Airway cooling. Stimulus for exercise-induced asthma.

Five patients were studied using a randomly assigned sequence of four inspired-air conditions during strenuous treadmill exercise for 10 min. The four inspired-air conditions were: (1) Cool, dry room air (CDA) at 23 degrees C with 3 mg of water and 7.3 cal of heat content/l, (2) over-saturated air (OSA) at room temperature containing 43 mg water and 16.3 cal/l, (3) hot, dry air (HDA) at 120 degrees C having 3 mg water and 24.4 cal/l, and (4) warm, humidified air (WHA) at 37 degrees C with 43 mg water and 34.7 cal/l. Using inspired-air CDA and OSA, all patients manifested exercise-induced asthma (EIA) while forced expiratory volume in 1 sec (FEV1) and maximal mid-expiratory flow (MMEF) decreased to an average of 81% and 63% of the baseline when breathing CDA and to 83% and 71% of the baseline when breathing OSA. With WHA, EIA was clearly prevented while the post-exercise FEV1 and MMEF were 101% and 103% of baseline, respectively. With HDA, the post-exercise FEV1 and MMEF were 95% and 86% of baseline, respectively. Analysis of variance revealed that the post-exercise pulmonary function changes had resulted solely from respiratory heat loss and not from water loss or from interaction of heat and water losses. These results indicate that exercise-induced asthma is associated with airway cooling incurred during exercise rather than airway dehydration.     

Airway inflammation in premenstrual asthma.

Premenstrual asthma (PMA) is a clinical picture with worsening of asthmatic symptoms and pulmonary functions in the late luteal phase of the menstrual cycle. The aim of this study was to evaluate the inflammatory changes in asthmatic women who complain of PMA. Forty asthmatic women attending our outpatient clinic were questioned about worsening of their asthma before menstruation. Eleven women (aged 17-40) who complained of PMA participated in the study. Subjects were asked to record peak expiratory flow rates, symptom scores, and beta-agonist use daily. After the first menses on the seventh day of their cycle, and before the onset of the next menstruation, on the 26+/-3rd day of the cycle, patients were evaluated with pulmonary function tests, methacholine challenge test, and fractionated exhaled nitric oxide (FE(NO)) levels. Eosinophils in peripheral blood and induced sputum were also evaluated. When comparing the two groups of results, the significant changes were in FENO levels, day-time symptom scores, and eosinophils in induced sputum (29.25 ppb/9.16 ppb p < 0.05, 1/0.45 p = 0.05, %6.63/%4.09 p < 0.01, respectively, before and after menstruation). These results show that PMA is not only a clinical picture with a decrease in airway calibre that can be related to the regulation of 2 receptors, but also a complex state with worsening of airway inflammation.     

Inhaled hyaluronic acid against exercise-induced bronchoconstriction in asthma

Hyaluronic acid (HA) is a polysaccharide that is present in human tissues and body fluids. HA has various functions, including a barrier effect, water homeostasis, stabilizing the extracellular matrix, increased mucociliary clearance and elastin injury prevention. It may therefore exert prophylactic activity in the treatment of asthma. We tested the hypothesis that HA inhalation will prevent exercise-induced bronchoconstriction (EIB) in a randomised double-blinded placebo-controlled crossover study. Sixteen asthmatic patients with EIB were included in the study (mean (SD)) (age 24.5 (7.3) yr, FEV1 88.6 (11.3) %predicted, PC20 methacholine (g-mean (SD in DD)) 0.4 (1.5) mg/ml). On two separate visits an exercise challenge was performed 15 min post-inhalation of either HA (3 ml 0.1% in PBS) or placebo (3 ml PBS). The maximum fall in FEV1 and the AUC 30 min post-exercise were used as outcomes. After inhalation of both HA and placebo, baseline FEV1 decreased significantly (HA 4.1 (3.1)%, placebo 2.9 (4.1)%, P<0.017). The maximum fall in FEV1 following exercise challenge was not significantly different between HA versus placebo (median HA 22.50%, placebo 27.20%, P=0.379), as was the AUC (median HA 379.3 min*%fall, placebo 498.9 min*%fall, P=0.501). We conclude that at the current dose, inhaled HA does not significantly protect against EIB. This suggests that HA is not effective as a prophylaxis for EIB in patients with asthma.     

Airway levels of mast cell-derived mediators in exercise-induced asthma.

