Fluticasone furoate/vilanterol versus fluticasone propionate in patients with asthma and exercise-induced bronchoconstriction.

Objective: To investigate whether once-daily (OD) fluticasone furoate (FF)/vilanterol (VI) provides greater long-term protection from postexercise fall in forced expiratory volume in 1 s (FEV1) than twice-daily (BD) fluticasone propionate (FP) in patients with asthma and exercise-induced bronchoconstriction. Methods: A randomized, double-blind, crossover study was conducted in patients (aged 12-50 years) on low-/mid-dose maintenance inhaled corticosteroid. Following a 4-week run-in period (FP 250 µg BD), patients with a ≥ 20% decrease in postexercise FEV1 received FF/VI 100/25 µg OD or FP 250 µg BD for 2 weeks. Exercise challenges were carried out 23 h after the first dose of study medication, and 12 and 23 h after evening clinic dose at the end of the 2-week treatment period. After a 2-week washout period (FP 250 µg), patients crossed over treatments, with procedures and tests repeated. The primary endpoint was mean maximal percentage decrease from pre-exercise FEV1 following exercise challenge 12-h postevening dose on Day 14. Results: The mean maximal percentage decrease from pre-exercise FEV1 after the 12-h exercise challenge (Day 14) was 15.02% with FF/VI, and 16.71% with FP (difference, -1.69; 95% confidence interval, -3.76 to 0.39; p = 0.109). After the 23-h exercise challenge (Day 14), respective mean maximal decreases were 11.90% and 14.05% (difference, -2.15; 95% confidence interval, -4.31 to 0.01). Conclusion: The study failed to show a difference between FF/VI and FP at providing long-term protection from exercise-induced bronchoconstriction.

The Effect of Aerosolized Chlorpheniramine Maleate on Exercise Induced Bronchospasm and Gas Exchange in Asthmatics.

INTRODUCTION: Exercise induced asthma (EIB) is an acute, reversible, usually selflimiting airways obstruction which sets in after exercise in patients with asthma. One popular mechanism of EIA is the increase in histamine and its metabolites in circulation after exercise, which leads to bronchoconstriction via histamine receptors in bronchi. Chlorpheniramine Maleate is potent, less sedative antihistaminic drug, which acts by inhibiting histamine release from mast cells. It is also said to have anticholinergic properties. The aerosol route of administration of a drug has the advantages of a faster onset of action, fewer side effects, and greater protection against EIB with respect to small airways function. This study was conducted to evaluate the effect of Chlorpheniramine Maleate aerosol inhalation on flow volumes and gas exchange. MATERIALS AND METHODS: 25 established patients of stabilized bronchial asthma (18 to 44 years) with history of EIA attending Allergy OPD, Medical OPD or Chest clinic were included in the present study. Patients were studied for 3 days in a week at the same time of day. Baseline spirometry was done to know test parameters, i.e. FEV1, PEFR and FEF50%. Gas exchange study during rest including minute ventilation (VE), oxygen consumption (VO2), Carbon dioxide produced per minute (VCO2), Respiratory quotient (R) was carried out. Patient was asked to perform exercise on bicycle ergometer. During exercise VE, VO2, VCO2 and R were recorded every 30 seconds. FEV1, PEFR and FEF50% were recorded immediately after and 5 min after completion of exercise. On day 2, same procedure was repeated with saline nebulisation before the exercise. On day 3, aerosolized Chlorpheniramine Maleate was used instead of saline for nebulisation. Values obtained were tabulated and analysed. OBSERVATIONS AND RESULTS: After exercise FEV1, PEFR, FEF50% decreased on all three days, but the fall in these parameters was less on Day III (prior nebulisation with Chlorpheniramine maleate) compared to previous days. There was significant increase in FEV1, PEFR and FEF50% (P<0.01, 0.05 and 0.05 respectively) which was seen 30 mins after inhalation of Chlorpheniramine maleate aerosol compared to placebo. Resting and exercise values of Minute Ventilation (VE), oxygen uptake (VO2) carbon dioxide expired, on all the three days were comparable and statistically not significant by the end of exercise. On day 2 and 3, 'R' as compared to that of day1 was slightly significant during rest and initial minutes of exercise but became insignificant after that till the end of exercise. CONCLUSION: This study shows that Chlorpheniramine causes bronchodilation during resting period by acting on the circulating or tissue histamine in asthmatics which contributes to an increase in resting bronchomotor tone. As there is incomplete inhibition of EIA by Chlorpheniramine, there may be some other associated mediator release for pathogenesis of EIA.

Small airway function in children with mild to moderate asthmatic symptoms.

