Editorial Exercised-induced the eosinophil?
asthma:
Wheezing with exercise is considered a universal feature of asthma if the exercise challenge is sufficiently intense and conducted under the optimal conditions of temperature and humidity. ’ This response to exercise can affect individuals of all ages and consequently becomes a significant limitation to a normal lifestyle for the patient with asthma. Furthermore, EIA has been noted in patients with allergic rhinitis’ and in children with a previous history of croup,3 cystic fibrosis,4 or bronchopulmonary dysplasia.4 Thus, the clinical frequency of EIA is appreciable and a significant problem for the clinician. FEATURES
OF EIA
Recognition and diagnosis of EIA is usually not a major problem for the informed physician. Furthermore, the clinical pattern of EIA is very characteristic.’ During the initial few minutes of exercise, there is usually a brief episode of bronchodilation, probably secondary to endogenous catecholamine release. If, however, exercise continues during the next 5 minutes and is then stopped, bronchial obstruction begins and reaches its peak approximately 10 minutes later. Occasionally, EIA becomes progressively more severe for 30 to 60 minutes after exercise before it improves. In contrast, symptoms in adults often begin later and last longer than they do in children.6 Interestingly, many patients indicate that they can continue to exercise despite experiencing symptoms in the first minutes of exertion and, in fact, “run through” their asthma. Finally, EIA is less frequent with interrupted exertion or less severe exercise.’ Many factors influence the likelihood of airway obstruction with exercise and the intensity of this response when it occurs. Not only have these factors had important clinical relevance but also, as will be discussed later, provide insights into mechanisms of asthma with exercise. First, the type of exercise often determines the probability of wheezing. Running is more “asthmagenic” than cycling or swimming, even From the University of Wisconsin Medical School, Madison, Wis. Reprint requests: William Busse, MD, University of Wisconsin Medical School, J5 / 220 Clinical Science Center, 600 Highland Ave., Madison, WI 53792. l/1/31503
696
A role for
Abbreviations
used
EIA: Exercise-induced asthma NCF-A: Neutrophil chemotactic factor of anaphylaxis EOS: Eosinophil ECP: Eosinophil cationic protein LAR: Late asthmatic reaction
though both involve similar work loads. These observations suggest that the environment of exercise is a contributing factor to the likelihood and intensity of bronchospasm. In addition, the time since the last episode of EIA also plays a role in the development of subsequent wheezing to exertion. Consequently, there appears to be a refractory period that follows the initial episode of EIA, and this period can be protective for subsequent episodes of wheezing with exercise. MECHANISMS
OF EIA
Most specialists in allergy and respiratory medicine have little problem recognizing EIA, confirming its presence with appropriate testing or preventing wheezing with exertion. Nonetheless, the basic mechanisms of EIA remain unresolved, complex, and controversial. Areas of attention have included heat and water loss as well as mediator release during exercise.s-‘o Heat and water loss As indicated above, running rather than swimming is more likely to provoke asthma. To explain these observations, the importance of airway heat and water loss has provided insight into clinical correlates. With normal respiration, heat and water are transferred from the airway bronchial mucosa to inspired air so that the air is warmed to body temperature and saturated with water. During exercise, there is a dramatic increase in minute ventilation, the upper airway (nose) is bypassed, and the inspired air is no longer warmed to body temperature or humidified to saturation. Consequently, the lower airways attempt to compensate and complete the conditioning process. This results in the loss of lower airway heat and water during
VOLUME NUMBER
88 5