In order to assess the role of mast cell-derived mediators in the pathogenesis of exercise-induced asthma (EIA), we completed pre- and postexercise bronchoalveolar lavage (BAL) in seven atopic subjects with EIA. The study subjects were defined as having EIA if they exhibited a greater than 15% decrease in FEV1 after completing 6 min of treadmill exercise. There were no significant differences between mean preexercise and mean postexercise mast cell-derived BAL histamine (186 +/- 67 versus 148 +/- 36 pg/ml), tryptase (4.5 +/- 2.0 versus 2.8 +/- 2.0 ng/ml), prostaglandin D2 (26 +/- 11 versus 32 +/- 25 pg/ml), or leukotriene C4 (less than 100 versus less than 100 pg/ml). In addition, mast cells present in BAL fluid after exercise contained similar amounts of cellular histamine compared with BAL mast cells obtained before exercise (preexercise BAL cellular histamine, 26.6 +/- 12.3 ng/10(6) BAL cells; postexercise BAL cellular histamine, 22.7 +/- 9.1 ng/10(6) BAL cells), indicating that depletion of preformed mast cell mediators are unlikely to account for the refractory period in EIA. This study suggests that the cellular pathogenesis of EIA (mast cell-independent) differs from current theories of the pathogenesis of extrinsic allergen-induced asthma (mast cell-dependent).     

Determinants of the severity of exercise-induced bronchoconstriction in patients with asthma.

AIM: In examining the mechanisms of exercise-induced bronchoconstriction (EIB), it is important to determine which factors most strongly affect the severity of EIB. We determined such factors in patients with asthma by stepwise multiple-regression analysis. METHODS: Twenty-three patients with asthma underwent pulmonary function tests, methacholine provocation test, and sputum induction. Eosinophilic inflammatory indices and airway vascular permeability index (ratio of albumin concentrations in induced sputum and serum) were examined in sputum samples, and then an exercise test was performed by all asthmatics. RESULTS: There was a significant correlation between the severity of EIB and degree of eosinophilic inflammation in induced sputum. Moreover, there was a significant correlation between the severity of EIB and airway vascular permeability index. Although we could not find a significant correlation between the severity of EIB and 1-sec forced expired volume, 20% provocation concentration of (PC20) methacholine tended to be correlated with the severity of EIB. By stepwise multiple-regression analysis, we also found that airway vascular permeability index, eosinophil cationic protein levels in sputum, and PC20 methacholine are independent predictors of the severity of EIB. CONCLUSION: We found that airway vascular hyperpermeability, eosinophilic inflammation, and bronchial hyperreactivity are independent factors predicting the severity of EIB.     

An update on exercise-induced bronchoconstriction with and without asthma

Exercise-induced bronchoconstriction (EIB) is defined as transient, reversible bronchoconstriction that develops after strenuous exercise. It is a heterogeneous syndrome made up of a spectrum of phenotypes ranging from the asymptomatic military recruit whose condition is detected by diagnostic exercise challenge to the athlete with known asthma to the elite athlete for whom EIB represents an overuse or injury syndrome. If exercise is the only identified trigger for bronchoconstriction, it is called EIB. However, when it is associated with known asthma, then it is defined as EIB with asthma. This review discusses the pathogenesis, presentation, diagnosis, and management of EIB and EIB with asthma.     

Airway inflammation in childhood asthma

Airway pathology has been extensively investigated in adulthood asthma, whereas only few studies examined bronchial biopsies in childhood asthma. To evaluate the airway pathology in children with asthma, we analyzed bronchial biopsies obtained from 23 children undergoing bronchoscopy for clinical indications other than asthma. Nine had mild/moderate asthma. Six had atopy without asthma, and eight had no atopy or asthma. We measured basement membrane thickness and quantified the number of eosinophils, mast cells, neutrophils, macrophages, T lymphocytes, and positive cells for transforming growth factor-beta1 (TGF-beta1) and its receptors I and II (TGFbeta-RI and TGFbeta-RII) in subepithelium. Children with asthma had an increase in basement membrane thickness and in the number of eosinophils compared with control subjects, but not compared with children with atopy. They also had a decreased expression of TGFbeta-RII compared with both those with atopy and control subjects. In children with asthma, the number of eosinophils correlated negatively with TGFbeta-RII and positively with symptom duration. In conclusion, airway eosinophilia and basement membrane thickening, which are the pathologic features that are characteristic of adulthood asthma, are already present in children with mild asthma, and even in children with atopy without asthma. Moreover, in children with asthma but not in children with atopy without asthma, there is a downregulation of TGFbeta-RII.     

