A proposal to account for the stimulus, the mechanism, and the mediators released in exercise-induced bronchoconstriction.

Exercise induced bronchoconstriction (EIB) describes the transient narrowing of the airways that follows vigorous exercise. It commonly occurs in children and adults who have asthma and in elite athletes. The primary stimulus is proposed to be loss of water, by evaporation, from the airway surface due to conditioning inspired air. The mechanism, whereby this evaporative loss of water provokes contraction of the bronchial smooth muscle, is thought to be an increase in osmolarity of the airway surface liquid. The increase in osmolarity causes mast cells to release histamines, prostaglandins, and leukotrienes. It is these mediators that contract smooth muscle causing the airways to narrow.

Repurposing drugs as inhaled therapies in asthma.

For the first 40 years of the 20th century treatment for asthma occurred in response to an asthma attack. The treatments were given by injection or orally and included the adrenergic agonists adrenalin/epinephrine and ephedrine and a phosphodiesterase inhibitor theophylline. Epinephrine became available as an aerosol in 1930. After 1945, isoprenaline, a non-selective beta agonist, became available for oral use but it was most widely used by inhalation. Isoprenaline was short-acting with unwanted cardiac effects. More selective beta agonists, with a longer duration of action and fewer side-effects became available, including orciprenaline in 1967, salbutamol in 1969 and terbutaline in 1970. The inhaled steroid beclomethasone was available by 1972 and budesonide by 1982. Spirometry alone and in response to exercise was used to assess efficacy and duration of action of these drugs for the acute benefits of beta2 agonists and the chronic benefits of corticosteroids. Early studies comparing oral and aerosol beta2 agonists found equivalence in bronchodilator effect but the aerosol treatment was superior in preventing exercise-induced bronchoconstriction. Inhaled drugs are now widely used including the long-acting beta2 agonists, salmeterol and formoterol, and the corticosteroids, fluticasone, ciclesonide, mometasone and triamcinolone, that act locally and have low systemic bio-availability. Repurposing drugs as inhaled therapies permitted direct delivery of low doses of drug to the site of action reducing the incidence of unwanted side-effects and permitting the prophylactic treatment of asthma.

Mechanisms and Biomarkers of Exercise-Induced Bronchoconstriction.

Exercise is a common trigger of bronchoconstriction. In recent years, there has been increased understanding of the pathophysiology of exercise-induced bronchoconstriction. Although evaporative water loss and thermal changes have been recognized stimuli for exercise-induced bronchoconstriction, accumulating evidence points toward a pivotal role for the airway epithelium in orchestrating the inflammatory response linked to exercise-induced bronchoconstriction. Overproduction of inflammatory mediators, underproduction of protective lipid mediators, and infiltration of the airways with eosinophils and mast cells are all established contributors to exercise-induced bronchoconstriction. Sensory nerve activation and release of neuropeptides maybe important in exercise-induced bronchoconstriction, but further research is warranted.

Repurposing excipients as active inhalation agents: The mannitol story.

The story of how we came to use inhaled mannitol to diagnose asthma and to treat cystic fibrosis began when we were looking for a surrogate for exercise as a stimulus to identify asthma. We had proposed that exercise-induced asthma was caused by an increase in osmolarity of the periciliary fluid. We found hypertonic saline to be a surrogate for exercise but an ultrasonic nebuliser was required. We produced a dry powder of sodium chloride but it proved unstable. We developed a spray dried preparation of mannitol and found that bronchial responsiveness to inhaling mannitol identified people with currently active asthma. We reasoned that mannitol had potential to replace the 'osmotic' benefits of exercise and could be used as a treatment to enhance mucociliary clearance in patients with cystic fibrosis. These discoveries were the start of a journey to develop several registered products that are in clinical use globally today.

'Indirect' challenges from science to clinical practice.

