EPITOMES-ALLERGY
active participation in sports. Others may offer excuses to avoid exercise due to fear or anxiety. Exercises and physical fitness programs designed to improve diaphragmatic breathing' apparently do not lessen the frequency, severity or duration of exercised-induced asthma attacks. Short exercise sessions of up to three minutes, however, often result in improved pulmonary function for several minutes. Consequently, short increments of running or other exercise can be tolerated by those in whom EIA may occur. Exercise-induced asthma occurs equally in both allergic and nonallergic asthmatic persons. Cold or dry air, and airborne irritants and allergens can increase the probability of EIA developing. Generally, EIA appears to be directly related to the amount of exercise or work done by a person. Most studies have shown that bronchodilators prevent EIA if given beforehand. Cromolyn sodium will also modify EIA in most allergic persons. Steroids, however, in any form have no apparent effect on EIA. EIA can be prevented with theophylline given orally or beta adrenergic drugs given either orally or by inhalation 30 minutes before exercise. Cromolyn sodium must be given about an hour before exercise to be helpful. ROGER M. KATZ, MD REFERENCES Rebuck AS, Read J: Exercise-induced asthma. Lancet, 2:429, 1968 Sly RM, Heimlich EM, Busser RJ, et al: Exercise-induced bronchospasm: Effect of adrenergic or cholinergic blockade. J Allergy 40:93-99, Aug 1967 Katz RM, Whipp BJ, Heimlich RM, et al: Exercise-induced bronchospasm, ventilation, and blood gases in asthmatic children. J Allergy 47:148-158, Mar 1971 Eggleston PA, Bierman CW, Pierson WE, et al: A doubleblind trial of the effect of cromolyn sodium on exercise-induced bronchospasm. J Allergy Clin Immunol 50:57-63, Jul 1972
Physical Agents That Mediate Urticaria URTICARIA, characterized by localized skin edema or wheals, may be caused by any of several immunologic and nonimmunologic factors. Although the cause of chronic urticaria is never found in three fourths of cases, reactions due to physical agents such as pressure (dermatographia), heat and effort (cholinergic urticaria), cold, vibration and light (solar urticaria) can be identified and appropriately treated. Dermatographia, one of the most common types of urticaria, is sometimes due to physical allergy. In certain cases, evidence indicates that it is mediated by, and can be passively transferred with, IgE. Dermatographia often accompanies urticaria induced by ohter causes. 318
OCTOBER 1979 * 131
* 4
Cholinergic urticaria is precipitated by heat, emotional stress and exercise as highly pruritic wheals (I to 3 mm in size) with erythematous flare. Intradermal injection of methacholine (1:5,000) may produce a large wheal with satellites. This test, however, is not reliable enough for routine use because there are many false-negatives and some false-positives. Release of histamine into venous blood during attacks has been shown in some but not all of these patients. Activation of the cholinergic nervous system appears to be important in causing the wheals. Solar urticaria is relatively uncommon. Several subtypes of solar urticaria are induced by light of wavelengths extending from 250 to 460 nM, with erythema and wheals developing in patients two to three minutes after exposure to sunlight. Repeated daily increments of solar exposure may prevent attacks. Heat urticaria is characterized by swelling, redness and temperature dependence, and is not related to sweating or exertion. The lesions are nonpruritic and indurated. The phenomenon is associated with activation of complement via the alternate complement system. A pathologic reaction at the level of the venules with vascular endothelial damage has been described, but these lesions can be controlled by avoidance of heat. There is no role for antihistamines or corticosteroids in therapy. Vibratory urticaria consists of prompt appearance of pruritus and swelling at the site of vibratory stimulation. The reaction is histamine mediated and is adequately controlled with antihistamine and avoidance of the source of vibratory stimuli. An autosomal dominant hereditary pattern has been described. The familial form of cold