Airway inflammation and occupational asthma

Airway inflammation due to exposure to a wide variety of agents encountered in the workplace is a major cause of occupational asthma. This article reviews major examples of occupational asthma linked to airway inflammation, including their epidemiology, pathophysiology, and clinical course.     

Airway inflammation and remodeling in asthma

An important advance in our understanding of the pathophysiology of asthma has been the discovery that airway inflammation is not confined to severe asthma but also characterizes mild and moderate asthma. Inflammation in asthma may be the result of a peculiar type of lymphocytic inflammation whereby Th2 lymphocytes secrete cytokines that orchestrate cellular inflammation and promote airway hyperresponsiveness. The term "airway remodeling" in asthma refers to structural changes that occur in conjunction with, or because of, chronic airway inflammation. Airway remodeling results in alterations in the airway epithelium, lamina propria, and submucosa, leading to thickening of the airway wall. The consequences of airway remodeling in asthma may include incompletely reversible airway narrowing, bronchial hyperresponsivenesss, airway edema, and mucus hypersecretion. Airway remodeling in asthma thus may predispose persons with asthma to asthma exacerbations and even death from airway obstruction caused by smooth muscle contraction, airway edema, and mucus plugging. Although much has been learned in the past 25 years about the pathophysiology of airway inflammation and airway remodeling in asthma, important questions remain about the relation between airway inflammation and remodeling, the natural history of airway remodeling, and the effects of current asthma treatments on remodeled airways.     

Ascorbic acid supplementation attenuates exercise-induced bronchoconstriction in patients with asthma

BACKGROUND: Previous research has shown that diet can modify the bronchoconstrictor response to exercise in asthmatic subjects. OBJECTIVE: Determine the effect of ascorbic acid supplementation on pulmonary function and several urinary markers of airway inflammation in asthmatic subjects with exercise-induced bronchoconstriction (EIB). METHODS: Eight asthmatic subjects with documented EIB participated in a randomized, placebo controlled double-blind crossover trial. Subjects entered the study on their usual diet and were placed on either 2 weeks of ascorbic acid supplementation (1500 mg/day) or placebo, followed by a 1-week washout period, before crossing over to the alternative diet. Pre- and post-exercise pulmonary function, asthma symptom scores, fraction of exhaled nitric oxide (FENO), and urinary leukotriene (LT) C4-E4 and 9alpha, 11beta-prostagladin (PG) F2] were assessed at the beginning of the trial (usual diet) and at the end of each treatment period. Results: The ascorbic acid diet significantly reduced (p < 0.05) the maximum fall in post-exercise FEV1 (-6.4 +/- 2.4%) compared to usual (-14.3 +/- 1.6%) and placebo diet (-12.9 +/- 2.4%). Asthma symptoms scores significantly improved (p<0.05) on the ascorbic acid diet compared to the placebo and usual diet. Post-exercise FENO, LTC4-E4 and 9alpha, 11beta-PGF2 concentration was significantly lower (p<0.05) on the ascorbic acid diet compared to the placebo and usual diet. CONCLUSION: Ascorbic acid supplementation provides a protective effect against exercise-induced airway narrowing in asthmatic subjects.     

Sputum eosinophils and the response of exercise-induced bronchoconstriction to corticosteroid in asthma

BACKGROUND: The relationship between eosinophilic airway inflammation and exercise-induced bronchoconstriction (EIB), and the response to inhaled corticosteroid (ICS) therapy was examined. METHODS: Twenty-six steroid-na?ve asthmatic patients with EIB were randomized to two parallel, double-blind, crossover study arms (13 subjects in each arm). Each arm compared two dose levels of inhaled ciclesonide that were administered for 3 weeks with a washout period of 3 to 8 weeks, as follows: (1) 40 vs 160 microg daily; and (2) 80 vs 320 microg daily. Baseline and weekly assessments with exercise challenge and sputum analysis were performed. RESULTS: Data were pooled and demonstrated that 10 subjects had baseline sputum eosinophilia >or= 5%. Only high-dose ICS therapy (ie, 160 and 320 microg) significantly attenuated the sputum eosinophil percentage. Sputum eosinophil percentage significantly correlated with EIB severity, and predicted the magnitude and temporal response of EIB to high-dose therapy, but not to low-dose therapy (ie, 40 and 80 microg). Low-dose ICS therapy provided a significant reduction in EIB at 1 week, with little additional improvement thereafter, irrespective of baseline sputum eosinophil counts. In contrast, high-dose ICS therapy provided a significantly greater improvement in EIB in subjects with sputum eosinophilia compared to those with an eosinophil count of < 5%. The difference between the eosinophilic groups in the magnitude of improvement in EIB was evident after the first week of high-dose ICS therapy and increased with time. CONCLUSIONS: These results suggest that eosinophilic airway inflammation may be important in modifying the severity of EIB and the response to ICS therapy. Measurements of sputum eosinophil percentage may, therefore, be useful in predicting the magnitude and temporal response of EIB to different dose levels of ICSs. Trial registration: clinicaltrial.gov; Identifier: NCT00525772.     

