Urticaria

Richard J. Sveum, MD

VOL 100 / NO 2 / AUGUST 1996 / POSTGRADUATE MEDICINE

This is the second of five articles on allergy

Preview : Patients who present with hives are often hoping their physician can tell them what caused the condition. In acute cases, that is often possible, but unfortunately, the majority of chronic cases are idiopathic. In this article, Dr Sveum puts the spotlight on urticaria. He stresses the importance of taking a careful medical history and describes treatment options.

U rticaria is part of a more severe allergic reaction called anaphylaxis, in which hypotension or respiratory distress can be present. When a patient presents with flaring or reddened skin and wheals, prompt evaluation is needed. Once the physician is sure anaphylaxis is not occurring, the next step is to proceed with careful history taking.

Urticaria, commonly known as hives, is a vascular reaction in the upper dermis, marked by the development of wheals on virtually any area of the body. Acute urticaria is defined as hives that last for less than 6 weeks (1); when the hives last for more than 6 weeks, however, the condition is considered chronic.

Chronic urticaria can be particularly frustrating to diagnose and treat, since most cases are idiopathic. Fortunately, the condition can often be controlled with appropriate medical management.

Mechanisms
Urticaria results from an immediate hypersensitivity reaction after exposure to an allergen or an antigen. Upon exposure, the skin mast cell releases the mediator histamine. Through histamine's effects on the histamine1 (H1) receptors, the capillaries are dilated. With the dilatation of the capillaries, vascular permeability occurs. Arteriolar dilatation through nerve reflex causes the typical flaring, and eventually the extravasation of fluid causes the wheals. Histamine also causes the pruritus that accompanies the condition. Other mast cell products act as chemotactic factors that attract other effector cells, such as eosinophils. Mast cells can also produce various kinins, leukotrienes, prostaglandins, and platelet activating factor.

Mast cells can be activated by specific IgE antibodies attached to receptors on the surface of the cells or by a non-IgE mechanism mediated by neurotransmitters or other cell products (table 1). A recent report (2) described a group of patients with chronic urticaria who had IgG autoantibodies directed against the high-affinity IgE receptor. These autoantibodies can also trigger the release of mediators from mast cells.

Table 1. Sources of mast cell activation in urticaria

IgE antibodies Foods Drugs Insect stings Animals Non-IgE mediated Endogenous mediators Components of complement (C3a, C5a) Neuropeptides (substance P) Eosinophil major basic protein Exogenous agents Drugs Radiocontrast media Autoantibodies (IgG) Directed against IgE or the high-affinity IgE receptor

Causes
The cause of acute urticaria can often be identified (table 2), although the self-limited nature in most mild episodes sometimes precludes the search for the cause. Foods, drugs, and insect stings are common precipitants. Acute urticaria may occur with infections, particularly viral infections (including hepatitis), but also parasitic and even bacterial infections. Hives may be part of an allergic reaction to inhalants, especially seasonal allergens such as ragweed pollen. Latex sensitivity is an emerging problem that can present with urticaria in some patients. Physical urticarias, which usually occur minutes to hours after stimulus, are also classified by trigger (3) (table 3).

Table 2. Causes of acute urticaria

Foods (eg, eggs, shellfish, nuts) Drugs (antibiotics, aspirin, and angiotensin-converting enzyme inhibitors) Infections (viral, parasitic, bacterial) Inhalants (seasonal: pollens, molds) Insect stings Latex sensitivity

Table 3. Types of physical urticaria

Mechanical Dermatographism Pressure urticaria (immediate and delayed) Thermal Cold urticaria (acquired and familial) Heat urticaria (cholinergic and local) Light Solar urticaria Porphyria Water Aquagenic urticaria (water, sweat)

In chronic urticaria, the cause is most often idiopathic. The condition can sometimes be associated with endocrine abnormalities, especially hyperthyroidism. A recent report (4) suggested that in some patients thyroid antibodies may be an important factor. Occasionally, chronic urticaria is a symptom of a more serious underlying disease, so it is important not to miss any associated systemic illnesses (table 4).

Table 4. Classification of chronic urticaria by cause

Idiopathic disease (80% to 90%) Endocrine abnormalities (eg, hyperthyroidism) Collagen vascular disease Malignant disease (eg, lymphoma, leukemia, colon cancer)

Clinical features
The first symptom of urticaria generally is pruritus, which is followed shortly by the appearance of relatively small (from a few millimeters to several centimeters in diameter) wheals, or hives, on the upper dermis with erythema. Ordinarily, hives come out in "crops" that appear, remain in one site for 2 to 3 hours, and then disappear, only to flare up elsewhere. They usually appear on the torso but can occur anywhere on the body.

Diagnosis
The patient history is the most helpful part of the evaluation. It can include questions about preexisting allergies, physical stimuli exposure, ingestion of foods or drugs, stress or exertion, and exposure to chemicals, new environments, animals, and insects, as well as inquiries about other symptoms.

Physical examination can confirm the presence of urticarial lesions and provide an opportunity to look for coexisting systemic diseases.

A history of urticaria following exposure to physical triggers can be confirmed with a challenge. Stroking the skin or challenging with physical agents such as ice or light can establish the diagnosis of physical urticaria.

Laboratory testing has to be considered from the standpoint of cost-effectiveness but usually includes a complete blood cell count with differential, erythrocyte sedimentation rate, and urinalysis. Skin testing for specific IgE antibodies is sometimes helpful, as are skin biopsy (especially if one suspects vasculitis [bruising, hives for more than 24 hours, or nonblanching urticaria]), examination of stool for ova and parasites, chest and sinus roentgenograms, measurement of liver enzyme levels, and tests for fluorescent antinuclear antibodies and cryoglobulins.

