A comparison of the asthmatic response to methacholine and exercise

The airway responses to methacholine and to exercise challenges were compared in 45 young adults with asthma. The spirometric response to five minutes of treadmill exercise was first documented. On a separate day methacholine dose-response relationships were determined. All asthmatics had an abnormal response to methacholine, and 36 had an abnormal response to exercise. Methacholine sensitivity and exercise-induced asthma were significantly related (r = 0.69, p < 0.001), but the relationship was nonlinear; the increased response to exercise related to the logarithm of the methacholine response. Between asthmatics with generally unreactive airways, small variation in methacholine sensitivity was associated with large variations in the severity of exercise-induced asthma; between more responsive asthmatics, there was a smaller effect. It is suggested that exercise-induced asthma is dependent on two factors: a stimulus generated during exercise and a response from abnormal bronchi. The bronchial response may be a limiting factor in asthmatics with less responsive airways.     

Metabolic changes in exercise-induced and methacholine-induced bronchoconstriction

Metabolic and physiological responses to graded exercise and methacholine challenge were investigated in asthmatics with or without exercise-induced bronchoconstriction. The results showed that after methacholine challenge, free fatty acid levels increased only in patients with exercise-induced asthma, while they increased in both groups of asthmatics after treadmill exercise. No significant changes were noted in plasma lactic acid levels, ventilation, or oxygen consumption among the groups studied. These data suggest that asthmatics with exercise-induced bronchoconstriction may differ from other asthmatics in some of their metabolic responses.     

A standardized method of evaluating exercise-induced asthma

In order to evaluate drug effects on exercise-induced asthma, and to study associated metabolic and pulmonary effects, a method for inducing a consistent response is needed. A method is presented, consisting of 5 min of treadmill exercise sufficiently strenuous to increase a subject's heart rate to 90% of the predicted maximum for age; the airway response is measured frequently for 20 min after exercise. Using this method, 48 asthmatics and 13 nonasthmatics were evaluated. Although none developed severe asthma, a significant airway response occurred in 71% of asthmatics. The severity of exercise-induced asthma depended on intensity and duration of exercise but not on time of day. The method described allows a consistent stress to be applied to a wide age range, and response to this stress was consistent at various ages. Variation of a subject's response following repeated testing was less than that reported with other methods, and could be further reduced by selecting only those subjects with greater than 20% change in one-second forced expiratory volume (FEV₁) and by completing studies in less than a month.     

Bronchial responsiveness to inhaled histamine and exercise.

Bronchial responsiveness to inhaled histamine and exercise was measured in 19 asthmatics. Histamine aerosol was inhaled to determine the provocative concentration producing a 20% fall in forced expired volume in one second (FEV1) (PC20). Exercise was performed on a treadmill and a cycle ergometer; following each procedure the percent fall in the FEV1 (delta FEV1) and the exercise lability (percent rise in FEV1 plus percent fall in FEV1) were calculated. Delta FEV1 and exercise lability after both forms of exercise were similar. PC20 correlated with delta FEV1 and exercise lability in both forms of exercise; however, the correlation with exercise lability was better. PC20 was more sensitive in demonstrating bronchial hyperresponsiveness. The close correlation between the level of bronchial responsiveness to histamine and exercise supports the view that release of endogenous chemical mediators is an important determinant of exercise-induced asthma. The treadmill exercise and cycle ergometry protocols were equally effective in producing exercise-induced asthma.     