Indirect challenges act to provoke bronchoconstriction by causing the release of endogenous mediators and are used to identify airway hyper-responsiveness. This paper reviews the historical development of challenges, with exercise, eucapnic voluntary hyperpnoea (EVH) of dry air, wet hypertonic saline, and with dry powder mannitol, that preceded their use in clinical practice. The first challenge developed for clinical use was exercise. Physicians were keen for a standardized test to identify exercise-induced asthma (EIA) and to assess the effect of drugs such as disodium cromoglycate. EVH with dry air became a surrogate for exercise to increase ventilation to very high levels. A simple test was developed with EVH and used to identify EIA in defence force recruits and later in elite athletes. The research findings with different conditions of inspired air led to the conclusion that loss of water by evaporation from the airway surface was the stimulus to EIA. The proposal that water loss caused a transient increase in osmolarity led to the development of the hypertonic saline challenge. The wet aerosol challenge with 4.5% saline, provided a known osmotic stimulus, to which most asthmatics were sensitive. To simplify the osmotic challenge, a dry powder of mannitol was specially prepared and encapsulated. The test pack with different doses and an inhaler provided a common operating procedure that could be used at the point of care. All these challenge tests have a high specificity to identify currently active asthma. All have been used to assess the benefit of treatment with inhaled corticosteroids. Over the 50 years, the methods for testing became safer, less complex, and less expensive and all used forced expiratory volume in 1 sec to measure the response. Thus, they became practical to use routinely and were recommended in guidelines for use in clinical practice.

Urinary excretion of lipid mediators in response to repeated eucapnic voluntary hyperpnea in asthmatic subjects.

Exercise-induced bronchoconstriction displays refractoriness manifested as a decreased response to repeated exercise challenge within hours. The refractoriness may be attenuated by inhibition of the biosynthesis of prostaglandins (PG). The aim of the study was to determine which PGs and other lipid mediators are excreted during the refractory period. First, 16 subjects with mild stable asthma performed two repeated 4-min challenges with eucapnic voluntary hyperpnea (EVH) 1 and 3 h apart. There was a similar degree of refractoriness in both protocols (∼15% protection). The 1-h interval was too short to study mediator excretion because the urinary levels did not return to baseline before the second challenge. With the 3-h protocol, there was increased urinary excretion of cysteinyl-leukotrienes and metabolites of the mast cell product PGD2 after both challenges. Next, another eight subjects performed two 6-min challenges with EVH 3 h apart, which produced a greater bronchoconstrictor response than the 4-min protocol (30.0 ± 5.4 vs. 17.7 ± 1.5%; P = 0.0029) and a greater degree of refractoriness (∼30%). Analysis by ultra-performance liquid chromatography triple quadrupole mass spectrometry confirmed excretion of the bronchoconstrictor cysteinyl-leukotrienes and PGD2 during both challenges. In addition, there was increased excretion of the bronchoprotective PGE2, and also of the main metabolite of PGI2. This is the first report of excretion of PGE2 and PGI2 during the refractory period to EVH challenge, suggesting that they may mediate the refractoriness. Maintained excretion of PGD2 and leukotriene E4 following the repeat challenge argues against mast cell mediator depletion as the mechanism of refractoriness.

An Apparatus to Deliver Mannitol Powder for Bronchial Provocation in Children Under Six Years Old.

BACKGROUND: Currently bronchial provocation testing (BPT) using mannitol powder cannot be performed in children under 6 years. A primary reason is it is challenging for children at this age to generate a consistent inspiratory effort to inhale mannitol efficiently from a dry powder inhaler. A prototype system, which does not require any inhalation training from the pediatric subject, is reported here. It uses an external source of compressed air to disperse mannitol powder into a commercial holding chamber. Then the subject uses tidal breathing to inhale the aerosol. METHOD: The setup consists of a commercially available powder disperser and Volumatic™ holding chamber. Taguchi experimental design was used to identify the effect of dispersion parameters (flow rate of compressed air, time compressed air is applied, mass of powder, and the time between dispersion and inhalation) on the fine particle dose (FPD). The prototype was tested in vitro using a USP throat connected to a next generation impactor. The aerosols from the holding chamber were drawn at 10 L/min. A scaling factor for estimating the provoking dose to induce a 15% reduction in forced expiratory volume in 1 second (FEV1) (PD15) was calculated using anatomical dimensions of the human respiratory tract at various ages combined with known dosing values from the adult BPT. RESULTS: Consistent and doubling FPDs were successfully generated based on the Taguchi experimental design. The FPD was reliable over a range of 0.8 (±0.09) mg to 14 (±0.94) mg. The calculated PD15 for children aged 1-6 years ranged from 7.1-30 mg. The FPDs generated from the proposed set up are lower than the calculated PD15 and therefore are not expected to cause sudden bronchoconstriction. CONCLUSION: A prototype aerosol delivery system has been developed that is consistently able to deliver doubling doses suitable for bronchial provocation testing in young children.