inspiration, some of which is recovered during the expiratory phase when warm, humidified air passes over the now cooler airway. Respiratory heat loss is governed Iby many factors, including the change in minute ventilation and water content of the inspired air. Furthermore, there is evidence that respiratory heat excha.nge will correlate with the degree of postexercise obstruction. ” Although both heat and water loss have been implicated in EIA, the degree to which each plays remains controversial. In this regard, McFadden et al. “5 I3 have made a number of interesting observations. First, since both exercise and hyperventilation produce bronchospasm, the belief had been that increased minute ventilation, rather than exercise itself, precipitates EIA. Furthermore, direct thermal recordings in thz lower airway document decreased temperature deep in the lungs exercise in cold, dry air. Finally, the rate of airway rewarming, rather than cooling, may determine the intensity of asthma with exercise. !3ubjects who exercised in cold air and recovered under cold conditions experienced less airway obstruction than subjects recovering in conditions of fully humidified body-temperature air. Based on these observations, it is postulated that airway cooling in exercise causes pulmonary vasoconstriction; with rapid rewarming, vasodilation, hyperemia, and edema occur to c,suse bronchial obstruction. I4 In contrast, Anderson et al.15 propose another theory in which evaporative water loss produces hyperosmolarity of the periciliary fluid. Inhalation of both hypotonic and hypertonic aerosols of saline produces bronchospasm16 that is the result of a direct effect on airway smooth muscle tone.” Airway changes in osmolarity from exercise could provoke mast cell18 or basophil mediator release. I9 However, since significant changes in osmolarity must develop (600 to 800 mOsm) to cause mast cell secretion of 20% of their histamine (content, some investigators argue that these independent observations are not physiologically achieved. Furthermore, the relationship of mediator release to EIA is controversial. Early attempts to correlate mast cell secretion and EIA focused on peripheral blood determinations of histamine and NCF-A. Circulating levels of histamine have been reported not to change”-‘, ” or increase after exercise.“, 23Changes in NCF-A, in relationship to exercise, have followed a similar pal:tem: no change” or a rise.22 Furthermore, most inve,stigators have not demonstrated increased circulating histamine or NCF-A after isocapnic hyperventilation-induced asthma.“’ 22,24; this suggests a difference in the pathogenesis of EIA and hyperventilation-induced airway obstruction. Finally, and per-
Exercise-induced
asthma
697
haps most directly, Broide et aLz5performed fiberoptic bronchoscopy and lavage on seven atopic subjects with asthma after EIA; no differences in mean values before and after exercise in histamine, tryptase, prostaglandin D2, or leukotriene C, were found. EOSs in EIA In this issue of the JOURNAL, Venge et aLz6 evaluated the influence of EIA on EOSs. Although the importance of EOSs to chronic asthma is of great interest and likely importance, the role of this inflammatory cell in EIA is largely unknown. As the authors suggest, EIA might “reflect the inflammation in the lung of the individual with asthma”26 and hypothesize that the enhanced activity of the EOS is one factor in EIA. To evaluate this possibility, Venge et al. studied the variations in EOS activity, as reflected in serum levels of ECP, to the development of EIA. In subjects with EIA, treadmill testing caused a slight, immediate rise in ECP and fall 60 minutes after exercise; no change in circulating ECP was noted in subjects without EIA, but their baseline levels were less than that of subjects with EIA. Furthermore, the preexercise circulating levels of ECP, but not circulating EOSs, demonstrated a correlation with the fall in peak expiratory flow to exercise. Finally, terbutaline blocked EIA but not the ECP response to exercise. In contrast, 4 weeks of budesonide treatment prevented the late fall in serum ECP. The clinical significance of these observations was not resolved by this investigation but rather raised a number of relevant questions as to mechanisms of asthma and, particularly, patient susceptibility to EIA. First, the authors indicate that the pattern of circulating concentration ECP in EIA is very similar to the ECP response to allergen-induced asthmaz7; patients with LAR to allergen had higher levels of ECP before challenge than did patients who did not have LAR.27 These data were interpreted to suggest that a prerequisite for LAR was the presence of circulating primed, or activated, EOSs that could then be attracted to the lung. However, this does not mesh with their current findings, since no LARs occurred in patients after exercise and since a similar pattern of responses in serum ECP values followed histamine inhalation. In contrast, and more feasible, in my prejudiced view, is their explanation that elevated levels of ECP reflect ongoing airway inflammation and thus an enhanced degree of airway responsiveness and potential for airway obstruction to various stimuli, including exercise. The correlation of ECP to intensity of EIA and a protective response to inhaled corticosteroids, budesonide, fit with this position.