Measurement of plasma prostaglandins during exercise-induced bronchospasm

Bronchospasm following exercise is a phenomenon which occurs in most patients with reversible airway disease. The pathophysiologic mechanism leading to this bronchoconstriction with exercise has not yet been defined. Recently, prostaglandins have been implicated in the etiology of asthma. The purpose of this investigation was to determine changes in plasma prostaglandins occurring during exercise-induced asthma. Eight ambulant asthmatics were chosen for baseline pulmonary spirometry and peripheral venous blood prostaglandin E and F levels. The asthmatics were then exercised to 80% of their age-predicted maximal heart rate via a multistage branching treadmill protocol. At 5, 15, and 30 min following exercise, pulmonary spirometry was again performed and peripheral venous blood collected at the indicated times. Clinical bronchospasm as characterised by audible wheezing and >15% decrease in FEV₁ and MMEFR was obtained in all of the asthmatics. Peripheral PGE and PGF_2α determinations following this exercise protocol were not altered significantly: (PGE: 0 mm, 238; 5 min, 185; 15 min, 248; 30 min, 256 pg/ml); (PGF_2α: 0 min, 50; 5 min, 24; 15 min, 25; 30 min, 17 pg/ml) (p > 0.1). In summary, no significant change in peripheral blood prostaglandin E and F_2α levels as determined by radioimmunoassay was noted at the time of exercise-induced bronchospasm.     

Effect of nasal and oral breathing on exercise-induced asthma

The effect of nasal as well as oral breathing during level-ground running for 6 min on the post exercise bronchial response was studied in fifteen people (five asthmatics with exercise liability, five asthmatics with no such liability and five normals). Each patient did the exercise twice; once with the nose clipped and once with the mouth closed. FEV₁ was measured before exercise, immediately after exercise and at 5,10, 15,20and 30 min thereafter. A fall in FEV₁ of 20% or more from the basal level was taken as evidence of bronchoconstriction. When the patients were required to breath only through the nose during the exercise, the post-exercise bronchoconstrictive response was markedly reduced as compared with the response obtained by oral breathing during exercise, indicating a beneficial effect of nasal breathing. Nasal breathing was beneficial as compared with oral breathing in normals as well. In the five asthmatics with no exercise liability no appreciable difference was observed. This study suggests that the oropharynx and nasopharynx play important roles in the causation of exercise-induced asthma.     

Exercise-induced biphasic responses and methacholine reactivity in asthma

Biphasic (early and late) asthmatic responses to exercise occurred in seven of 43 children with reproducible exercise-induced asthma. As biphasic allergen-induced asthma is associated with a prolonged increase in nonspecific bronchial hyperreactivity, this effect was not sought in the 43 asthmatic children. There was no significant change in methacholine PD20 FEV1 before and after exercise challenge, either in children who had early, or early and late, exercise responses. Late reactions after allergen exposure are likely to be of considerable clinical significance in relation to the enhancement of bronchial responsiveness. It is reassuring that this is not the case for exercise challenge, as it would have major implications in relation to the recommendations that asthmatics should participate in normal activities and even in training programs. Furthermore, it suggests that there are differences between the pathophysiology of asthma induced by exercise and that produced by allergens.     

Seasonal variability of exercise-induced asthma especially outdoors. Effect of birch pollen allergy

A study was made to determine whether natural allergenic exposure modulates exercise-induced asthma. Eighteen asthmatic men, ten non-allergic and eight allergic to birch pollen, underwent heart rate-monitored outdoor exercise tests during both the cold winter season and in the spring, the birch pollen season. The mean fall in FEV1 after the outdoor exercise test increased in the allergic group from 17 +/- 3% in the winter to 27 +/- 6% in the spring, while it decreased in the non-allergic group from 31 +/- 6% to 22 +/- 4%, respectively (P less than 0.01). Initial FEV1 and FCV values remained unchanged in both groups. The non-specific airway responsiveness to histamine did not change significantly in birch pollen allergic or non-allergic subjects during the spring, when compared with the winter values. We conclude that the exercise-induced asthma is aggravated in the birch pollen allergic asthmatics during the pollen season, when compared to the non-birch pollen allergic asthmatics, in whom the exercise-induced bronchoconstriction is attenuated as expected, because of the warmer and more humid weather in the spring.     