BACKGROUND: Clinical significance of small airway obstruction in mild pediatric asthma is unclear. OBJECTIVE: To evaluate small airway properties in children with mild to moderate asthmatic symptoms and the association of small airway function with asthma control and exercise-induced bronchoconstriction (EIB). METHODS: Children (5-10 years old) with recurrent wheezing (n = 42) or persistent troublesome cough (n = 16) and healthy controls (n = 19) performed impulse oscillometry (IOS), spirometry, and a multiple-breath nitrogen washout (MBNW) test. Exhaled nitric oxide (NO) was measured at multiple flow rates to determine alveolar NO concentration (Calv). Asthma control was evaluated with the Childhood Asthma Control Test (C-ACT), short-acting ß2-agonist (SABA) use within the past month, and asthma exacerbations within the past year. RESULTS: IOS, spirometry, and exhaled NO indexes that are related to small airway function differed between children with recurrent wheezing and healthy controls, whereas only forced expiratory flow at 25% to 75% of the forced vital capacity was associated with persistent cough. The MBNW indexes showed no difference between the groups. Among symptomatic children, conducting airway ventilation inhomogeneity and Calv were associated with asthma exacerbations (P = .03 and P = .002, respectively), and lung clearance index and Calv were associated with EIB (P = .04 and P = .004, respectively). None of the proposed small airway indexes was associated with the C-ACT score or SABA use. CONCLUSION: Subtle changes were observed in the proposed small airway indexes of IOS, spirometry, and exhaled NO among children with mild to moderate recurrent wheezing. Small airway dysfunction, expressed as ventilation inhomogeneity indexes and Calv, was also associated with asthma exacerbations and EIB.

Asthma and exercise-induced respiratory symptoms in the athlete: new insights.

PURPOSE OF REVIEW: Asthma and exercise-induced bronchoconstriction (EIB) are common in the athlete and can interfere with sport performances. In this review, we report recent findings on the prevalence, diagnosis and evaluation of these conditions, in addition to specific issues regarding their treatment and antidoping regulations. RECENT FINDINGS: Recent studies confirmed the high prevalence of exercise-induced respiratory symptoms, asthma and EIB, in athletes and showed that these conditions are still underdiagnosed and undertreated. Recent studies highlight the suboptimal use of asthma medication in asthmatic and allergic athletes. Regarding the diagnosis and treatment, questions about the role and criteria for positivity of eucapnic voluntary hyperpnea test were raised. It was confirmed that there is a subgroup of athletes with poor response to asthma medication. Finally, regarding antidoping regulations, new methods and changes in criteria for urinary bronchodilator thresholds were suggested. SUMMARY: Recent publications confirm that exercise-induced respiratory symptoms, asthma and EIB are common in athletes but often unrecognized and not optimally or successfully treated. It was suggested that current criteria for diagnostic bronchoprovocation test responses could be reassessed, as well as antidoping criteria for ß2-agonists urinary levels. There is a need for more research on prevention of airways dysfunction in athletes, identification of different asthma phenotypes and the benefits of standard asthma medication in this population.

Serum tryptase level and inflammatory markers in exhaled breath condensate of children with exercise-induced symptoms.

BACKGROUND: The pathogenesis of exercise-induced bronchoconstriction (EIB) is poorly understood. OBJECTIVE: To evaluate the biomarkers concentration in exhaled breath condensate (EBC) in schoolchildren with postexercise symptoms. We also evaluated changes in fractional exhaled nitric oxide (FeNO) value and the serum tryptase level after exercise. METHODS: One hundred children with postexercise symptoms were included. Methacholine challenge testing (MCT) was performed at visit 2, and exercise challenge testing (ECT) was performed at visit 3. Before and after ECT serum tryptase levels and FeNO values were measured. EBC was collected after ECT from 10 randomly selected children from each group. The children were assigned to the following groups: ECT(+) MCT(+), ECT(+) MCT(-), ECT(-) MCT(+), ECT(-) MC(-). We measured the following molecules: eotaxin, interleukin (IL) 8, IL-1ra, IL-1 beta, IL-6, IL-1 alpha, IL-12(p40), IL-5, granulocyte-macrophage colony-stimulating factor, IL-7, IL-15, IL-4, IL-2, IL-10, tumor necrosis factor alpha, interferon gamma, IL-13, tumor necrosis factor beta, monocyte chemoattractant protein-1, IL-17A, macrophage inflammatory proteins-1 alpha, macrophage inflammatory proteins-1 beta, IL-12(p70), and regulated on activation, normal T-cell expressed and secreted by using a multiplex immunoassay. Prostaglandin E2 (PGE2), leukotriene B4, and cysteinyl leukotriene were analyzed by using separate enzyme-linked immunosorbent assay kits. RESULTS: In the MCT(+) group, a detectable level of IL4 in EBC and detectible levels of eicosanoids were seen in the ECT(+) group. We observed the opposite direction of ECT-induced changes in FeNO and serum tryptase concentrations in patients with detectable compared with patients without detectable levels of cytokines in EBC. We showed ECT-induced reduction in the tryptase level in patients with a nondetectable PGE2 level in EBC and an increase in tryptase levels in patients who had detectable levels of PGE2 in EBC. CONCLUSIONS: EBC was a useful method to estimate inflammation but only in children with symptoms and with EIB shown by a positive ECT. Children with a positive ECT had detectable levels of eicosanoids in EBC; the opposite direction of ECT-induced changes in FeNO and serum tryptase concentrations was observed. The results of above study confirm the role of mast cells and eicosanoids in the pathogenesis of EIB in children.