898
J. ALLERGY
Busse
The importance of the observations by Venge et al. to clinical asthma have yet to be resolved. Nonetheless, their findings open a new area of investigation in EIA into the role of the EOS and its inflammatory products to this process. Furthermore, their observations potentially unify current concepts of asthma and EIA to the importance of airway inflammation. Unification of “all” types of asthma to have airway inflammation and treatment focus on this component of bronchial obstruction are in keeping with current therapeutic approaches; substantiation of such observations in EIA will await further insightful investigation. William Busse, MD University of Wisconsin Medical School Madison, WI 53792 REFERENCES 1. McFadden ER. Exercise-induced asthma: assessmentof current etiologic concepts. Chest 1987;91:515-75. 2. Pierson WE, Biennan W, Kawabori I, Van Arsdel PP. The incidence of exercise-induced bronchospasm in “normal” and “atopic” children [Abstract]. J ALLERGY CLIN IMMUNOL 1972;49: 129-30. 3. Loughlin GM, Taussig LM. Pulmonary function in children with a history of laryngotracheobronchitis. J Pediatr 1979; 94:365-9. 4.
5.
6. 7. 8. 9. 10.
Bader D, Ramos AD, Lew CD, Platzker ACG, Stabile MW, Keens TG. Childhood sequelae of infant lung disease, exercise, and pulmonary function abnormalities after bronchopulmonary dysplasia. J Pediatr 1987;110:693-9. Lemanske RF Jr, Henke KG. Exercise-induced asthma. In: Gisolfi CV, Lamb DR, eds. Perspectives in exercise science and sports medicine, vol 2. Carmel, Ind.: Benchmark Press, 1989:465-506. Anderson SD, Silverman M, Konig P, Godfrey S. Exerciseinduced asthma. Br J Dis Chest 1975;69:1-10. Godfrey S. Symposium on special problems and management of allergic athletes. J ALLERGY CLW IMMUNOL 1984;73:630-3. Chen WY, Horton DJ. Heat and water loss from the airways and exercise-induced asthma. Respiration 1977;34:305-10. McFadden ER. Exercise and asthma. N Engl J Med 1987;317:502-3. Anderson SD. Issues in exercise-induced asthma. J ALLERGY CUN IMMLJNOL 1985;76:763-72.
11. Deal EC Jr, McFadden ER Jr, Ingram RH Jr, Strauss RH, Jeager JJ. Role of respiratory heat exchange in production of exercise-induced asthma. J Appl Physiol 1979;46:467-75. 12. McFadden ER Jr, Denison DM, Waller JF, Assoufi B, Pencock
CLIN. IMMUNOL. NOVEMBER 1991
A, Sopwitb T. Direct recordings of temperature in the tracheobronchial tree in normal man. J Clin Invest 1982;69: 700-5.