Bronchial hyperresponsiveness to methacholine after exercise in asthmatics

We studied the effect of exercise on bronchial responsiveness to methacholine in 10 asthmatics. Bronchial responsiveness to methacholine was compared before and 20 minutes after exercise. Although five out of 10 asthmatics showed exercise-induced bronchoconstriction (EIB), nine out of 10 asthmatics became more hypersensitive after exercise, irrespective of EIB.     

Adrenergic responses of asthmatic and normal subjects to submaximal and maximal work levels

The response of the adrenergic system of asthmatic subjects to exercise and the role of plasma catecholamines in exercise-induced asthma were investigated. Plasma levels of norepinephrine and epinephrine were measured at rest, during and after exercise in 7 asthmatic and 9 matched normal subjects. Exercise-induced bronchospasm occurred in all asthmatic subjects following exercise, while no significant change was observed in the normal subjects. The results showed that plasma levels of norepinephrine and epinephrine at rest and changes that occcurred during and after exercise were similar in both normal and asthmatic subjects. These data suggest that the adrenergic response of asthmatics to the same relative exercise stress as reflected in plasma catecholamine levels does not differ from that of normal subjects. It appears that changes in the circulating catecholamines do not play a significant role in the pathogenesis of exercised-induced asthma.     

Serum dopamine β-hydroxylase and free fatty acids in exercise-induced asthma

Serum dopamineβ-hydroxylase activity, which is thought to reflect noradrenaline secretion, and free fatty acid level were measured in twenty atopic asthmatic children, of whom ten had exercise-induced asthma (EIA), after exercise on the treadmill. There was a significant decrease in the level of serum dopamine β-hydroxylase activity in the asthmatics who developed EIA and this closely accompanied the onset of airflow obstruction. There was no change in the free fatty acid levels. In contrast, the asthmatics, who did not have EIA showed a significant rise in the levels of dopamine β-hydroxylase activity and free fatty acids after the same exercise task. Our results suggest that the atopic children studied, who developed EIA, may have had an impaired noradrenaline response to exercise. It is further suggested that this impaired noradrenaline secretion may facilitate mediator release and contribute to the airflow obstruction in EIA.     

Exercise-induced release of histamine and neutrophil chemotactic factor in atopic asthmatics

Concentrations of plasma histamine and serum neutrophil chemotactic factor (NCF) were measured in seven atopic asthmatics who developed exercise-induced asthma (EIA) after a treadmill task. The results were compared with those obtained after inhalation of specific antigen or methacholine. Plasma histamine concentrations were measured with a novel double-isotope radiometric assay, and NCF was identified by its elution in the void volume fractions of Sephadex G-200 and as a single peak of activity at approximately 0.20 molar NaCl after anion exchange chromatography on diethylaminoethyl-Sephacel (pH 7.8). After exercise or antigen challenge, the time courses of appearance of both mediators were virtually identical and accompanied the increase in airways obstruction. There was a statistically significant correlation between the concentrations of histamine or NCF and the magnitude of airflow obstruction after exercise and antigen challenge. This suggested that there may be a direct association between mediator release and EIA or antigen-induced bronchoconstriction. In contrast, there were no significant elevations in circulating histamine and NCF after inhalation of methacholine, at concentrations giving a fall in FEV1 comparable to that induced by exercise or antigen. The prior administration of cromolyn to three asthmatics inhibited both their EIA and the release of histamine and NCF. When four asthmatics were exercised for periods of 1, 3, and 6 min, the release of NCF and fall in peak expiratory flow rate were directly related to the duration of the exercise. The rise of NCF activity in subjects with EIA was fivefold greater than that observed in asthmatics who did not experience airways obstruction when subjected to the same exercise task. These results provide further evidence that mediators of hypersensitivity are released during EIA.     

