section name header

Introduction

ICD codes

ICD-10: L50

Epidemiology

Epidemiology and Etiology

INCIDENCE Fifteen percent to 23% of the population may have this condition during their lifetime.

ETIOLOGY Urticaria/angioedema is not a disease but a cutaneous reaction pattern. For classification and etiology, see Table 14-1.

Clinical Types

ACUTE URTICARIACommon Acute onset and recurring over <30 days. Usually large wheals are often associated with angioedema (Figs. 14-1and 14-3); often IgE dependent with atopic diathesis; related to foods, parasites, and penicillin. Also, complement mediated in serum sickness-like reactions (whole blood, immunoglobulins, and penicillin) (see also "Drug-Induced Acute Urticaria" in Section 23).

CHRONIC URTICARIA(Fig. 14-2) Rarely IgE dependent but often resulting from anti-FcεRI (high-affinity IgE receptor) autoantibodies; etiology unknown in 80% and therefore considered idiopathic. Intolerance to salicylates and benzoates. Chronic idiopathic urticaria affects adults predominantly and is approximately twice as common in women as in men. Up to 40% of patients with chronic urticaria of >6 months' duration still have urticaria 10 years later.

SYMPTOMSPruritus Angioedema of tongue, pharynx interferes with speech, food intake, and breathing. Angioedema of larynx may lead to asphyxia. Can also involve palms and toes.

Etiology and Pathogenesis

Special Features/As Related to Pathogenesis

Immunologic Urticaria. IgE Mediated Lesions in acute IgE-mediated urticaria result from antigen-induced release of biologically active molecules from mast cells or basophilic leukocytes sensitized with specific IgE antibodies (type I anaphylactic hypersensitivity). Released mediators increase venular permeability and modulate the release of biologically active molecules from other cell types. Often in atopic background. Antigens: food (milk, eggs, wheat, shellfish, nuts), therapeutic agents, drugs (penicillin) (see also "Drug-Induced Acute Urticaria, Angioedema, Edema, and Anaphylaxis" in Section 23), helminths. Most often acute (Fig. 14-1and Drug-induced angioedema, Section 23).

Complement MediatedAcute. By way of immune complexes activating complement and releasing anaphylatoxins that induce mast cell degranulation. Serum sickness, administration of whole blood, and immunoglobulins.

Autoimmune Common, chronic. Autoantibodies against FcεRI and/or IgE. Positive autologous serum skin test is noted. Clinically, patients with these autoantibodies (up to 40% of patients with chronic urticaria) are indistinguishable from those without them (Fig. 14-2). These autoantibodies may explain why plasmapheresis, intravenous immunoglobulins, and cyclosporine induce remission of disease activity in these patients.

Immunologic Contact Urticaria Usually in children with atopic dermatitis sensitized to environmental allergens (grass and animals) or individuals sensitized to wearing latex rubber gloves; can be accompanied by anaphylaxis.

PHYSICAL URTICARIASDermographism Linear urticarial lesions occur after stroking or scratching the skin; they itch and fade in 30 min (Fig. 14-4); 4.2% of the normal population have it; symptomatic dermographism is a nuisance.

Cold Urticaria Usually in children or young adults; urticarial lesions confined to sites exposed to cold occurring within minutes after rewarming. "Ice cube" test (application of an ice cube for a few minutes to skin) causes wheal.

Solar Urticaria Urticaria after solar exposure. Action light spectrum from 290 to 500 nm; whealing lasts for <1 hour, may be accompanied by syncope; histamine is one of the mediators (see Section 10 and Fig. 10-11).

Cholinergic Urticaria Exercise to the point of sweating provokes typical small, papular, highly pruritic urticarial lesions (Fig. 14-5). May be accompanied by wheezing.

Aquagenic Urticaria Very rare. Contact with water of any temperature induces eruption similar to cholinergic urticaria.

Pressure Angioedema Erythematous swelling induced by sustained pressure (for instance, buttock swelling when seated, hand swelling after hammering, foot swelling after walking). Delayed (30 minutes to 12 hours). Painful, may persist for several days, and interferes with quality of life. No laboratory abnormalities; fever may occur.