13. McFadden ER Jr, Lenner KAM, Strohl KP. Post exertional airway rewarming and thermally induced asthma. J Clin Invest 1986;78:18-25. 14. McFadden ER Jr. Hypothesis: exercise-induced asthma as a vascular phenomenon. Lancet 1990;335:880-3. 15. Anderson SD, Daviskas E, Smith CM. Exercise-induced asthma: a difference in opinion regarding the stimulus. Allergy Proc 1989:10:215-26. 16. Shoeffel RE, Anderson SD, Altonnyan REC. Bronchial hyperreactivity in response to inhalation of ultrasonically nebulized solutions of distilled water and saline. Br Med J 1981;283:1285-7. 17. Finney MJB, Anderson SD, Black JL. The effect of nonisotonic solutions in human isolated airway smooth muscle. Respir Physiol 1987;69:277-86. 18. Eggleston PA, Kagey-Sobotka A, Schleimer RP, Lichtenstein LM. Interaction between hyperosmolar and IgE-mediated histamine release form basophils and mast cells. Am Rev Respir Dis 1989;130:86-91. 19. Findlay SR, Dvorak AM, Kagey-Sobotka A, Lichtenstein LM. Hyperosmolar triggering of histamine release form human basophils. J Clin Invest 1981;67:604-13. 20. Deal EC Jr, Wasserman SI, Soter NA, Ingram RH Jr, McFadden ER Jr. Evaluation of the role of mediators of immediate hypersensitivity in exercise-induced asthma. J Clin Invest 1980;65:659-65. 21. Howarth PH, Pao GJ-K, Church MK, Holgate ST. Exercise and isocapnic hyperventilation-induced bronchoconstriction in asthma: relevance of circulating basophils to measurement of plasma histamine. J ALLERGY CLIN IMMUNOL 1984;73:391-9. 22. Lee TH, Brown MJ, Nagy L, Causon R, Walport MJ, Kay AB. Exercise-induced release of histamine and neutrophil chemotactic factor in atopic asthmatics. J ALLERGY CLIN IMMUNOL 1982;70:73-81.
23. Barnes PJ, Brown MJ. Venous histamine in exercise and hyperventilation-induced asthma in man. Clin Sci 1962;61:15962.
Morgan DJR, Moodley I, Phillips MJ, Davis RJ. Plasma histamine in asthmatic and control subjects following exercise: influence of circulation basophils and different assay techniques. Thorax 1983;38:771-7. 25. Broide DH, Eisman S, Ramsdell JW, Ferguson P, Schwartz LB, Wasserman SI. Airway levels of mast cell-derived mediators in exercise-induced asthma. Am Rev Respir Dis 1990;141:563-8. 26. Venge P, Hemicksen J, Dahl R. Eosinophils in exercise-induced asthma. J ALLERGY CLIN IMMUNOL 1991;88:699-704. 27. Venge P, Dahl R. Are blood eosinophil number and activity important for the development of the late asthmatic reaction after allergen challenge? Eur Respir J 1989;2(suppl 6):4305-
24.
45.
asthma:
Wheezing with exercise is considered a universal feature of asthma if the exercise challenge is sufficiently intense and conducted under the optimal conditions of temperature and humidity. ’ This response to exercise can affect individuals of all ages and consequently becomes a significant limitation to a normal lifestyle for the patient with asthma. Furthermore, EIA has been noted in patients with allergic rhinitis’ and in children with a previous history of croup,3 cystic fibrosis,4 or bronchopulmonary dysplasia.4 Thus, the clinical frequency of EIA is appreciable and a significant problem for the clinician. FEATURES
OF EIA
Recognition and diagnosis of EIA is usually not a major problem for the informed physician. Furthermore, the clinical pattern of EIA is very characteristic.’ During the initial few minutes of exercise, there is usually a brief episode of bronchodilation, probably secondary to endogenous catecholamine release. If, however, exercise continues during the next 5 minutes and is then stopped, bronchial obstruction begins and reaches its peak approximately 10 minutes later. Occasionally, EIA becomes progressively more severe for 30 to 60 minutes after exercise before it improves. In contrast, symptoms in adults often begin later and last longer than they do in children.6 Interestingly, many patients indicate that they can continue to exercise despite experiencing symptoms in the first minutes of exertion and, in fact, “run through” their asthma. Finally, EIA is less frequent with interrupted exertion or less severe exercise.’ Many factors influence the likelihood of airway obstruction with exercise and the intensity of this response when it occurs. Not only have these factors had important clinical relevance but also, as will be discussed later, provide insights into mechanisms of asthma with exercise. First, the type of exercise often determines the probability of wheezing. Running is more “asthmagenic” than cycling or swimming, even From the University of Wisconsin Medical School, Madison, Wis. Reprint requests: William Busse, MD, University of Wisconsin Medical School, J5 / 220 Clinical Science Center, 600 Highland Ave., Madison, WI 53792. l/1/31503
