Atarax) 10 mg four times/day 50 mg four times/day
Suspension 25 mg/5 mL		 10 mg/5 mL 10, 25, 50, 100 mg
Diphenhydramine (Benadryl) 25 mg bid 50 mg four times/day Elixir 12.5 mg/5 mL
Syrup 6.25 mg/5 mL		 25, 50 mg; 12.5-mg chewable tablet
Cyproheptadine (Periactin) 4 mg four times/day 8 mg four times/day 2 mg/5 mL 8 mg
H 2 -RECEPTOR ANTAGONISTS
Cimetidine (Tagamet) 400 mg bid 800 mg bid 300 mg/5 mL 200, 300, 400, 800 mg
Ranitidine (Zantac) 150 mg bid 300 mg bid 75 mg/5 mL 150, 300 mg
Famotidine (Pepcid) 20 mg bid 40 mg bid 40 mg/5 mL 20, 40 mg
H 1 - AND H 2 -RECEPTOR ANTAGONISTS
Doxepin (Sinequan) 10 mg four times/day 50 mg four times/day 10 mg/mL 10, 25, 50, 75, 100, 150 mg
CORTICOSTEROIDS
Prednisone 20 mg every other day with gradual tapering Many other dose schedules 5 mg/5 mL 2.5, 5, 10, 20, 50 mg
Methylprednisolone (Medrol) 16 mg every other day with gradual tapering Many other dose schedules – 2, 4, 8, 16, 24, 32 mg
LEUKOTRIENE ANTAGONISTS – –
Zafirlukast (Accolate) 20 mg bid – – 10, 20 mg
Montelukast (Singulair) 10 mg daily – – 4-mg chewable, 5-mg chewable, 10 mg
EPINEPHRINE Injection
Ana-Guard (1 : 1000) 0.3 ml/dose Sub-Q
EpiPen (1 : 1000) 0.3 mg/dose
EpiPen Jr (1 : 2000) Children <12 yr: 0.15 mg/dose
IMMUNOTHERAPY
Cyclosporine 2–3 mg/kg daily 4–6 mg/kg daily 100 mg/mL 25, 50, 100 mg
Methotrexate 2.5 mg PO bid for 3 days of week 5 mg PO bid for 3 days of week 25 mg/mL 2.5 mg
Mycophenolate mofetil See guidelines in Box 8.19
Omalizumab 150 or 300 mg subcutaneously every 4 weeks.
bid, twice daily; PO, orally.

* Higher dosages than recommended by the manufacturer may be required for maximum therapeutic effect.

Approach to Treatment

First-Line Therapy

Nonsedating H 1 antihistamines (e.g., fexofenadine 180 mg daily) are the first choice for treatment. Previously established sedating H 1 antihistamines are more effective and so should be used to treat severe urticaria (e.g., 100 to 200 mg of hydroxyzine or diphenhydramine per day). For patients with severe angioedema (involving swelling of the face, tongue, and pharynx), diphenhydramine is particularly effective.

Patients become accustomed to the sedating effects after about a week, but their performance on driving tests remains impaired. H 2 -receptor antagonists have very few side effects and may be useful as adjunctive therapy. Leukotriene antagonists (montelukast 10 mg per day) are considered safe and are worth trying, but severe disease may require prednisone; many regimens have been suggested.

One approach is to start prednisone at 15 to 20 mg as a single morning dose every other day, gradually tapering to 2.5 to 5 mg every 3 weeks, depending on the patient's response, and discontinue after 4 to 5 months. Side effects are minimized with the use of dietary discretion and exercise. Some patients require a combination of all of these medications.

Patients who have no response to any of these approaches may respond to cyclosporine (200 to 300 mg of cyclosporine per day) or methotrexate (15 mg/week).

Antihistamines

For the majority of patients, acute and chronic urticaria may be controlled with antihistamines.