Vibration Angioedema May be familial (autosomal dominant) or sporadic. Rare. It is believed to result from histamine release from mast cells caused by a "vibrating" stimulusrubbing a towel across the back produces lesions, but direct pressure (without movements) does not.

URTICARIA CAUSED BY MAST CELL-RELEASING AGENTS AND PSEUDOALLERGENS AND CHRONIC IDIOPATHIC URTICARIA Urticaria/angioedema and even anaphylaxis-like symptoms may occur with radiocontrast media and as a consequence of intolerance to salicylates, food preservatives, and additives (e.g., benzoic acid and sodium benzoate), several azo dyes, including tartrazine and sunset yellow (pseudoallergens) (Fig. 14-2); also to ACE inhibitors. May be acute and chronic. In chronic idiopathic urticaria, histamine derived from mast cells in the skin is considered the major mediator, also eicosanoids and neuropeptides.

Nonimmune Contact Urticaria Caused by direct effects of exogenous urticants penetrating into skin or blood vessels. Localized to the site of contact. Sorbic acid, benzoic acid in eye solutions and foods, cinnamic aldehydes in cosmetics, histamine, acetylcholine, serotonin in nettle stings.

URTICARIA ASSOCIATED WITH VASCULAR/CONNECTIVE TISSUE AUTOIMMUNE DISEASE Urticarial lesions may be associated with systemic lupus erythematosus (SLE) and Sjögren syndrome. However, in most instances, they represent urticarial vasculitis (see Urticarial Vasculitis).

DISTINCT ANGIOEDEMA (± URTICARIA) SYNDROMESHereditary Angioedema (HAE) A serious autosomal-dominant disorder; may follow trauma (physical and emotional). Angioedema of the face (Fig. 14-6) and extremities, episodes of laryngeal edema, and acute abdominal pain caused by angioedema of the bowel wall presenting as surgical emergency. Urticaria rarely occurs. Laboratory abnormalities involve the complement system: decreased levels of C1-esterase inhibitor (85%) or dysfunctional inhibitor (15%), low C4 value in the presence of normal C1 and C3 levels. Angioedema results from bradykinin formation, since C1-esterase inhibitor is also the major inhibitor of the Hageman factor and kallikrein, the two enzymes required for kinin formation. Episodes can be life threatening.

Angioedema-Urticaria-Eosinophilia Syndrome Severe angioedema, only occasionally with pruritic urticaria, involving the face, neck, extremities, and the trunk that lasts for 7 to 10 days. There is fever and marked increase in normal weight (increased by 10% to 18%) owing to fluid retention. No other organs are involved. Laboratory abnormalities include striking leukocytosis (20,000 to 70,000/µL) and eosinophilia (60% to 80% eosinophils), which are related to the severity of attack. There is no family history. This condition is rare and prognosis is good.

Clinical Manifestation

SKIN LESIONS Sharply defined wheals (Fig. 14-1), small (<1 cm) to large (>8 cm), erythematous or white with an erythematous rim, round, oval, arciform, annular, serpiginous (Figs. 14-1and 14-2), caused by confluence and resolution in one area and progression in another (Fig. 14-2). Lesions are pruritic and transient.

Angioedemaskin colored, transient enlargement of portion of face (eyelids, lips, or tongue) (Fig. 14-3and Drug-induced angioedema, Section 23), extremity, or other sites resulting from subcutaneous edema.

Distribution Usually regional or generalized. Localized in solar, pressure, vibration, and cold urticaria/angioedema and confined to the site of the trigger mechanism (see below).

Laboratory Examinations

SEROLOGY Search for hepatitis B-associated antigen, assessment of the complement system, assessment of specific IgE antibodies by radioallergosorbent test (RAST), anti-FcεRI autoantibodies. Serology for lupus and Sjögren syndrome. Autologous serum skin test for autoimmune urticaria.

HEMATOLOGY The erythrocyte sedimentation rate (ESR) is often elevated in urticarial vasculitis, and there may be hypocomplementemia; transient eosinophilia in urticaria from reactions to foods, parasites, and drugs; high levels of eosinophilia in the angioedema- urticaria-eosinophilia syndrome.