696
A role for
Abbreviations
used
EIA: Exercise-induced asthma NCF-A: Neutrophil chemotactic factor of anaphylaxis EOS: Eosinophil ECP: Eosinophil cationic protein LAR: Late asthmatic reaction
though both involve similar work loads. These observations suggest that the environment of exercise is a contributing factor to the likelihood and intensity of bronchospasm. In addition, the time since the last episode of EIA also plays a role in the development of subsequent wheezing to exertion. Consequently, there appears to be a refractory period that follows the initial episode of EIA, and this period can be protective for subsequent episodes of wheezing with exercise. MECHANISMS
OF EIA
Most specialists in allergy and respiratory medicine have little problem recognizing EIA, confirming its presence with appropriate testing or preventing wheezing with exertion. Nonetheless, the basic mechanisms of EIA remain unresolved, complex, and controversial. Areas of attention have included heat and water loss as well as mediator release during exercise.s-‘o Heat and water loss As indicated above, running rather than swimming is more likely to provoke asthma. To explain these observations, the importance of airway heat and water loss has provided insight into clinical correlates. With normal respiration, heat and water are transferred from the airway bronchial mucosa to inspired air so that the air is warmed to body temperature and saturated with water. During exercise, there is a dramatic increase in minute ventilation, the upper airway (nose) is bypassed, and the inspired air is no longer warmed to body temperature or humidified to saturation. Consequently, the lower airways attempt to compensate and complete the conditioning process. This results in the loss of lower airway heat and water during
VOLUME NUMBER
88 5
inspiration, some of which is recovered during the expiratory phase when warm, humidified air passes over the now cooler airway. Respiratory heat loss is governed Iby many factors, including the change in minute ventilation and water content of the inspired air. Furthermore, there is evidence that respiratory heat excha.nge will correlate with the degree of postexercise obstruction. ” Although both heat and water loss have been implicated in EIA, the degree to which each plays remains controversial. In this regard, McFadden et al. “5 I3 have made a number of interesting observations. First, since both exercise and hyperventilation produce bronchospasm, the belief had been that increased minute ventilation, rather than exercise itself, precipitates EIA. Furthermore, direct thermal recordings in thz lower airway document decreased temperature deep in the lungs exercise in cold, dry air. Finally, the rate of airway rewarming, rather than cooling, may determine the intensity of asthma with exercise. !3ubjects who exercised in cold air and recovered under cold conditions experienced less airway obstruction than subjects recovering in conditions of fully humidified body-temperature air. Based on these observations, it is postulated that airway cooling in exercise causes pulmonary vasoconstriction; with rapid rewarming, vasodilation, hyperemia, and edema occur to c,suse bronchial obstruction. I4 In contrast, Anderson et al.15 propose another theory in which evaporative water loss produces hyperosmolarity of the periciliary fluid. Inhalation of both hypotonic and hypertonic aerosols of saline produces bronchospasm16 that is the result of a direct effect on airway smooth muscle tone.” Airway changes in osmolarity from exercise could provoke mast cell18 or basophil mediator release. I9 However, since significant changes in osmolarity must develop (600 to 800 mOsm) to cause mast cell secretion of 20% of their histamine (content, some investigators argue that these independent observations are not physiologically achieved. Furthermore, the relationship of mediator release to EIA is controversial. Early attempts to correlate mast cell secretion and EIA focused on peripheral blood determinations of histamine and NCF-A. Circulating levels of histamine have been reported not to change”-‘, ” or increase after exercise.“, 23Changes in NCF-A, in relationship to exercise, have followed a similar pal:tem: no change” or a rise.22 Furthermore, most inve,stigators have not demonstrated increased circulating histamine or NCF-A after isocapnic hyperventilation-induced asthma.“’ 22,24; this suggests a difference in the pathogenesis of EIA and hyperventilation-induced airway obstruction. Finally, and per-
Exercise-induced
asthma
697