New insights into treatment of children with exercise-induced asthma symptoms.

BACKGROUND: Exercise is one of the most common triggers of bronchoconstriction and affects up to 80% of children with asthma. OBJECTIVE: The purpose of this randomized, double-blind, placebo-controlled study was to assess the effectiveness of treatment with ciclesonide 160 microgram, either alone, with a higher dose, with a leukotriene receptor antagonist (LTRA), or with a long-acting beta-agonist (LABA) in children with asthma with postexercise-induced symptoms. METHODS: Eighty adolescents, ages 1218 years, with asthma and postexercise symptoms were enrolled. Children were treated in one of four treatment groups: ciclesonide 160 microgram daily dose (cic 160), ciclesonide 320 microgram daily dose (cic 320), ciclesonide 160 microgram daily dose combined with montelukast (cic + LTRA), or ciclesonide 160 microgram daily combined with formoterol (cic + LABA). The impact of treatment on clinical symptoms, maximum percentage decrease in forced expiratory volume in 1 second after intense exercise effort, fractional exhaled nitric oxide in exhaled breath, and the contribution of inflammatory mediators in exhaled breath condensate were assessed. RESULTS: In children with asthma and with postexercise symptoms, 8-week daily administration of ciclesonide 320 microgram, ciclesonide 160 microgram plus LABA, and ciclesonide 160 microgram alone decreased daytime symptoms; decrease in maximal fall in forced expiratory volume in 1 second reached the level of significance in the cic 320, cic + LABA, and cic + LTRA groups. A higher prevalence of positive responses to treatment after addition of an LTRA or LABA to ciclesonide 160 microgram for patients with exercise treadmill challengeinduced clinical symptoms only was revealed. CONCLUSION: Monotherapy with ciclesonide 320 microgram can be as effective as combined therapy in reducing exercise-induced bronchoconstriction. We revealed a higher prevalence of positive responses to treatment after the addition of LTRA or LABA to ciclesonide 160 microgram for patients with exercise treadmill challengeinduced clinical symptoms only. ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.ClinicalTrials.gov"www.ClinicalTrials.gov/ext-link NCT01798823.

The athlete "out of breath".

Athletes often complain about breathing problems. This is a crucial issue due to potential implications not only on their general health, but also on their competing performance. Asthma and exercise-induced bronchoconstriction are prevalent conditions in elite athletes, which leads doctors to rely most of the times on asthma medication to treat athletes feeling "out of breath". However, there are several other conditions that may mimic asthma and cause dyspnea in athletes. Effective treatment of dyspnea requires appropriate identification and treatment of all disorders. Proper knowledge and accurate diagnosis of such entities is mandatory, since asthma medication is not effective in those conditions. Herein we review the most common differential diagnosis of dyspnea in athletes, and describe the diagnostic strategies in order to increase awareness and to improve doctor's confidence on dealing with these patients.

Vitamins C and E for asthma and exercise-induced bronchoconstriction.