urticaria is characterized by autosomal dominance, fever, arthralgia, leukocytosis and burning, erythematous papules. The ice cube test is negative and cannot be passively transferred. The papules occur about 30 minutes after cold exposure. A more common, acquired form of cold urticaria is associated with a positive ice cube test in all patients. In about 50 percent of patients, the test can be passively transferred with serum to normal persons. Urticaria in these persons is not associated with fever, arthralgia or leukocytosis. Cold-induced symptoms of systemic diseases such as cryoglobulinemia, cryofibrinogenemia, syphilis, connective tissue diseases and hematologic malignancies must be ruled out. Sporadic cold urticaria is definitely
EPITOMES-ALLERGY
associated with IgE-mediated release of histamine which can be inhibited with antihistamines. Delayed cold urticaria is a rare disease consisting of a painful induration occurring 12 to 24 hours after local cold exposure. The treatment of urticaria induced by physical agents should be based primarily on removal of the cause. As with patients with other types of urticaria, these patients should be advised to minimize their exposure to alcohol, heat, acetylsalicylic acid, exertion and emotional stress. Topical agents and corticosteroids as well as attempts to desensitize patients with allergens are of no help in these situations. Appropriate sun screens may be of value in patients with solar urticaria, and antihistamines, including cyproheptadine and hydroxyzine, are of particular value in patients with dermatographia, cholinergic urticaria or cold urticaria. CH=ITUR EASWARAN,
MD
GILDON BEALL, MD REFERENCES Monroe EW, Jones HE: Urticaria: An updated review. Arch Dermatol 113:80-90, Jan 1977 Rhoades RB, Leifer KN, Cohan R, et al: Suppression of histamine-induced pruritus by three antihistaminic drugs. J Allergy Clin Immunol 55:180-185, Mar 1975
Factors That Influence Theophylline Metabolism MANY ALLERGISTS in the United States consider theophylline to be the initial bronchodilator of choice. Serum levels of theophylline of 7 to 20 Mg per ml are generally accepted as therapeutic. Although symptoms of toxicity may occur when the level of theophylline in the serum is in the therapeutic range, toxicity is generally associated with levels in excess of 20 ,ug per ml. It is incumbent on the physician using this valuable but potentially toxic drug to appreciate the number of factors that influence its biotransformation and clearance.
Body Weight The apparent volume of distribution for theophylline is reduced in obese patients. When calculating dosage, one must use a patient's ideal weight to avoid toxicity. Age The dosage of theophylline required for children less than 1 year of age varies greatly. In this group, monitoring of serum levels of theophylline may be required to avoid problems with toxicity.
Children 1 to 8 years of age have average plasma clearance values above those noted for adults. The recommended oral dose for this group varies from 16 to 24 mg per kg of body weight per day. For those between 9 and 16 years of age, the recommended oral dose is 16 to 20 mg, and for adults it is 9.6 to 19 mg per kg of body weight per day. Diet Dietary methylxanthines, particularly caffeine, have been shown to interfere with theophylline elimination in normal persons. A decrease in theophylline elimination has also been noted in patients on high carbohydrate-low protein diets while a high protein-low carbohydrate diet increases theophylline elimination. Charcoal-broiled foods with a high polycycic carbon content may increase the rate of theophylline biotransformation. Diseases Altering Theophylline Metabolism Theophylline clearance is affected by a variety of diseases involving the cardiorespiratory systems and the liver. These include congestive heart failure, acute pulmonary edema, chronic obstructive pulmonary disease, pneumonia, and cirrhosis and other hepatic diseases. Reduction in the dose of theophylline administered to these patients and careful monitoring of serum theophylline levels is required for proper management. Acute febrile illness has also been reported as a cause of transient increase in serum theophylline levels.