Protective effect of fish oil supplementation on exercise-induced bronchoconstriction in asthma

BACKGROUND: Previous research has demonstrated that fish oil supplementation has a protective effect on exercise-induced bronchoconstriction (EIB) in elite athletes, which may be attributed to its antiinflammatory properties. Since EIB in asthma involves proinflammatory mediator release, it is feasible that fish oil supplementation may reduce the severity of EIB in asthmatic subjects. STUDY OBJECTIVES: To determine the efficacy of fish oil supplementation on severity of EIB in subjects with asthma. DESIGN: Randomized, double-blind, crossover study. SETTING: Lung function and exercise testing in a university research laboratory.Patients and measurements: Sixteen asthmatic patients with documented EIB entered the study on their normal diet and then received either fish oil capsules containing 3.2 g of eicosapentaenoic acid and 2.0 g of docohexaenoic acid (fish oil diet, n = 8) or placebo capsules (placebo diet, n = 8) daily for 3 weeks. At the beginning of the study (normal diet) and at the end of each treatment phase, the following pre-exercise and postexercise measures were assessed: (1) pulmonary function; (2) induced sputum differential cell count percentage and proinflammatory eicosanoid metabolite (leukotriene C4 [LTC4]-leukotriene E4 [LTE4] and prostaglandin D2 [PGD2]) and cytokine (interleukin [IL]-1beta and tumor necrosis factor [TNF]-alpha) concentrations; and (3) eicosanoid metabolites leukotriene B4 (LTB4) and leukotriene B5 (LTB(5)) generation from activated polymorphonuclear leukocytes (PMNLs). RESULTS: On the normal and placebo diet, subjects exhibited EIB. However, the fish oil diet improved pulmonary function to below the diagnostic EIB threshold, with a concurrent reduction in bronchodilator use. Induced sputum differential cell count percentage and concentrations of LTC4-LTE4, PGD2, IL-1beta, and TNF-alpha were significantly reduced before and following exercise on the fish oil diet compared to the normal and placebo diets. There was a significant reduction in LTB4 and a significant increase in LTB5 generation from activated PMNLs on the fish oil diet compared to the normal and placebo diets. CONCLUSION: Our data suggest that fish oil supplementation may represent a potentially beneficial nonpharmacologic intervention for asthmatic subjects with EIB.     

Inhibition of exercise-induced bronchoconstriction by nebulised sodium cromoglycate in patients with bronchial asthma.

In this double blind study, 10 patients with bronchial asthma underwent exercise challenge on five occasions. The first of these was a control test carried out without prior drug administration; the other tests were preceded by the administration, in random order, of a sodium cromoglycate (SCG) capsule, a placebo capsule, an ampoule of sodium cromoglycate solution, and a placebo ampoule. Comparisons of the largest falls in PEFR after exercise showed statistically significant inhibition of exercise-induced bronchospasm, compared with control, with both SCG inhalation solution (P less than 0.01) and SCG powder (P less than 0.01). SCG powder was more active, but the difference was not significant. A significant difference in protection was found between SCG powder and its placebo (P less than 0.01). SCG inhalation solution was also more effective than its placebo, but the difference did not reach significance, since the latter conferred some protection.     