BACKGROUND: The association between dietary antioxidants and asthma or exercise-induced bronchoconstriction (EIB) is not fully understood. Vitamin C and vitamin E are natural antioxidants that are predominantly present in fruits and vegetables; inadequate vitamin E intake is associated with airway inflammation. It has been postulated that the combination may be more beneficial than either single antioxidant for people with asthma and exercise-induced bronchoconstriction. OBJECTIVES: To assess the effects of supplementation of vitamins C and E versus placebo (or no vitamin C and E supplementation) on exacerbations and health-related quality of life (HRQL) in adults and children with chronic asthma. To also examine the potential effects of vitamins C and E on exercise-induced bronchoconstriction in people with asthma and in people without a diagnosis of asthma who experience symptoms only on exercise. SEARCH METHODS: Trials were identified from the Cochrane Airways Review Group Specialised Register and from trial registry websites. Searches were conducted in September 2013. SELECTION CRITERIA: We included randomised controlled trials of adults and children with a diagnosis of asthma. We separately considered trials in which participants had received a diagnosis of exercise-induced bronchoconstriction (or exercise-induced asthma). Trials comparing vitamin C and E supplementation versus placebo were included. We included trials in which asthma management for treatment and control groups included similar background therapy. Short-term use of vitamins C and E at the time of exacerbation or for cold symptoms in people with asthma is outside the scope of this review. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of potential studies and subsequently screened full-text study reports for inclusion. We used standard methods as expected by The Cochrane Collaboration. MAIN RESULTS: It was not possible to aggregate the five included studies (214 participants). Four studies (206 participants) addressed the question of whether differences in outcomes were seen when vitamin C and E supplementation versus placebo was provided for participants with asthma, and only one of those studies (160 children) included a paediatric population; the remaining three studies included a combined total of just 46 adults. An additional study considered the question of whether differences in outcomes were noted when vitamin C and E supplementation was compared with placebo for exercise-induced asthma; this trial included only eight participants. The randomisation process of the trials were unclear leading us to downgrade the quality of the evidence. Four of the studies were double blind while the other study was single blind.None of these studies provided data on our two prespecified primary outcome measures: exacerbations and HRQL. Lung function data obtained from the studies were inconclusive. The only studies that provided any suggestion of an effect, and only with some outcomes, were the paediatric study, especially for children with moderate to severe asthma, and the small study on exercise-induced asthma. Even so, this evidence was judged to be at moderate/low quality. Only one study contributed data on asthma symptoms and adverse events, reporting no evidence of an effect of the intervention for symptoms and that one participant in the treatment group dropped out due to cystitis. AUTHORS' CONCLUSIONS: It is not possible to draw firm conclusions from this review with respect to the comparison of vitamin C and E supplementation versus placebo in the management of asthma or exercise-induced bronchoconstriction. We found only one study relevant to exercise-induced bronchoconstriction; most included participants came from studies designed to assess the effect of vitamin supplementation on the impact of atmospheric pollutants (such as ozone). Evidence is lacking on the comparison of vitamin C and E supplementation versus placebo for asthma with respect to outcomes such as HRQL and exacerbations, which were not addressed by any of the included studies.When compared with lung function tests alone, HRQL scores and exacerbation frequency are better indicators of the severity of asthma, its impact on daily activities and its response to treatment in a patient population. These end points are well recognised in good quality studies of asthma management. However, clinical studies of vitamins C and E in the management of asthma using these important end points of exacerbations and effects on quality of life are not available, and evidence is insufficient to support robust conclusions on the role of vitamin C and E supplementation in asthma and exercise-induced breathlessness.

An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction.

BACKGROUND: Exercise-induced bronchoconstriction (EIB) describes acute airway narrowing that occurs as a result of exercise. EIB occurs in a substantial proportion of patients with asthma, but may also occur in individuals without known asthma. METHODS: To provide clinicians with practical guidance, a multidisciplinary panel of stakeholders was convened to review the pathogenesis of EIB and to develop evidence-based guidelines for the diagnosis and treatment of EIB. The evidence was appraised and recommendations were formulated using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: Recommendations for the treatment of EIB were developed. The quality of evidence supporting the recommendations was variable, ranging from low to high. A strong recommendation was made for using a short-acting ß(2)-agonist before exercise in all patients with EIB. For patients who continue to have symptoms of EIB despite the administration of a short-acting ß(2)-agonist before exercise, strong recommendations were made for a daily inhaled corticosteroid, a daily leukotriene receptor antagonist, or a mast cell stabilizing agent before exercise. CONCLUSIONS: The recommendations in this Guideline reflect the currently available evidence. New clinical research data will necessitate a revision and update in the future.

Loss of salmeterol bronchoprotection against exercise in relation to ADRB2 Arg16Gly polymorphism and exhaled nitric oxide.

RATIONALE: ß2-Agonists are the treatment of choice for exercise-induced bronchoconstriction (EIB) and act through specific receptors (ADRB2). Arg16Gly polymorphisms have been shown to affect responses to regular use of ß2-agonists. OBJECTIVES: To evaluate the influence of the Arg16Gly receptor polymorphism on salmeterol bronchoprotection in EIB and assess predictors of bronchoprotection. METHODS: A prospective, genotype-blinded, randomized trial was performed in 26 subjects (12 Arg16Arg and 14 Gly16Gly) with EIB who were not on controller therapy. Subjects were administered salmeterol, 50 µg twice a day for 2 weeks, and underwent an exercise challenge 9 hours after the first and last drug dose. In addition to genotype, FEV1, response to salmeterol, degree of EIB, and exhaled nitric oxide (FE(NO)) at baseline were examined for their association with loss of bronchoprotection (LOB). MEASUREMENTS AND MAIN RESULTS: The maximum exercise-induced FEV1 fall was 27.9 ± 1.4% during the run-in period, 8.1 ± 1.2% (70.3 ± 4.1% bronchoprotection) after the first salmeterol dose, and 22.8 ± 3.2% (18.9 ± 11.5% bronchoprotection) after 2 weeks of salmeterol (P = 0.0001). The Arg16Gly polymorphisms were not associated with the LOB in response to salmeterol. FeNO values at baseline were significantly related to the LOB (r = 0.47; P = 0.01). Mean change was a 74 ± 13% LOB in subjects with FE(NO) levels greater than 50 ppb and a 7 ± 16% gain in bronchoprotection in those with FE(NO) levels less than 25 ppb (P = 0.01). CONCLUSIONS: The LOB that occurs with chronic long-acting ß2-agonists use is not affected by ADRB2 Arg16Gly polymorphisms. High FE(NO) was associated with marked LOB. Use of long-acting ß2-agonists before achieving a reduction in FeNO may need to be avoided. Clinical trial registered with www.clinicaltrials.gov (NCT 00595361).