Smoking In cigarette and marijuana smokers, there is a faster plasma theophylline clearance and a shorter half-life than in nonsmokers. Jusko and co-workers have shown that an additive increase in theophylline clearance occurs in those who smoke both substances. An approximate reduction of 50 percent in theophylline clearance has been reported in patients who were receiving troleandomycin (250 mg four times daily). A similar but less pronounced effect due to erythromycin has been reported recently and appears due to reduced clearance and consequent prolonged half-life of theophylline. A reduction in theophylline dose is necessary for patients already receiving high-dose treatment when erythromycin or troleandomycin is coadministered. The possibility of other, as yet unrecognized, drug interactions with theophylline must be appreciated. If symptoms suggestive THE WESTERN JOURNAL OF MEDICINE
319
active participation in sports. Others may offer excuses to avoid exercise due to fear or anxiety. Exercises and physical fitness programs designed to improve diaphragmatic breathing' apparently do not lessen the frequency, severity or duration of exercised-induced asthma attacks. Short exercise sessions of up to three minutes, however, often result in improved pulmonary function for several minutes. Consequently, short increments of running or other exercise can be tolerated by those in whom EIA may occur. Exercise-induced asthma occurs equally in both allergic and nonallergic asthmatic persons. Cold or dry air, and airborne irritants and allergens can increase the probability of EIA developing. Generally, EIA appears to be directly related to the amount of exercise or work done by a person. Most studies have shown that bronchodilators prevent EIA if given beforehand. Cromolyn sodium will also modify EIA in most allergic persons. Steroids, however, in any form have no apparent effect on EIA. EIA can be prevented with theophylline given orally or beta adrenergic drugs given either orally or by inhalation 30 minutes before exercise. Cromolyn sodium must be given about an hour before exercise to be helpful. ROGER M. KATZ, MD REFERENCES Rebuck AS, Read J: Exercise-induced asthma. Lancet, 2:429, 1968 Sly RM, Heimlich EM, Busser RJ, et al: Exercise-induced bronchospasm: Effect of adrenergic or cholinergic blockade. J Allergy 40:93-99, Aug 1967 Katz RM, Whipp BJ, Heimlich RM, et al: Exercise-induced bronchospasm, ventilation, and blood gases in asthmatic children. J Allergy 47:148-158, Mar 1971 Eggleston PA, Bierman CW, Pierson WE, et al: A doubleblind trial of the effect of cromolyn sodium on exercise-induced bronchospasm. J Allergy Clin Immunol 50:57-63, Jul 1972
Physical Agents That Mediate Urticaria URTICARIA, characterized by localized skin edema or wheals, may be caused by any of several immunologic and nonimmunologic factors. Although the cause of chronic urticaria is never found in three fourths of cases, reactions due to physical agents such as pressure (dermatographia), heat and effort (cholinergic urticaria), cold, vibration and light (solar urticaria) can be identified and appropriately treated. Dermatographia, one of the most common types of urticaria, is sometimes due to physical allergy. In certain cases, evidence indicates that it is mediated by, and can be passively transferred with, IgE. Dermatographia often accompanies urticaria induced by ohter causes. 318
OCTOBER 1979 * 131
* 4
Cholinergic urticaria is precipitated by heat, emotional stress and exercise as highly pruritic wheals (I to 3 mm in size) with erythematous flare. Intradermal injection of methacholine (1:5,000) may produce a large wheal with satellites. This test, however, is not reliable enough for routine use because there are many false-negatives and some false-positives. Release of histamine into venous blood during attacks has been shown in some but not all of these patients. Activation of the cholinergic nervous system appears to be important in causing the wheals. Solar urticaria is relatively uncommon. Several subtypes of solar urticaria are induced by light of wavelengths extending from 250 to 460 nM, with erythema and wheals developing in patients two to three minutes after exposure to sunlight. Repeated daily increments of solar exposure may prevent attacks. Heat urticaria is characterized by swelling, redness and temperature dependence, and is not related to sweating or exertion. The lesions are nonpruritic and indurated. The phenomenon is associated with activation of complement via the alternate complement system. A pathologic reaction at the level of the venules with vascular endothelial damage has been described, but these lesions can be controlled by avoidance of heat. There is no role for antihistamines or corticosteroids in therapy. Vibratory urticaria consists of prompt appearance of pruritus and swelling at the site of vibratory stimulation. The reaction is histamine mediated and is adequately controlled with antihistamine and avoidance of the source of vibratory stimuli. An autosomal dominant hereditary pattern has been described. The familial form of cold urticaria is characterized by autosomal dominance, fever, arthralgia, leukocytosis and burning, erythematous papules. The ice cube test is negative and cannot be passively transferred. The papules occur about 30 minutes after cold exposure. A more common, acquired form of cold urticaria is associated with a positive ice cube test in all patients. In about 50 percent of patients, the test can be passively transferred with serum to normal persons. Urticaria in these persons is not associated with fever, arthralgia or leukocytosis. Cold-induced symptoms of systemic diseases such as cryoglobulinemia, cryofibrinogenemia, syphilis, connective tissue diseases and hematologic malignancies must be ruled out. Sporadic cold urticaria is definitely