Air quality and temperature effects on exercise-induced bronchoconstriction.

Exercise-induced bronchoconstriction (EIB) is exaggerated constriction of the airways usually soon after cessation of exercise. This is most often a response to airway dehydration in the presence of airway inflammation in a person with a responsive bronchial smooth muscle. Severity is related to water content of inspired air and level of ventilation achieved and sustained. Repetitive hyperpnea of dry air during training is associated with airway inflammatory changes and remodeling. A response during exercise that is related to pollution or allergen is considered EIB. Ozone and particulate matter are the most widespread pollutants of concern for the exercising population; chronic exposure can lead to new-onset asthma and EIB. Freshly generated emissions particulate matter less than 100 nm is most harmful. Evidence for acute and long-term effects from exercise while inhaling high levels of ozone and/or particulate matter exists. Much evidence supports a relationship between development of airway disorders and exercise in the chlorinated pool. Swimmers typically do not respond in the pool; however, a large percentage responds to a dry air exercise challenge. Studies support oxidative stress mediated pathology for pollutants and a more severe acute response occurs in the asthmatic. Winter sport athletes and swimmers have a higher prevalence of EIB, asthma and airway remodeling than other athletes and the general population. Because of fossil fuel powered ice resurfacers in ice rinks, ice rink athletes have shown high rates of EIB and asthma. For the athlete training in the urban environment, training during low traffic hours and in low traffic areas is suggested.

Inspiratory flows and volumes in subjects with cystic fibrosis using a new dry powder inhaler device.

INTRODUCTION: Drug inhalation via a dry-powder inhaler (DPI) is a convenient, time efficient alternative to nebulizers in the treatment of cystic fibrosis (CF). Efficient drug administration via DPIs depends on the device resistance and adequate (≥ 45L/min) inspiratory flows and volumes generated by individuals. Dry-powder mannitol is delivered using a RS01 breath-actuated device developed by Plastiape, for Pharmaxis. The study aim was to determine in vivo if CF patients' inspiratory flows and volumes are adequate to use the RS01 DPI device. MATERIALS AND METHODOLOGY: An open, non-interventional study; enrolled 25 CF subjects, aged ≥ 6 years with FEV1 ≥ 30 to < 90‰ predicted. Inspiratory flows and volumes were measured when subjects inhaled in a controlled manner through the RS01 device in series with a spirometer. RESULTS: The mean inspiratory volume (IV) of CF subjects was 1.83L ± 0.97. Their achieved mean ± SD peak inspiratory flow (PIF) was 75.5 ± 27.2L/min. Twenty-three subjects (92%) achieved PIF of > 45L/min with the inhaler device; eighteen of those subjects (78%) had a baseline FEV1 of > 1L. CONCLUSION: Use of the RS01 DPI device allowed adequate inspiratory flow and volume for dispersion of dry-powder mannitol in CF patients.

Inspiratory Flows and Volumes in Subjects with Non-CF Bronchiectasis Using a New Dry Powder Inhaler Device.

INTRODUCTION: Drug inhalation via a dry-powder inhaler (DPI) is a convenient, time efficient alternative to nebulizers in the treatment of cystic fibrosis (CF) or non-CF bronchiectasis. Efficient drug administration via DPIs depends on the device resistance and adequate (≥45L/min) inspiratory flows and volumes generated by individuals. Drypowder mannitol is delivered using a RS01 breath-actuated device developed by Plastiape, for Pharmaxis. The study aim was to determine in vivo if non-CF bronchiectasis patients' inspiratory flows and volumes are adequate to use the RS01 DPI device. MATERIALS AND METHODOLOGY: An open, non-interventional study; enrolled 17 subjects with non-CF bronchiectasis, 18 to 80 years, with baseline FEV1 ≥1.0L and ≥50‰ predicted. Inspiratory flows and volumes were measured when subjects inhaled in a controlled manner through the RS01 device in series with a spirometer. RESULTS: The mean inspiratory volume (IV) of non-CF bronchiectasis subjects was 2.08 ± 0.5L and achieved a mean PIF of 78.6 ± 11.2L/min with the inhaler device. CONCLUSION: Use of the RS01 DPI device allowed adequate inspiratory flow and volume for dispersion of dry-powder mannitol in non-CF bronchiectasis patients.