An open-label study examining the effect of pharmacological treatment on mannitol- and exercise-induced airway hyperresponsiveness in asthmatic children and adolescents with exercise-induced bronchoconstriction.

BACKGROUND: Mannitol- and exercise bronchial provocation tests are both used to diagnose exercise-induced bronchoconstriction. The study aim was to compare the short-term treatment response to budesonide and montelukast on airway hyperresponsiveness to mannitol challenge test and to exercise challenge test in children and adolescents with exercise-induced bronchoconstriction. METHODS: Patients were recruited from a paediatric asthma rehabilitation clinic located in the Swiss Alps. Individuals with exercise-induced bronchoconstriction and a positive result in the exercise challenge test underwent mannitol challenge test on day 0. All subjects then received a treatment with 400 µg budesonide and bronchodilators as needed for 7 days, after which exercise- and mannitol-challenge tests were repeated (day 7). Montelukast was then added to the previous treatment and both tests were repeated again after 7 days (day 14). RESULTS: Of 26 children and adolescents with exercise-induced bronchoconstriction, 14 had a positive exercise challenge test at baseline and were included in the intervention study. Seven of 14 (50%) also had a positive mannitol challenge test. There was a strong correlation between airway responsiveness to exercise and to mannitol at baseline (r = 0.560, p = 0.037). Treatment with budesonide and montelukast decreased airway hyperresponsiveness to exercise challenge test and to a lesser degree to mannitol challenge test. The fall in forced expiratory volume in one second during exercise challenge test was 21.7% on day 0 compared to 6.7% on day 14 (p = 0.001) and the mannitol challenge test dose response ratio was 0.036%/mg on day 0 compared to 0.013%/mg on day 14 (p = 0.067). CONCLUSION: Short-term treatment with an inhaled corticosteroid and an additional leukotriene receptor antagonist in children and adolescents with exercise-induced bronchoconstriction decreases airway hyperresponsiveness to exercise and to mannitol.

Exercise-induced wheezing among Japanese pre-school children and pupils.

BACKGROUND: Exercise-induced wheezing (EIW) may be a symptom of asthma and is a predictor of exercise-induced bronchoconstriction, transient narrowing of the lower airway following exercise in the presence or absence of diagnosed asthma. Population-based studies with a large sample of EIW in relation to age, sex, current asthma severity and medication usage have been sparse. METHODS: International Study of Asthma and Allergies in Childhood questionnaires were distributed at 885 nurseries, 535 primary schools, 321 junior high schools and 190 high schools, respectively, across Japan, and the corresponding data on 46,597, 41,216, 45,960 and 51,104 children were analyzed. RESULTS: Prevalence of EIW was 4.8, 4.7, 17.9 and 15.4% for each of the four educational facility types, respectively. Among 24,103 current asthmatics, 20.9, 28.7, 76.1 and 73.6% of subjects for the 4 educational facility groups reported to have experienced EIW, respectively. Severity of current asthma was associated with the risk of EIW; odds ratio (95% confidence interval) of children with asthma attack every day for having EIW once a week or more, using intermittent asthmatics as reference group, were 24.48 (19.33 to 31.01) adjusted for other covariates. Among current asthmatic kindergartners, increase in risk for EIW due to ascending severity of current asthma was mitigated by daily use of leukotriene receptor antagonist (p for interaction = 0.071). CONCLUSIONS: EIW was not rare among current asthmatic children. An increased risk for EIW was in accordance with increasing severity of current asthma and this relation was mitigated with leukotriene receptor antagonist daily use among kindergartners.

[Exercise-induced asthma in athletes--a review]. / Astma potaknuta naporom u sportasa--pregledni clanak.

Elite athletes are often subjected to endurance training in the environment in which they are chronically exposed to pollutants/irritants, allergens or cold air. These factors lead to an increased risk of upper and lower respiratory tract dysfunction. The diagnosis of asthma is crucial in elite athletes because of potential implications on athlete's general well-being as well as their competitive ability. Symptoms of asthma in elite athletes are not necessarily associated with the classic features of asthma seen in general population. Other clinical entities can create symptoms similar to those of asthma and therefore can lead to an incorrect diagnosis and ineffective treatment. The diagnosis requires a combination of symptoms and positive laboratory tests. Currently, there is no evidence that the treatment of asthma in athletes should be different from the treatment of asthma in non-athletes. However, some specific issues need to be considered in the elite athletes, such as compliance with the rules of World Anti-Doping Agency and International Olympic Committee.