EPITOMES-ALLERGY
associated with IgE-mediated release of histamine which can be inhibited with antihistamines. Delayed cold urticaria is a rare disease consisting of a painful induration occurring 12 to 24 hours after local cold exposure. The treatment of urticaria induced by physical agents should be based primarily on removal of the cause. As with patients with other types of urticaria, these patients should be advised to minimize their exposure to alcohol, heat, acetylsalicylic acid, exertion and emotional stress. Topical agents and corticosteroids as well as attempts to desensitize patients with allergens are of no help in these situations. Appropriate sun screens may be of value in patients with solar urticaria, and antihistamines, including cyproheptadine and hydroxyzine, are of particular value in patients with dermatographia, cholinergic urticaria or cold urticaria. CH=ITUR EASWARAN,
MD
GILDON BEALL, MD REFERENCES Monroe EW, Jones HE: Urticaria: An updated review. Arch Dermatol 113:80-90, Jan 1977 Rhoades RB, Leifer KN, Cohan R, et al: Suppression of histamine-induced pruritus by three antihistaminic drugs. J Allergy Clin Immunol 55:180-185, Mar 1975
Factors That Influence Theophylline Metabolism MANY ALLERGISTS in the United States consider theophylline to be the initial bronchodilator of choice. Serum levels of theophylline of 7 to 20 Mg per ml are generally accepted as therapeutic. Although symptoms of toxicity may occur when the level of theophylline in the serum is in the therapeutic range, toxicity is generally associated with levels in excess of 20 ,ug per ml. It is incumbent on the physician using this valuable but potentially toxic drug to appreciate the number of factors that influence its biotransformation and clearance.
Body Weight The apparent volume of distribution for theophylline is reduced in obese patients. When calculating dosage, one must use a patient's ideal weight to avoid toxicity. Age The dosage of theophylline required for children less than 1 year of age varies greatly. In this group, monitoring of serum levels of theophylline may be required to avoid problems with toxicity.
Children 1 to 8 years of age have average plasma clearance values above those noted for adults. The recommended oral dose for this group varies from 16 to 24 mg per kg of body weight per day. For those between 9 and 16 years of age, the recommended oral dose is 16 to 20 mg, and for adults it is 9.6 to 19 mg per kg of body weight per day. Diet Dietary methylxanthines, particularly caffeine, have been shown to interfere with theophylline elimination in normal persons. A decrease in theophylline elimination has also been noted in patients on high carbohydrate-low protein diets while a high protein-low carbohydrate diet increases theophylline elimination. Charcoal-broiled foods with a high polycycic carbon content may increase the rate of theophylline biotransformation. Diseases Altering Theophylline Metabolism Theophylline clearance is affected by a variety of diseases involving the cardiorespiratory systems and the liver. These include congestive heart failure, acute pulmonary edema, chronic obstructive pulmonary disease, pneumonia, and cirrhosis and other hepatic diseases. Reduction in the dose of theophylline administered to these patients and careful monitoring of serum theophylline levels is required for proper management. Acute febrile illness has also been reported as a cause of transient increase in serum theophylline levels.
Smoking In cigarette and marijuana smokers, there is a faster plasma theophylline clearance and a shorter half-life than in nonsmokers. Jusko and co-workers have shown that an additive increase in theophylline clearance occurs in those who smoke both substances. An approximate reduction of 50 percent in theophylline clearance has been reported in patients who were receiving troleandomycin (250 mg four times daily). A similar but less pronounced effect due to erythromycin has been reported recently and appears due to reduced clearance and consequent prolonged half-life of theophylline. A reduction in theophylline dose is necessary for patients already receiving high-dose treatment when erythromycin or troleandomycin is coadministered. The possibility of other, as yet unrecognized, drug interactions with theophylline must be appreciated. If symptoms suggestive THE WESTERN JOURNAL OF MEDICINE
319
