Grifulvin V

Although urticaria has been known to clinicians for centuries, physical urticaria was distinguished from other causes of chronic urticaria in the 19th century. The reproducibility of various forms of physical urticaria has greatly contributed to our understanding of mast cell mediator release in other urticarial syndromes. About 20 different types of physical urticaria have been identified (Table 1). The most common types are dermographism, cholinergic urticaria, cold urticaria and delayed pressure urticaria.[1] Coexistence of more than one type is not uncommon.

Pathogenesis

Elevated cutaneous and serum levels of histamine have been reported in association with essentially all major forms of physical urticaria.[2] Prostaglandins, leukotrienes, serotonin, platelet-activating factor and chemotactic factors for eosinophils and neutrophils also seem to be involved in the urticarial response.[3,4] However, the number of mast cells are not increased in such patients and, therefore, the exact mechanism of mediator release by physical agents is not known. In some forms, IgE- or IgM-mediated release has been proposed because of passive cutaneous transfer of sensitivity.

Decreased levels of serum protease inhibitors have been demonstrated in several types of physical urticaria. However, it remains unclear whether this decrease represents consumptive depression of the enzyme or whether a primary defect in enzyme production exists. In addition, neural pathways have been shown to contribute to the symptoms in these patients.[5]

General Features

Urticarias caused by physical agents share certain features that distinguish them from other types of chronic urticaria. All are reproducible with an appropriate stimulus, as long as the challenge is not performed shortly after a natural occurrence.

Wheal formation is episodic and occurs shortly after the application of the stimulus. Except in cases of delayed pressure urticaria, the eruption generally lasts less than two hours. Additional characteristics of physical urticarias include a more frequent occurrence in young adults and a distinctive appearance and location of the wheals. If the stimulus is strong, systemic features such as flushing, headaches, dizziness or even hypotension can occur as a result of systemic mast cell mediator release.

Types of Physical Urticaria

DERMOGRAPHISM

Dermographism--urticaria in response to skin pressure--is the most common type of physical urticaria. Depending on the instrument used, 1.5 to 5 percent of healthy individuals will demonstrate a dermographic response. The majority of these individuals remain asymptomatic. In a subgroup of these patients, an urticarial response is elicited using a lower threshold force and is accompanied by pruritus. The peak age of onset is between 20 to 29 years, and the patients are not atopic.

Wheals generally reach maximum size in 5 to 10 minutes and fade 15 to 20 minutes after the application of a stimulus. Although all skin surfaces can be affected, the palms, soles of the feet, genitalia and scalp are less frequently involved. The condition is exacerbated by hot baths, exercise or emotional stress. The diagnosis can be made by observing linear wheals in areas under tight clothing or in areas that have been scratched with a firm object or a dermographometer (Figure 1).

The majority of patients improve over several months to a few years. Severely affected patients may continue to have symptoms for more than 10 years.[6]

CHOLINERGIC URTICARIA

Cholinergic urticaria is a common type of physical urticaria marked by distinctive monomorphic wheals 2 to 3 mm in size that are surrounded by bright red flare and accompanied by intense pruritus. The eruptions occur in response to a rise in core body temperature, which can be precipitated by a hot bath, fever or exercise, and particularly by occlusive dress and emotional stress. The rash tends to be prominent on the upper trunk and arms, and usually lasts up to one hour. In severe cases, lesions may coalesce and may be accompanied by angioedema of the face and trunk.

Systemic symptoms such as headaches, salivation, palpitation, abdominal cramps and, rarely, exercise-induced anaphylaxis have been noted with severe attacks. Mast cell mediator release and a change in pulmonary function (with a drop in forced expiratory volume in one second, maximal mid-expiratory flow rate) have been noted during experimentally induced attacks. This may be associated with symptoms of dyspnea and wheezing.[7,8]

The natural course of cholinergic urticaria is quite variable, with most patients experiencing slow resolution over several years.