A World Allergy Organization international survey on physical activity as a treatment option for asthma and allergies.

BACKGROUND: Physical exercise has been shown to improve asthma symptoms, QoL, exercise capacity, bronchial hyperresponsiveness and lung function and is recommended as a supplementary treatment to pharmacotherapy for asthma. Clinicians are well placed to promote physically active lifestyles, but their role and practice towards promoting physically active lifestyles among patients has not been fully investigated. This study was designed to investigate the knowledge, propensity, attitude and practices of clinicians towards the promotion of physical activity among patients with asthma and allergies. METHODS: Two hundred and eighty clinicians (mean age; 46 ± 13 years; with a clinical experience of practice for 15 ± 7 years) participated in a global survey. The survey comprised a 29-item questionnaire, which gathered information on attitudes of the clinicians towards promoting physical activity, their knowledge and their beliefs regarding evidence for benefits of physical activity as a supplementary treatment in patients with asthma and allergies. RESULTS: Almost all respondents were aware of the strong evidence in favor of physical activity for the psychological well-being, weight control, decreased risk of diabetes, ischemic heart disease and arterial hypertension. Evidence for reduction in the risk for developing asthma and for better asthma control were reported by 60.0% and 85.4% of participants, respectively. The majority (85.0%) of clinicians strongly agreed that promoting physical activity is important to health care, although 95.5% considered they required more educational training. Although two thirds of them usually recommended exercise to their asthmatic/allergic patients, only 24.0% reported having previous training on the subject of such counseling. Almost all believed that effective counseling about a healthy diet, exercise and weight management would be easier if the clinician himself/herself was physically fit and healthy. CONCLUSIONS: The results of this global survey indicate that clinicians working in the field of allergy and respiratory diseases are well aware of the evidence supporting the benefits of physical activity for asthma and allergic diseases although they need more training in such counseling. Therefore, concerted efforts are needed towards educating clinicians towards promoting physical activity and weight management, as a supplementary treatment for asthma and allergies.

Urinary CC16 after challenge with dry air hyperpnoea and mannitol in recreational summer athletes.

Airway epithelial injury is regarded as a key contributing factor to the pathogenesis of exercise-induced bronchoconstriction (EIB) in athletes. The concentration of the pneumoprotein club cell (Clara cell) CC16 in urine has been found to be a non-invasive marker for hyperpnoea-induced airway epithelial perturbation. Exercise-hyperpnoea induces mechanical, thermal and osmotic stress to the airways. We investigated whether osmotic stress alone causes airway epithelial perturbation in athletes with suspected EIB. Twenty-four recreational summer sports athletes who reported respiratory symptoms on exertion performed a standard eucapnic voluntary hyperpnoea test with dry air and a mannitol test (osmotic challenge) on separate days. Median urinary CC16 increased from 120 to 310 ρg µmol creatinine(-1) after dry air hyperpnoea (P = 0.002) and from 90 to 191 ρg µmol creatinine(-1) after mannitol (P = 0.021). There was no difference in urinary CC16 concentration between athletes who did or did not bronchoconstrict after dry air hyperpnoea or mannitol. We conclude that, in recreational summer sports athletes with respiratory symptoms, osmotic stress per se to the airway epithelium induces a rise in urinary excretion of CC16. This suggests that hyperosmolarity of the airway surface lining perturbs the airway epithelium in symptomatic athletes.

Pathogenesis of exercise-induced bronchoconstriction.

This article presents the various potential mechanisms responsible for the development of exercise-induced bronchoconstriction (EIB). Although the etiology of EIB is multifactorial, and the physiologic processes involved may vary between individuals (especially between those with and without asthma), drying of the small airways with an associated inflammatory response seems prerequisite for EIB. Dysregulated repair processes following exercise-induced airway epithelial injury may also serve as basis for EIB development/progression.

Refractoriness to exercise challenge: a review of the mechanisms old and new.

This article discusses the available literature on refractoriness in exercise-induced bronchoconstriction, namely, a decrease in airway responsiveness with repeated exercise challenges. The mechanisms of this naturally occurring protective feature is unknown. Reviewing previous studies together with findings in more recent studies, the authors propose desensitization of the G protein-coupled cysteinyl leukotriene receptor1 as the mechanism of refractoriness and that this desensitization occurs as a result of interplay between leukotrienes and prostaglandins.