Exercise-induced bronchoconstriction, allergy and sports in children.

Exercise-induced bronchoconstriction (EIB) is characterized by the narrowing of airways during or after physical activity, leading to symptoms such as wheezing, coughing, and shortness of breath. Distinguishing between EIB and exercise-induced asthma (EIA) is essential, given their divergent therapeutic and prognostic considerations. EIB has been increasingly recognized as a significant concern in pediatric athletes. Moreover, studies indicate a noteworthy prevalence of EIB in children with atopic predispositions, unveiling a potential link between allergic sensitivities and exercise-induced respiratory symptoms, underpinned by an inflammatory reaction caused by mechanical, environmental, and genetic factors. Holistic management of EIB in children necessitates a correct diagnosis and a combination of pharmacological and non-pharmacological interventions. This review delves into the latest evidence concerning EIB in the pediatric population, exploring its associations with atopy and sports, and emphasizing the appropriate diagnostic and therapeutic approaches by highlighting various clinical scenarios.

Exercise-induced bronchoconstriction in school-aged children who had chronic lung disease in infancy.

OBJECTIVES: To assess for exercise-induced bronchoconstriction in 8- to 12-year-old children who had chronic lung disease (CLD) in infancy, and to evaluate the response of bronchoconstriction to bronchodilation with albuterol in comparison with preterm and term controls. STUDY DESIGN: Ninety-two children, including 29 with CLD, 33 born preterm at ≤32 weeks' gestation, and 30 born at term, underwent lung spirometry before and after cycle ergometry testing and after postexercise bronchodilation with albuterol. RESULTS: Doctor-diagnosed asthma and exercise-induced wheeze were reported more frequently in the CLD group than in the preterm and term groups, but only 10% were receiving a bronchodilator. There were no differences among the groups in peak minute ventilation, oxygen uptake, or carbon dioxide output at maximum exercise. After maximal exercise, predicted forced expiratory volume in 1 second (FEV1) decreased from a mean baseline value of 81.9% (95% CI, 76.6-87.0%) to 70.8% (95% CI, 65.5-76.1%) after exercise in the CLD group, from 92.0% (95% CI, 87.2-96.8%) to 84.3% (95% CI, 79.1-89.4%) in the preterm group, and from 97.5% (95% CI, 92.5-102.6%) to 90.3% (95% CI, 85.1-95.5%) in the term group. After albuterol administration, FEV1 increased to 86.8% (95% CI, 81.7-92.0%) in the CLD group, 92.1% (95% CI, 87.3-96.9%) in the preterm group, and 97.1% (95% CI, 92.0-102.3%) in the term group. The decrease in predicted FEV1 after exercise and increase in predicted FEV1 after bronchodilator use were greatest in the CLD group (-11.0% [95% CI, -18.4 to -3.6%] and 16.0% [95% CI, 8.6-23.4%], respectively; P < .005 for both), with differences of <8% in the 2 control groups. CONCLUSION: School-age children who had CLD in infancy had significant exercise-induced bronchoconstriction that responded significantly to bronchodilation. Reversible exercise-induced bronchoconstriction is common in children who experienced CLD in infancy and should be actively assessed for and treated.

Vitamin C for asthma and exercise-induced bronchoconstriction.