COLD URTICARIA

Cold urticaria is a relatively uncommon and very heterogeneous disorder. The various syndromes can be classified according to the nature of the response to a provocative test (Table 2).[9] Application of an ice cube wrapped in cellophane results in a wheal that conforms to the area of contact on rewarming. Cooling of a larger area of the body, especially in a patient with a history of systemic symptoms, is contraindicated. Manifestations of cold urticaria syndromes vary widely, from contact urticaria to hypotension and collapse. Because of the potential risk of drowning, all patients with cold urticaria should be supervised during aquatic activities.

Patients with acquired cold urticaria may have an associated disease, such as an infectious disease or primary or secondary cryoglobulinemia. Drugs, such as penicillin, oral contraceptives and griseofulvin Fulvicin, Grifulvin V, Grisactin, etc.), may also be a cause. Because diagnosis of the more common, primary form of acquired cold urticaria can only be made after excluding underlying causes, a detailed medical history, including other illnesses, current medications and recent exposure to infection, should be taken. Laboratory tests should include a complete blood count and blood chemistry (liver and renal profiles), erythrocyte sedimentation rate, antinuclear antibodies, rheumatoid factor, serum complement, rapid plasma reagin and Monospot. Cryoglobulins and other cryoproteins, such as cold hemolysin and cryofibrinogen, should be assessed.

Patients with systemic atypical cold urticaria do not react to cold contact testing. They will, however, develop urticaria with systemic symptoms and hypotension after exposure to a cold environment. Serologic studies of these patients are nondiagnostic.[10]

DELAYED PRESSURE URTICARIA

Delayed pressure urticaria occurs either alone or, more commonly, in association with chronic idiopathic urticaria.[11] In contrast to other physical urticarias, whealing in delayed pressure urticaria develops four to six hours after the application of the stimulus. Eruptions result after the application of deep, prolonged pressure that is applied perpendicular to the skin surface. Examples of such pressures include wearing a tight belt or a watch strap, standing on the rung of a ladder for a prolonged period of time or working briskly with a screwdriver.

Whealing, accompanied by pain and variable degrees of erythema, occurs on the contact surface and can last as long as 48 hours. Commonly affected areas include extremities, trunk, buttocks, lips and face.[12] Systemic manifestations include malaise, fever, flu-like symptoms, arthralgia and leukocytosis. The wheals can be experimentally induced by the application of sustained pressure.

Delayed pressure urticaria tends to run a long but variable course, with a mean duration of symptoms of eight to nine years.[11]

SOLAR URTICARIA

Solar urticaria is an uncommon disorder characterized by the development of erythema and wheals within minutes of exposure to sunlight. Solar urticaria has been divided into four groups (I-IV) depending on the wavelength of light that elicits the urticarial response. Phototesting can be performed using natural or artificial sources of light with appropriate filters. Chronically sun-exposed areas such as the face and hands are less reactive, and testing of these areas may produce a false-negative result.

Most reported cases are idiopathic. In a few cases, porphyria cutanea tarda and erythropoietic protoporphyria were found to be the cause of photosensitivity.[2] The presence of porphyria should be suspected if phototesting indicates that reactivity is limited to wavelengths in the range of 400 to 500 nm.

Photosensitivity in solar urticaria usually lasts for several years. In one study, over 50 percent of the patients were symptomatic after 10 years.[2]

Therapy

Proper diagnosis and patient education about precipitating stimuli are key to the management of physical urticarias.[13] In mild cases, no additional therapy may be needed. Symptomatic treatment with histamine [H.sub.1]-receptor blockers alone or in combination with [H.sub.2] antagonists is at least partially effective in several forms of physical urticaria (Table 3). Hydroxyzine (Atarax, Vistaril) is the drug of choice for the treatment of symptomatic dermographism and cholinergic urticaria. Terfenadine (Seldane) may provide a less sedating, yet effective, alternative.