haps most directly, Broide et aLz5performed fiberoptic bronchoscopy and lavage on seven atopic subjects with asthma after EIA; no differences in mean values before and after exercise in histamine, tryptase, prostaglandin D2, or leukotriene C, were found. EOSs in EIA In this issue of the JOURNAL, Venge et aLz6 evaluated the influence of EIA on EOSs. Although the importance of EOSs to chronic asthma is of great interest and likely importance, the role of this inflammatory cell in EIA is largely unknown. As the authors suggest, EIA might “reflect the inflammation in the lung of the individual with asthma”26 and hypothesize that the enhanced activity of the EOS is one factor in EIA. To evaluate this possibility, Venge et al. studied the variations in EOS activity, as reflected in serum levels of ECP, to the development of EIA. In subjects with EIA, treadmill testing caused a slight, immediate rise in ECP and fall 60 minutes after exercise; no change in circulating ECP was noted in subjects without EIA, but their baseline levels were less than that of subjects with EIA. Furthermore, the preexercise circulating levels of ECP, but not circulating EOSs, demonstrated a correlation with the fall in peak expiratory flow to exercise. Finally, terbutaline blocked EIA but not the ECP response to exercise. In contrast, 4 weeks of budesonide treatment prevented the late fall in serum ECP. The clinical significance of these observations was not resolved by this investigation but rather raised a number of relevant questions as to mechanisms of asthma and, particularly, patient susceptibility to EIA. First, the authors indicate that the pattern of circulating concentration ECP in EIA is very similar to the ECP response to allergen-induced asthmaz7; patients with LAR to allergen had higher levels of ECP before challenge than did patients who did not have LAR.27 These data were interpreted to suggest that a prerequisite for LAR was the presence of circulating primed, or activated, EOSs that could then be attracted to the lung. However, this does not mesh with their current findings, since no LARs occurred in patients after exercise and since a similar pattern of responses in serum ECP values followed histamine inhalation. In contrast, and more feasible, in my prejudiced view, is their explanation that elevated levels of ECP reflect ongoing airway inflammation and thus an enhanced degree of airway responsiveness and potential for airway obstruction to various stimuli, including exercise. The correlation of ECP to intensity of EIA and a protective response to inhaled corticosteroids, budesonide, fit with this position.
898
J. ALLERGY
Busse
The importance of the observations by Venge et al. to clinical asthma have yet to be resolved. Nonetheless, their findings open a new area of investigation in EIA into the role of the EOS and its inflammatory products to this process. Furthermore, their observations potentially unify current concepts of asthma and EIA to the importance of airway inflammation. Unification of “all” types of asthma to have airway inflammation and treatment focus on this component of bronchial obstruction are in keeping with current therapeutic approaches; substantiation of such observations in EIA will await further insightful investigation. William Busse, MD University of Wisconsin Medical School Madison, WI 53792 REFERENCES 1. McFadden ER. Exercise-induced asthma: assessmentof current etiologic concepts. Chest 1987;91:515-75. 2. Pierson WE, Biennan W, Kawabori I, Van Arsdel PP. The incidence of exercise-induced bronchospasm in “normal” and “atopic” children [Abstract]. J ALLERGY CLIN IMMUNOL 1972;49: 129-30. 3. Loughlin GM, Taussig LM. Pulmonary function in children with a history of laryngotracheobronchitis. J Pediatr 1979; 94:365-9. 4.
5.
6. 7. 8. 9. 10.
Bader D, Ramos AD, Lew CD, Platzker ACG, Stabile MW, Keens TG. Childhood sequelae of infant lung disease, exercise, and pulmonary function abnormalities after bronchopulmonary dysplasia. J Pediatr 1987;110:693-9. Lemanske RF Jr, Henke KG. Exercise-induced asthma. In: Gisolfi CV, Lamb DR, eds. Perspectives in exercise science and sports medicine, vol 2. Carmel, Ind.: Benchmark Press, 1989:465-506. Anderson SD, Silverman M, Konig P, Godfrey S. Exerciseinduced asthma. Br J Dis Chest 1975;69:1-10. Godfrey S. Symposium on special problems and management of allergic athletes. J ALLERGY CLW IMMUNOL 1984;73:630-3. Chen WY, Horton DJ. Heat and water loss from the airways and exercise-induced asthma. Respiration 1977;34:305-10. McFadden ER. Exercise and asthma. N Engl J Med 1987;317:502-3. Anderson SD. Issues in exercise-induced asthma. J ALLERGY CUN IMMLJNOL 1985;76:763-72.