BACKGROUND: Dietary antioxidants, such as vitamin C, in the epithelial lining and lining fluids of the lung may be beneficial in the reduction of oxidative damage (Arab 2002). They may therefore be of benefit in reducing symptoms of inflammatory airway conditions such as asthma, and may also be beneficial in reducing exercise-induced bronchoconstriction, which is a well-recognised feature of asthma and is considered a marker of airways inflammation. However, the association between dietary antioxidants and asthma severity or exercise-induced bronchoconstriction is not fully understood. OBJECTIVES: To examine the effects of vitamin C supplementation on exacerbations and health-related quality of life (HRQL) in adults and children with asthma or exercise-induced bronchoconstriction compared to placebo or no vitamin C. SEARCH METHODS: We identified trials from the Cochrane Airways Group's Specialised Register (CAGR). The Register contains trial reports identified through systematic searches of a number of bibliographic databases, and handsearching of journals and meeting abstracts. We also searched trial registry websites. The searches were conducted in December 2012. SELECTION CRITERIA: We included randomised controlled trials (RCTs). We included both adults and children with a diagnosis of asthma. In separate analyses we considered trials with a diagnosis of exercise-induced bronchoconstriction (or exercise-induced asthma). We included trials comparing vitamin C supplementation with placebo, or vitamin C supplementation with no supplementation. We included trials where the asthma management of both treatment and control groups provided similar background therapy. The primary focus of the review is on daily vitamin C supplementation to prevent exacerbations and improve HRQL. The short-term use of vitamin C at the time of exacerbations or for cold symptoms in people with asthma are outside the scope of this review. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of potential studies, and subsequently screened full text study reports for inclusion. We used standard methods expected by The Cochrane Collaboration. MAIN RESULTS: A total of 11 trials with 419 participants met our inclusion criteria. In 10 studies the participants were adults and only one was in children. Reporting of study design was inadequate to determine risk of bias for most of the studies and poor availability of data for our key outcomes may indicate some selective outcome reporting. Four studies were parallel-group and the remainder were cross-over studies. Eight studies included people with asthma and three studies included 40 participants with exercise-induced asthma. Five studies reported results using single-dose regimes prior to bronchial challenges or exercise tests. There was marked heterogeneity in vitamin C dosage regimes used in the selected studies, compounding the difficulties in carrying out meaningful analyses.One study on 201 adults with asthma reported no significant difference in our primary outcome, health-related quality of life (HRQL), and overall the quality of this evidence was low. There were no data available to evaluate the effects of vitamin C supplementation on our other primary outcome, exacerbations in adults. One small study reported data on asthma exacerbations in children and there were no exacerbations in either the vitamin C or placebo groups (very low quality evidence). In another study conducted in 41 adults, exacerbations were not defined according to our criteria and the data were not available in a format suitable for evaluation by our methods. Lung function and symptoms data were contributed by single studies. We rated the quality of this evidence as moderate, but further research is required to assess any clinical implications that may be related to the changes in these parameters. In each of these outcomes there was no significant difference between vitamin C and placebo. No adverse events at all were reported; again this is very low quality evidence.Studies in exercise-induced bronchoconstriction suggested some improvement in lung function measures with vitamin C supplementation, but theses studies were few and very small, with limited data and we judged the quality of the evidence to be low. AUTHORS' CONCLUSIONS: Currently, evidence is not available to provide a robust assessment on the use of vitamin C in the management of asthma or exercise-induced bronchoconstriction. Further research is very likely to have an important impact on our confidence in the estimates of effect and is likely to change the estimates. There is no indication currently that vitamin C can be recommended as a therapeutic agent in asthma. There was some indication that vitamin C was helpful in exercise-induced breathlessness in terms of lung function and symptoms; however, as these findings were provided only by small studies they are inconclusive. Most published studies to date are too small and inconsistent to provide guidance. Well-designed trials with good quality clinical endpoints, such as exacerbation rates and health-related quality of life scores, are required.

Beta2-agonists for exercise-induced asthma.

BACKGROUND: It is well known that physical exercise can trigger asthma symptoms and can induce bronchial obstruction in people without clinical asthma. International guidelines on asthma management recommend the use of beta2-agonists at any stage of the disease. At present, however, no consensus has been reached about the efficacy and safety of beta2-agonists in the pretreatment of exercise-induced asthma and exercise-induced bronchoconstriction. For the purpose of the present review, both of these conditions are referred to by the acronymous EIA, independently from the presence of an underlying chronic clinical disease. OBJECTIVES: To assess the effects of inhaled short- and long-acting beta2-agonists, compared with placebo, in the pretreatment of children and adults with exercise-induced asthma (or exercise-induced bronchoconstriction). SEARCH METHODS: Trials were identified by electronic searching of the Cochrane Airways Group Specialised Register of Trials and by handsearching of respiratory journals and meetings. Searches are current as of August 2013. SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled trials of any study design, published in full text, that assessed the effects of inhaled beta2-agonists on EIA in adults and children. We excluded studies that did not clearly state diagnostic criteria for EIA. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by The Cochrane Collaboration. MAIN RESULTS: We included 53 trials consisting of 1139 participants. Forty-eight studies used a cross-over design, and five were performed in accordance with a parallel-group design. Forty-five studies addressed the effect of a single beta2-agonist administration, and eight focused on long-term treatment. We addressed these two different intervention regimens as different comparisons.Among primary outcomes for short-term administration, data on maximum fall in forced expiratory volume in 1 second (FEV1) showed a significant protective effect for both short-acting beta-agonists (SABA) and long-acting beta-agonists (LABA) compared with placebo, with a mean difference of -17.67% (95% confidence interval (CI) -19.51% to -15.84%, P = 0.00001, 799 participants from 72 studies). The subgroup analysis of studies performed in adults compared with those performed in children showed high heterogeneity confined to children, despite the comparable mean bronchoprotective effect.Secondary outcomes on other pulmonary function parameters confirmed a more positive and protective effect of beta2-agonists on EIA compared with placebo. Occurrence of side effects was not significantly different between beta2-agonists and placebo.Overall evaluation of the included long-term studies suggests a beta2-agonist bronchoprotective effect for the first dose of treatment. However, long-term use of both SABA and LABA induced the onset of tolerance and decreased the duration of drug effect, even after a short treatment period. AUTHORS' CONCLUSIONS: Evidence of low to moderate quality shows that beta2-agonists, both SABA and LABA, when administered in a single dose, are effective and safe in preventing EIA.Long-term regular administration of inhaled beta2-agonists induces tolerance and lacks sufficient safety data. This finding appears to be of particular clinical relevance in view of the potential for prolonged regular use of beta2-agonists as monotherapy in the pretreatment of EIA, despite the warnings of drug agencies (FDA, EMA) regarding LABA.