Exercise-induced asthma in Nepalese children

Three hundred and one children between 5 and 15 years old in the hills of east Nepal were studied to determine the prevalence and the main causes of asthma and atopy. Asthma was diagnosed on the basis of history, clinical examination and the results of a 6-min exercise test (step test). Asthma was diagnosed in six children, none of whom was skin prick test positive. We present here normal values of baseline peak expiratory flow rate (PEFR), and the exercise-induced changes in PEFR in normals, asthmatics, other wheezy children and others with atopic histories. The results of the skin prick tests are presented with the atopic histories in another paper.     

Effect of triamcinolone acetonide aerosol upon exercise-induced asthma.

The effect of triamcinolone acetonide aerosol upon exercise-induced asthma was compared with that of placebo in a double-blind, crossover study in 11 asthmatic children. Measurement of pulmonary function before and after treatment and before and after exercise disclosed inhibition of exercise-induced asthma in only three of nine children in whom exercise after inhalation of placebo caused bronchospasm.     

Evaluation of exercise-induced bronchospasm in the adult asthmatic

It has been shown that most asthmatics respond to exercise with bronchospasm. This study was undertaken to develop a safe and reliable method for quantifying exercise-induced bronchospasm in the asthmatic adult. Five normal adult volunteers and 12 stable asthmatics were exercised to 80% of their predicted maximal heart rate according to a multistage branching treadmill protocol. Their responses in terms of forced expiratory volume in 1 sec (FEV₁) and maximum midexpiratory flow rate (MMEFR) at 5, 15, and 30 min after exercise were assessed, while standing, with a Jones Pulmonar II waterless spirometer. This submaximal stress test was chosen because 80% of predicted maximal heart rate could be obtained by all individuals and allowed the asthmatics to exercise long enough for inducible bronchospasm to occur. Audible wheezing was induced in 100% of the asthmatics and in none of the nonasthmatics. In the normal individuals, FEV₁ and MMEFR increased significantly during the postexercise period. When compared to normal subjects, the 12 asthmatic patients demonstrated a significant reduction in FEV₁ an MMEFR (ΔFEV₁: 5 min, ?300; 15 min, ?304; 30 min, ?208 ml; ?18%, ?17%, and ?15%; ΔMMEFR: 5 min, ?15; 15 min, ?9; 30 min, ?1L/M; ?23%, ?18%, and ?6%) (p < 0.01). The use of a rigidly controlled exercise stress with a cardiovascular endpoint in the measurement of FEV₁ and MMEFR in the postexercise period appears to be a useful tool in assessing the presence and severity of exercise-induced bronchospasm in the adult asthmatic.     

Oxatomide and exercise-induced asthma in children: the value of serial exercise tests

Two groups of eight asthmatic children carried out serial treadmill exercise tests at 2-hourly intervals, after double-blind premedication with oxatomide (2 mg/kg by mouth), sodium cromoglycate powder (20 mg by inhalation) or matched placebo preparations. The drugs were studied in one group up to 6 hr and in the other group (omitting sodium cromoglycate) from 4 to 10hr after administration. Peak expiratory flow rate was measured before and after exercise to give an index of exercise-induced asthma. Oxatomide had a slight but significant bronchodilator effect. After a lag period of up to 4 hours, oxatomide exerted a significant protective effect against exercise-induced asthma which lasted until at least 8 hr. At 10 hr after ingestion, the effect had gone. A mean maximum diminution of exercise-induced asthma of 49% was found, in comparison with placebo. Oral oxatomide after a lag period, exerts a significant protective effect against exercise-induced asthma. The relevance of these observations for the clinical management of asthma remains to be determined.     