Mechanism of Action

Antihistamines control urticaria by inhibiting vasodilation and vessel fluid loss. Antihistamines do not block the release of histamine. If histamine has been released before an antihistamine is taken, the receptor sites will be occupied and the antihistamine will have no effect.

Initiation of Treatment

Antihistamines are the preferred initial treatment for urticaria and angioedema. Cetirizine, loratadine, or fexofenadine are first-line agents and are given once daily. Higher doses than suggested by the manufacturers may be required; see Table 6.3 for medications to treat urticaria. Patients with daytime and nighttime symptoms can be treated with combination therapy. These patients can be treated with a low-sedating antihistamine in the morning (e.g., loratadine 10 mg, or fexofenadine 180 mg, or cetirizine 10 to 20 mg) and a sedating antihistamine (e.g., hydroxyzine 25 mg) in the evening. Cetirizine can be mildly sedating. Doxepin is an alternative bedtime medication especially effective for anxious or depressed patients. The initial dose is 10 to 25 mg. Gradually increase the dose up to 75 mg for optimal control. Some patients with CU respond when an H 2 -receptor antagonist such as cimetidine is added to conventional antihistamines. This may be worth trying in refractory cases.

Side Effects

Antihistamines are structurally similar to atropine; therefore they produce atropine-like peripheral and central anticholinergic effects such as dry mouth, blurred vision, constipation, and dizziness. First-generation antihistamines (H 1 -receptor antagonists) such as chlorpheniramine, hydroxyzine, and diphenhydramine cross the blood–brain barrier and produce sedation. There is marked individual variation in response and side effects. Antihistamines may produce paradoxical psychomotor stimulation in children, especially in those ages 6 through 12.

Long-Term Administration

Prolonged use of H 1 antagonists does not lead to autoinduction of hepatic metabolism. The efficacy of H 1 -receptor blockade does not decrease with prolonged use. Tolerance of adverse central nervous system effects may or may not develop.

H 1 and H 2 Antihistamines

The majority of available antihistamines are H 1 antagonists (i.e., they compete for the H 1 -receptor sites). Cimetidine, ranitidine, and famotidine are H 2 antagonists that are used primarily for the treatment of gastric hyperacidity. Approximately 85% of histamine receptors in the skin are the H 1 subtype, and 15% are H 2 receptors. The addition of an H 2 -receptor antagonist to an H 1 -receptor antagonist augments the inhibition of a histamine-induced wheal-and-flare reaction once H 1 -receptor blockade has been maximized. It would seem that the combination of H 1 and H 2 antihistamines would provide optimal effects. The results of studies are conflicting but generally show that the combination is only slightly more effective than an H 1 -blocking agent used alone.

First-Generation (Sedating) H 1 Antihistamines

The first-generation H 1 antihistamines are divided into five classes (see Table 6.3 ). They are lipophilic, cross the blood–brain barrier, cause sedation, weight gain, and atropine-like complications including dry mouth, blurred vision, constipation, and dysuria. Metabolism occurs via the hepatic cytochrome P-450 (CYP) system. In patients with liver disease, or in patients who are taking CYP 3A4 inhibitors such as erythromycin or ketoconazole, the plasma half-life may be prolonged. The H 1 antagonists suppress the wheal caused by histamine. Antihistamines given during or after the onset of a hive are less effective. They prevent wheals rather than treat them.

Second-Generation (Low-Sedating) H 1 Antihistamines

The second-generation antihistamines are not lipophilic and do not readily cross the blood–brain barrier. They cause little sedation and little or no atropine-like activity.

Fexofenadine (Allegra)

Fexofenadine in a single dose of 180 mg daily or 60 mg twice daily is the recommended dosage for treating urticaria. Dosage adjustment is not necessary in the elderly or in patients with mild renal or hepatic impairment. Fexofenadine may offer the best combination of effectiveness and safety of all of the low-sedating antihistamines. A dose that is higher than recommended may be required.

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