[TABULAR DATA 3 OMITTED]

Primary acquired cold urticaria responds better to cyproheptadine (Periactin). Cetirizine, an agent not yet available in the United States, is the only H, antagonist that is effective in the treatment of delayed pressure urticaria. It has been shown to significantly decrease the eosinophilic infiltrate present in the dermis.[14] Oral corticosteroids and nonsteroidal anti-inflammatory agents are beneficial in selected patients with delayed pressure urticaria.

Terfenadine can increase the whealing threshold in patients with solar urticaria.[15] In severe cases, antimalarial agents have been used with close monitoring of side effects.

Ketotifen has been shown to inhibit cutaneous mast-cell degranulation and is effective in controlling symptoms in several forms of physical urticaria.[16] However, it is not yet available in the United States.

Desensitization to physical stimuli, performed under careful supervision, has a role in the treatment of well-motivated patients with cold or solar urticarias. The effectiveness of desensitization therapy depends on the development of tolerance to the physical agent and requires repeated exposure to the stimulus.[4]

Figure 1 supplied by Roger H. Brodkin, M.D.

REFERENCES

[1.] Meynadier J, Guillot B, Boulanger A, Meynadier JM, Pourailly E Aetiology of chronic urticaria--a series of 225 new cases. In: Champion RH, et al., eds. The urticarias. New York: Churchill Livingstone, 1985:130-1. [2.] Black AK. The physical urticarias. In: Champion RH, ed. The urticarias. New York: Churchill Livingstone, 1985:168-90. [3.] Kobza Black A, Greaves MW, Champion RH, Pye RJ. The urticarias 1990. Br J Dermatol 1991;124:100-8. [4.] Champion RH. A practical approach to the urticarial syndromes. Clin Exper Allergy 1990;20:221-4. [5.] Ormerod AD, Greaves MW. Physical urticaria and angioedema. In: Lichtenstein LM, Fauci AS, eds. Current therapy in allergy, immunology, and rheumatology-3. St. Louis: Mosby, 1988:62-5. [6.] Breathnach SM, Allen R, Ward AM, Greaves MW. Symptomatic dermographism. Clin Exper Dermatol 1983;8:463-76. [7.] Silvers WS. Exercise-induced allergies: the role of histamine release. Ann Allergy 1992;68:58-63. [8.] Soter NA, Wasserman SI, Austen KF, McFadden ER Jr. Release of mast-cell mediators and alterations in lung function in patients with cholinergic urticaria. N Engl J Med 1980;302:604-8. [9.] Wanderer AA. Cold urticaria syndromes. J Allergy Clin Immunol 1990;85:965-81. [10.] Kaplan AP. Unusual cold-induced disorders. J Allergy Clin Immunol 1984;73:453-6. [11.] Dover JS, Black AK, Ward AM, Greaves MW. Delayed pressure urticaria. J Am Acad Dermatol 1988;18:1289-98. [12.] Greaves MW The physical urticarias. Clin Exper Allergy 1991;21(Suppl 1):284-9. [13.] Soter NA. Urticaria: current therapy J Allergy Clin Immunol 1990;86(6 Pt 2):1009-14. [14.] Kontou-Fili K, Maniatakou G, Demaka P, Gonianakis M, Paleologos G. Therapeutic effects of cetirizine in delayed pressure urticaria. Ann Allergy 1990;65:517-9. [15.] Diffey BL, Farr PM. Treatment of solar urticaria with terfenadine. Photo Dermatol 1988;5:25-9. [16.] Huston DP, Bressler RB, Kaliner M, Sowell LK, Baylor MW. Prevention of mast-cell degranulation by ketotifen in patients with physical urticarias. Ann Intern Med 1986;104:507-10.

The Author

TARIQ MAHMOOD, M.D. is assistant professor of clinical medicine at UMDNJ--New Jersey Medical School in Newark. He graduated from King Edward Medical College in Lahore, Pakistan, and completed a fellowship in allergy, immunology and rheumatology at the University of Kansas Medical Center, Kansas City, Kan.

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