Treatment
Acute urticaria generally subsides in 1 to 7 days. When patients need symptom relief, epinephrine and H1 antihistamines, specifically diphenhydramine hydrochloride (eg, Benadryl) and hydroxyzine hydrochloride (Atarax), are the mainstays of therapy. On rare occasions, oral corticosteroids may be required. For urticaria caused by IgE-mediated reactions to allergens or by physical stimuli, identifying and eliminating the cause can prevent further episodes.

The management of chronic urticaria is more challenging (table 5). It is best to warn patients with chronic urticaria that they may be dealing with this condition for 1 to 2 years, so that they know not to expect an immediate resolution. Nonsedating antihistamines, including terfenadine (Seldane), astemizole (Hismanal), loratadine (Claritin), and now cetirizine hydrochloride (Zyrtec), can be helpful in mild cases. Since histamine stimulation of the H2 histamine receptor can sometimes contribute to symptoms, a 10-day trial of either cimetidine (Tagamet) or ranitidine hydrochloride (Zantac) is suggested.

Table 5. Pharmacologic treatment of chronic urticaria

H1 antihistamines Diphenhydramine HCl (eg, Benadryl), 5 mg/kg per day up to 50 to 100 mg qid Hydroxyzine HCl (Atarax), 2 mg/kg per day up to 50 to 100 mg qid Cyproheptadine HCl (Periactin), 0.25 mg/kg per day up to 4 mg qid Terfenadine (Seldane), 60 mg bid Astemizole (Hismanal), 10 mg qd Loratadine (Claritin), 10 mg qd Cetirizine HCl (Zyrtec), 10 mg qd H2 antihistamines (10-day trial) Cimetidine (Tagamet), 300 mg bid Ranitidine HCl (Zantac), 150 mg bid Antidepressant Doxepin HCl (Adapin, Sinequan), start 25 mg qhs up to 150 mg qhs Corticosteroids Avoid if possible Prednisone, 1 to 2 mg/kg per day in divided doses until remission, then taper

In some patients whose chronic urticaria is particularly difficult to control, tricyclic antidepressants such as doxepin hydrochloride (Adapin, Sinequan) can be used for their antihistaminic properties. Only in the most resistant cases should use of oral corticosteroids be considered. Prednisone (1 to 2 mg/kg per day in divided doses) is given for 5 to 7 days or until remission, and then the dosage may be tapered.

Angioedema
Angioedema is a nonpruritic, painful swelling of loose connective tissues that is generally found on the face, involving eyelids and lips, but can also occur on the tongue and in the extremities. If angioedema involves the larynx, it can be life-threatening. In the acute setting, it can occur with urticaria.

Angioedema without urticaria is classified as either hereditary or acquired. In hereditary angioedema, there is an abnormality of a serum protein, the C1 esterase inhibitor. Eighty-five percent of the time the abnormality is a deficiency, that is, antigenic measurement shows the amount of C1 esterase inhibitor to be decreased. Fifteen percent of the time the C1 esterase inhibitor is present in normal levels but has an abnormal function. Acquired angioedema can be due to an underlying malignancy that consumes the C1 esterase inhibitor or to the presence of autoantibodies. When a patient has angioedema, the family history becomes important, since hereditary angioedema is an autosomal dominant condition.

Management of angioedema involves, first and foremost, the maintenance of an airway in an acute episode. Management of the chronic form mostly revolves around prophylaxis, in which androgens, such as danazol (Danocrine), have been used to increase the C1 esterase inhibitor levels. If surgery is required and androgens cannot be used, C1 esterase inhibitor can be infused with fresh frozen plasma.

Summary
Hives pose a diagnostic challenge to physicians. With an acute episode, a careful look for possible triggers and relief of symptoms with H1 antihistamines are usually sufficient. For both urticaria and angioedema, the most helpful diagnostic tool may be a carefully taken medical history, including a family history. When a patient's urticaria lasts for more than 6 weeks, further physical and laboratory evaluation is warranted.

Treatment of chronic urticaria generally involves the use of antihistamines first. Corticosteroids are to be avoided, if possible.

References

1. Goldstein SM. Urticaria and angioedema. In: Lawlor GJ Jr, Fischer TJ, Adelman DC, eds. Manual of allergy and immunology. 3d ed. Boston: Little, Brown, 1995:228-43
2. Greaves MW. Chronic urticaria. N Engl J Med 1995;332(26):1767-72 [Erratum, N Engl J Med 1995;333(16):1091]
3. Casale TB, Sampson HA, Hanifin J, et al. Guide to physical urticarias. J Allergy Clin Immunol 1988;82(5 Pt 1):758-63
4. Rumbyrt JS, Katz JL, Schocket AL. Resolution of chronic urticaria in patients with thyroid autoimmunity. J Allergy Clin Immunol 1995;96(6 Pt 1):901-5

Dr Sveum is a consultant, department of allergy, Park Nicollet Clinic, and clinical associate professor of medicine and pediatrics, University of Minnesota Medical School-Minneapolis. Mailing address: Richard J. Sveum, MD, Park Nicollet Clinic, 3800 Park Nicollet Blvd, Minneapolis, MN 55416.

Symposium

• Introduction
• Allergic and nonallergic rhinitis: Directing medical therapy at specific symptoms by David F. Graft, MD
• Urticaria: The diagnostic challenge of hives by Richard J. Sveum, MD
• Anaphylaxis: How to recognize, treat, and prevent potentially fatal attacks by Richard Wyatt, MD
• Asthma: Specific preventive strategies by Richard J. Morris, MD
• Safe allergen immunotherapy: The correct allergen, the appropriate patient, the adequate dose by William F. Schoenwetter, MD

Copyright (C) 1997. The McGraw-Hill Companies. All Rights Reserved