A breathing filter exchanging heat and moisture prevents asthma induced by cold air

In order to devise a protective aid against bronchial obstruction induced by cold air, we have tested a breathing filter with heat and moisture exchanging properties. Nine asthma patients, who all had a history of cold-induced asthma, took part in exercise tests on an ergometer bicycle at a temperature of approximately −10deg;C, without and with a breathing filter. Without a breathing filter, the maximum reduction in FEV₁ was, on average, 36%. With the breathing filter, the maximum reduction in FEV₁ was, on average, 11%. The difference was clearly significant ( P < 0.001). A further five cold-sensitive asthmatics performed similar exercise tests at −10°C on three occasions: 1) without and 2) with a breathing filter as above, and 3) with two breathing filters connected in parallel: one for inspiration and the other for expiration. Thus, no heat-moisture exchange could take place. The fall in FEV₁ after provocation without a breathing filter and with parallel breathing filters was similar but attenuated when rebreathing took place through the breathing filter. The results confirm the theory that in cold/exercise-induced asthma, it is indeed the heat and or water loss from the airways that triggers airway narrowing, and that a heat and moisture exchanging filter has a considerable protective effect and can be of value in the treatment of asthma.     

Atopy may be related to exercise-induced bronchospasm in asthma

BACKGROUND: Recent studies suggest that atopy may be associated with exercise-induced bronchospasm (EIB) in asthma. However, it is not clear whether atopy is related to EIB, regardless of airway hyper-responsiveness (AHR) to methacholine, because asthmatic subjects often show AHR to exercise and methacholine simultaneously. OBJECTIVE: To investigate whether atopy is related to EIB in asthmatic subjects, independently of AHR to methacholine. METHODS: Fifty-eight male asthmatic subjects were studied. Initial spirometry was performed. Skin prick test was carried out, using 53 common allergens including mites dust antigen. Atopy score was defined as a sum of mean weal diameters to all allergens tested. Methacholine bronchial provocation testing was performed. Twenty-four hours later, free running test was performed. Positive EIB was defined as a 15% reduction or more in FEV1 from baseline after exercise. RESULTS: All subjects had AHR to methacholine. The degree of AHR to methacholine in asthmatics with EIB was similar to that in asthmatics without EIB. However, atopy score and skin reaction to Dermatophagoides pteronyssinus significantly increased in asthmatics with EIB compared with those without EIB (P < 0.05, respectively). Furthermore, the degree of EIB significantly correlated with atopy score in all subjects (r = 0.35, P < 0.01). This relationship was maintained even after the exclusion of EIB-negative asthmatic subjects. CONCLUSION: Atopy defined as skin test reactivity may contribute to the development of EIB in asthma, independently of AHR to methacholine.     

Problems of interpreting exercise-induced asthma

Factors affecting exercise-induced asthma are reviewed based on studies in large numbers of children and young adults. Evidence is presented to show that running is a more potent and reproducible stimulus than cycling and that walking and swimming have a small and variable effect. The greatest amount of exercise-induced asthma is found after 6 to 8 minutes of steady-state running at a work rate equivalent to about two thirds of the working capacity of the subject. Exercise may be repeated every 2 hours throughout the day without any diminution of its effect in causing postexercise bronchoconstriction. The use of exercise in assessing drugs used to treat asthma is discussed, and the importance of the type of exercise test and the use of placebo preparations is emphasized. Serial exercise tests may be used to study the duration of protection from exercise-induced asthma afforded by drugs such as cromolyn sodium.     

The functional conversion hypothesis: A contributor to exercise-induced asthma?

Studies on receptor stability suggest that functional conversion of adrenoceptors between alpha and beta can occur in mammalian myocardium due to variations in the environment such as temperature changes, pH or hormonal changes. If adrenoceptors of the respiratory system behave similarly, heat and water loss of airways noted during hyperventilation could lead to functional loss of inhibitory beta and expression of excitatory alpha adrenoceptors. This would have the effect of counter-action of adrenergic homeostatic mechanisms which may be of particular importance in asthmatic subjects. The hypothesis of adrenoceptor interconversion could contribute to the airway obstruction observed during exercise in asthmatics. This concept is supported by scattered reports of the efficacy of alpha adrenergic antagonists in preventing exercise-induced asthma.