Does bronchial hyperresponsiveness in childhood predict active asthma in adolescence?

RATIONALE: Bronchial hyperresponsiveness (BHR) is an important, but not specific, asthma characteristic. OBJECTIVES: We aimed to assess the predictive value of BHR tested by methacholine and exercise challenge at age 10 years for active asthma 6 years later. METHODS: From a Norwegian birth cohort, 530 children underwent methacholine challenge and exercise-induced bronchoconstriction (EIB) test (n = 478) at 10 years and structured interview and clinical examination at age 16 years. The methacholine dose causing 20% reduction in FEV(1) (PD(20)) and the reduction in FEV(1) (%) after a standardized treadmill test were used for BHR assessment. Active asthma was defined with at least two criteria positive: doctor's diagnosis of asthma, symptoms of asthma, and/or treatment for asthma in the last year. MEASUREMENTS AND MAIN RESULTS: PD(20) and EIB at 10 years of age increased the risk of asthma (ß = 0.94 [95% confidence interval (CI), 0.92-0.96] per µmol methacholine and ß = 1.10 [95% CI, 1.06-1.15] per %, respectively). Separately the tests explained 10 and 7%, respectively, and together 14% of the variation in active asthma 6 years later. The predicted probability for active asthma at the age of 16 years increased with decreasing PD(20) and increasing EIB. The area under the curve (receiver operating characteristic curves) was larger for PD(20) (0.69; 95% CI, 0.62-0.75) than for EIB (0.60; 95% CI, 0.53-0.67). CONCLUSIONS: BHR at 10 years was a significant but modest predictor of active asthma 6 years later, with methacholine challenge being superior to exercise test.

Mechanisms and management of exercise-induced asthma in elite athletes.

OBJECTIVE AND METHODS: Asthma is often reported by elite athletes, especially endurance athletes. The aim of this article is to review current knowledge of mechanisms and management of exercise-induced asthma (EIA) in adult elite athletes. RESULTS: The mechanisms underlying EIA is incompletely understood, but the two prevailing hypotheses are the hyper-osmolarity and the thermal hypothesis. Both hypotheses consider inflammation and activation of mast cells as being crucial for the development of EIA, although the assumed mechanisms triggering the inflammatory response differ. Objective testing is of utmost importance in the diagnosis of EIA in elite athletes. Management of EIA can be divided into pharmacologic and non-pharmacologic treatment. The basic principles for the treatment of EIA in elite athletes should be as for any asthmatic individual, including use of inhaled corticosteroids (ICS), ß(2)-agonists, and leukotriene antagonists. However, evidence suggests that daily use of ß(2)-agonists might lead to the development of tolerance. ICS therapy is, due to its anti-inflammatory effects, the recommended primary therapy for EIA also in elite athletes. All doctors treating individuals with asthma, especially elite athletes, should remain updated on doping aspects of asthma therapy. Non-pharmacologic management of EIA in elite athletes includes physical warm-up, which takes advantage of the refractory period following an attack of EIA, whereas high intake of antioxidants may reduce airway inflammation. Wearing heat masks, specially designed for outdoor winter athletes, might protect against bronchoconstriction triggered by inhalation of cold and dry air. CONCLUSION: EIA in elite athletes should be managed as in any individual with asthma, but the risk of developing tolerance to bronchodilators as well as doping aspects should always be taken into account.

The actual role of sodium cromoglycate in the treatment of asthma--a critical review.

INTRODUCTION: Despite international consensus and clearly written guidelines urging wider use of corticosteroids or combinations of inhaled short- and long-acting ß-agonists (SABA and LABA) and corticosteroids in persistent asthma, prescribing patterns and compliance rates fall far short of recommendations. OBJECTIVES: The failure to use steroids more aggressively is due, in part, to their side effects, even with inhaled forms of the drug. There is a role for expanded use of sodium cromolyn in asthma. Its potent anti-inflammatory effects, lack of side effects, and acceptable dosing and method of delivery, as well as its special role in exercise-induced asthma, make it a very suitable choice in the initial therapy for control of asthma. CONCLUSION: Compared to SABA and LABA, cromoglycates alone are unsuspicious of being used to enhance physical performance.