COMPLEMENT STUDIES Screening for functional C1 inhibitor in HAE.

ULTRASONOGRAPHY For early diagnosis of bowel involvement in HAE; if abdominal pain is present, this may indicate edema of the bowel.

PARASITOLOGY Stool specimen for presence of parasites.

Diagnosis and Differential Diagnosis

Diagnosis

A detailed history (previous diseases, drugs, foods, parasites, physical exertion, and solar exposure) is of utmost importance. History should differentiate between type of lesionsurticaria, angioedema, or urticaria + angioedema; duration of lesions (<1 hour or 1 hour), pruritus; pain on walking (in foot involvement), flushing, burning, and wheezing (in cholinergic urticaria). Fever in serum sickness and in the angioedema-urticaria-eosinophilia syndrome; in angioedema, hoarseness, stridor, and dyspnea. Arthralgia (serum sickness, urticarial vasculitis), abdominal colicky pain in HAE. A careful history of medications including penicillin, aspirin, nonsteroidal anti-inflammatory drugs, and ACE inhibitors should be obtained.

Dermographism is evoked by stroking the skin; pressure urticaria is tested by application of pressure (weight) perpendicular to the skin; vibration angioedema by a vibratory stimulus, like rubbing the back with a towel. Cholinergic urticaria can best be diagnosed by exercise to sweating and intracutaneous injection of acetylcholine or mecholyl, which will produce micropapular whealing. Solar urticaria is verified by testing with UVB, UVA, and visible light (see Solar Urticara, Section 10). Cold urticaria is verified by a wheal response to the application of an ice cube to the skin or a test tube containing ice water. Autoimmune urticaria is tested by the autologous serum skin test and determination of anti-FcεRI antibody. If urticarial wheals do not disappear in 24 hours, urticarial vasculitis should be suspected and a biopsy done. The person with angioedema-urticaria-eosinophilia syndrome has high fever, high leukocytosis (mostly eosinophils), a striking increase in body weight caused by retention of water, and a cyclic pattern that may occur and recur over a period of years. HAE has a positive family history and is characterized by angioedema as the result of trauma, abdominal pain, and decreased levels of C4 and C1-esterase inhibitor.

A practical approach to the diagnosis of urticaria/angioedema is shown in Figure 14-7and to angioedema alone in Figure 14-8.

Course and Prognosis

Half of the patients with urticaria alone are free of lesions within 1 year, but 20% have lesions for >20 years. Prognosis is good in most syndromes except HAE, which may be fatal if untreated.

Management

Prevention by elimination of etiologic chemicals or drugs: aspirin and food additives, especially in chronic recurrent urticariararely successful; prevent trigger in physical urticarias.

ANTIHISTAMINES H1-blockers, e.g., hydroxyzine, terfenadine; or loratadine, cetirizine, fexofenadine; 180 mg/d of fexofenadine or 10 to 20 mg/d of loratadine usually controls most cases of chronic urticaria, but cessation of therapy usually results in a recurrence; if they fail, H1 and H2 blockers (cimetidine) and/or mast cell-stabilizing agents (ketotifen). Doxepin, a tricyclic antidepressant with marked H1 antihistaminic activity, is valuable when severe urticaria is associated with anxiety and depression.

PREDNISONE In acute urticaria with angioedema; also for angioedema-urticaria-eosinophilia syndrome.

DANAZOL OR STANOZOLOL Long-term therapy for HAE; watch out for hirsutism, irregular menses; whole fresh plasma or C1-esterase inhibitor in the acute attack. Icatibant, a very effective bradikin-B2-receptor antagonist for subcutaneous application, is now available.

OTHER In chronic idiopathic or autoimmune urticaria, if no response to antihistamines: switch to cyclosporine and taper gradually, if glucocorticoids are contraindicated or if side effects occur.

OMALIZUMAB Chronic idiopathic urticaria that is not controlled by antihistamines (double the conventional dose) will respond to Omalizumab 300 mg SC every 4 weeks.

C1 Inhibitor Deficiency (hereditary and acquired):

Ecallantide

Icatibant