Assessment of EIB: What you need to know to optimize test results.

Respiratory symptoms and asthma control questionnaires are poor predictors of the presence or severity of exercise-induced bronchoconstriction (EIB), and objective measurement is recommended. To optimize the chance of a positive test result, there are several factors to consider when exercising patients for EIB, including the ventilation achieved and sustained during exercise, water content of the inspired air, and the natural variability of the response. The high rate of negative exercise test results has led to the development of surrogates to identify EIB in laboratory or office settings, including eucapnic voluntary hyperpnea of dry air and inhalation of hyperosmolar aerosols.

The effects of mannitol on the transport of ciprofloxacin across respiratory epithelia.

Inhalation of antibiotics and mucolytics is the most important combination of inhaled drugs for chronic obstructive lung diseases and has become a standard part of treatment. However, it is yet to be determined whether the administration of a mucolytic has an effect on the transport rate of antibiotics across the airway epithelial cells. Consequently, the aim of this study was to investigate the effects of inhalation dry powder, specifically mannitol, on ciprofloxacin transport using a Calu-3 air-interface cell model. Transport studies of ciprofloxacin HCl were performed using different configurations including single spray-dried ciprofloxacin alone, co-spray-dried ciprofloxacin with mannitol, and deposition of mannitol prior to ciprofloxacin deposition. To understand the mechanism of transport and interactions between the drugs, pH measurements of apical surface liquid (ASL) and further transport studies were performed with ciprofloxacin base, with and without the presence of ion channel/transport inhibitors such as disodium cromoglycate and furosemide. Mannitol was found to delay absorption of ciprofloxacin HCl through the increase in ASL volume and subsequent reduction in pH. Conversely, ciprofloxacin base had a higher transport rate after mannitol deposition. This study clearly demonstrates that the deposition of mannitol prior to ciprofloxacin on the air-interface Calu-3 cell model has an effect on its transport rate. This was also dependent on the salt form of the drug and the timing and sequence of formulations administered.

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.

Phase 3 randomized study of the efficacy and safety of inhaled dry powder mannitol for the symptomatic treatment of non-cystic fibrosis bronchiectasis.

BACKGROUND: Inhaled dry powder mannitol enhanced mucus clearance and improved quality of life over 2 weeks in non-cystic fibrosis bronchiectasis. This study's objective was to investigate the efficacy and safety of dry powder mannitol over 12 weeks. METHODS: Patients with bronchiectasis confirmed by high-resolution CT (HRCT) scan, aged 15 to 80 years, with FEV1≥50% predicted and ≥1 L participated in a randomized, placebo-controlled, double-blind study. Patients with a negative mannitol provocation test were randomized to inhale 320 mg mannitol (n=231) or placebo (n=112) bid for 12 weeks. To further assess safety, the same mannitol dose/frequency was administered to a patient subset in an open-label extension over 52 weeks. Primary end points were changes from baseline at 12 weeks in 24-h sputum weight and St. George's Respiratory Questionnaire (SGRQ) score. RESULTS: There was a significant difference of 4.3 g in terms of change in sputum weight over 12 weeks (95% CI, 1.64-7.00; P=.002) between mannitol and placebo; however, this was largely driven by a decrease in sputum weight in the placebo group. This was associated, in turn, with more antibiotic use in the placebo group (50 of 112 [45%]) than in the inhaled mannitol group (85 of 231 [37%]). There was no statistical difference between the groups (P=.304) in total SGRQ score (mannitol, -3.4 points [95% CI, -4.81 to -1.94] vs placebo, -2.1 points [95% CI, -4.12 to -0.09]). In a subgroup study (n=82), patients receiving mannitol showed less small airway mucus plugging on HRCT scan at 12 weeks compared with patients receiving placebo (P=.048). Compliance rates were high, and mannitol was well tolerated with adverse events similar to those of placebo. CONCLUSION: Because the difference in sputum weights appears to be associated with increased antibiotic use in the placebo group, a larger controlled study is now required to investigate the long-term mannitol effect on pulmonary exacerbations and antibiotic use. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT0027753; URL: www.clinicaltrials.gov.