运动与运动诱发支气管痉挛的关系

运动与运动诱发支气管痉挛（exerciseinducedbronchoconstriction,EIB）的关系错综复杂,缺乏运动的生活方式有可能是EIB的易患因素,不恰当的过度运动容易导致EIB的发生,低一中等强度的有氧运动及热身运动有可能成为EIB的非药物治疗方法。深入研究不同运动与EIB的关系及其机制,对于EIB的筛查及治疗有重要的意义。     

Value of surrogate tests to predict exercise-induced bronchoconstriction in atopic childhood asthma

Exercise challenge tests are helpful in the diagnosis and management of childhood asthma, but methodology is complex and time-consuming. The aim of this study was to investigate whether exercise-induced bronchoconstriction (EIB) can be predicted by the results of different surrogate tests in a pediatric population. Eighty-five children (mean age: 11 years, range: 5-16 years) with atopic asthma were studied. Measurements of exhaled nitric oxide (eNO), spirometry and whole body plethysmography were performed followed by a standardized exercise testing. Questionnaires were completed asking for respiratory symptoms within 2 weeks preceding the study protocol. In 12/85 children (14%), forced expiratory volume in 1 sec (FEV1) was significantly reduced by > or = 15% after exercise testing. eNO was significantly elevated in this group of 12 patients as compared to patients without EIB (51.3 (31.1-67.3) parts per billion (ppb) versus 20.2 (10.9-42.3) ppb; P = 0.003). All children with normal eNO levels (< or = 25 ppb) had normal lung function results after exercise; hence the negative predictive value (NPV) of elevated eNO levels for prediction of EIB was 100%. However, the positive predictive value (PPV) was only 28%. The NPV and PPV for reported asthma symptoms within 2 weeks preceding the study were 96% and 26%, respectively. Considering recent symptom history in addition to elevated eNO improved the PPV to 40%, and resulted in the best combination of sensitivity and specificity. No baseline lung function parameter predicted whether a patient would develop EIB or not. In conclusion, eNO measurements, symptom questionnaires and most efficiently a combination of both surrogate tests can be used as time-saving methods to exclude EIB in atopic childhood asthma.     

Role of alpha-adrenergic receptors in exercise-induced bronchoconstriction.

The role of alpha-adrenergic receptors in exercise-induced bronchoconstriction (EIB) was studied. 9 asthmatic patients with a marked degree of EIB (group I) and 6 asthmatic patients with no or a less severe EIB (group II) were investigated and compared with 8 healthy control persons. Pulse rate, airway resistance and end-expiratory thoracic gas volume were measured at rest and immediately and 15 min after exercise. Group I subjects showed a significant inhibition of EIB after alpha-adrenergic blockade with phentolamine (10 mg as aerosol) and after cholinergic blockade with an atropine-ester (60 mg as aerosol). In 7 of 9 patients who had received phentolamine, and in 3 of 6 patients who had received atropine-ester, the EIB was completely suppressed. In group II the administration of propranolol (40 mg orally) produced a significant increase in EIB. The effect of propranolol could be inhibited by the addition of alpha-adrenergic blockade with phentolamine (10 mg as aerosol). The control subjects had no measurable EIB, even after the administration of propranolol (40 mg orally). It is concluded that, in addition to the vagal system, an activated alpha-adrenergic system is involved in the phenomenon of EIB.     

Acute relief of exercise-induced bronchoconstriction by inhaled formoterol in children with persistent asthma

STUDY OBJECTIVE: To compare the acute bronchodilatory effect of the long-acting beta2-agonist formoterol against the short-acting beta2-agonist (SABA) terbutaline during exercise-induced bronchoconstriction (EIB) in children with asthma. DESIGN: A randomized, double-blind, placebo-controlled, crossover study of the immediate effect of formoterol, 9 microg, vs terbutaline, 0.5 mg, and placebo administered as dry powder at different study days. Exercise challenge test was used as a model of acute bronchoconstriction. PATIENTS: Twenty-four 7- to 15-year-old children with persistent asthma. INTERVENTIONS: The children performed standardized treadmill exercise tests, breathing dry air, with a submaximal workload. Study medication was administered 5 min after exercise if FEV1 dropped > or = 15% within 5 min after exercise. FEV1 and forced expiratory flows were measured repeatedly until 60 min after dose. RESULTS: Formoterol and terbutaline offered a significant acute bronchodilatory effect from 3 min after dose compared with placebo (p < 0.001). There was no difference between formoterol and terbutaline in FEV1 5 min after dose (p = 0.15), with a mean increase from each predrug baseline of 62% of the maximum increase for both. Median times to recovery within 5% of baseline FEV1 were 5.0 min and 7.4 min for formoterol and terbutaline, respectively (p = 0.33). CONCLUSION: Single-dose formoterol, 9 microg, via dry powder inhaler provided an acute bronchodilatory effect similar to terbutaline during EIB in schoolchildren with persistent asthma. Formoterol is at least as effective as SABA and may be considered an alternative in the treatment of acute bronchoconstriction in school children.