11. Deal EC Jr, McFadden ER Jr, Ingram RH Jr, Strauss RH, Jeager JJ. Role of respiratory heat exchange in production of exercise-induced asthma. J Appl Physiol 1979;46:467-75. 12. McFadden ER Jr, Denison DM, Waller JF, Assoufi B, Pencock
CLIN. IMMUNOL. NOVEMBER 1991
A, Sopwitb T. Direct recordings of temperature in the tracheobronchial tree in normal man. J Clin Invest 1982;69: 700-5.
13. McFadden ER Jr, Lenner KAM, Strohl KP. Post exertional airway rewarming and thermally induced asthma. J Clin Invest 1986;78:18-25. 14. McFadden ER Jr. Hypothesis: exercise-induced asthma as a vascular phenomenon. Lancet 1990;335:880-3. 15. Anderson SD, Daviskas E, Smith CM. Exercise-induced asthma: a difference in opinion regarding the stimulus. Allergy Proc 1989:10:215-26. 16. Shoeffel RE, Anderson SD, Altonnyan REC. Bronchial hyperreactivity in response to inhalation of ultrasonically nebulized solutions of distilled water and saline. Br Med J 1981;283:1285-7. 17. Finney MJB, Anderson SD, Black JL. The effect of nonisotonic solutions in human isolated airway smooth muscle. Respir Physiol 1987;69:277-86. 18. Eggleston PA, Kagey-Sobotka A, Schleimer RP, Lichtenstein LM. Interaction between hyperosmolar and IgE-mediated histamine release form basophils and mast cells. Am Rev Respir Dis 1989;130:86-91. 19. Findlay SR, Dvorak AM, Kagey-Sobotka A, Lichtenstein LM. Hyperosmolar triggering of histamine release form human basophils. J Clin Invest 1981;67:604-13. 20. Deal EC Jr, Wasserman SI, Soter NA, Ingram RH Jr, McFadden ER Jr. Evaluation of the role of mediators of immediate hypersensitivity in exercise-induced asthma. J Clin Invest 1980;65:659-65. 21. Howarth PH, Pao GJ-K, Church MK, Holgate ST. Exercise and isocapnic hyperventilation-induced bronchoconstriction in asthma: relevance of circulating basophils to measurement of plasma histamine. J ALLERGY CLIN IMMUNOL 1984;73:391-9. 22. Lee TH, Brown MJ, Nagy L, Causon R, Walport MJ, Kay AB. Exercise-induced release of histamine and neutrophil chemotactic factor in atopic asthmatics. J ALLERGY CLIN IMMUNOL 1982;70:73-81.
23. Barnes PJ, Brown MJ. Venous histamine in exercise and hyperventilation-induced asthma in man. Clin Sci 1962;61:15962.
Morgan DJR, Moodley I, Phillips MJ, Davis RJ. Plasma histamine in asthmatic and control subjects following exercise: influence of circulation basophils and different assay techniques. Thorax 1983;38:771-7. 25. Broide DH, Eisman S, Ramsdell JW, Ferguson P, Schwartz LB, Wasserman SI. Airway levels of mast cell-derived mediators in exercise-induced asthma. Am Rev Respir Dis 1990;141:563-8. 26. Venge P, Hemicksen J, Dahl R. Eosinophils in exercise-induced asthma. J ALLERGY CLIN IMMUNOL 1991;88:699-704. 27. Venge P, Dahl R. Are blood eosinophil number and activity important for the development of the late asthmatic reaction after allergen challenge? Eur Respir J 1989;2(suppl 6):4305-
24.
45.
