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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.

The need for a diagnostic test for asthma was established when it was realized that asthma symptoms could not be relied upon to predict the presence, or not, of airway hyper-responsiveness and inflammation, the hallmarks of asthma. A need to identify asthmatic patients who were overtreated or undert

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.

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.

OVERVIEW: Calciphylaxis is most common in patients with end-stage renal disease, and hyperparathyroidism is often present as well. But several cases in patients with normal renal and parathyroid function have been reported; this article describes one such case. The etiology and pathophysiology of calciphylaxis aren't well understood. There are many risk factors, and the reported median survival time is 2.6 months after diagnosis. The condition is characterized by isolated or multiple lesions that progress to firm, nonulcerated plaques and then to ischemic skin necrosis and ulceration. In August 2010, a female patient arrived at the hospital with multiple deep, painful necrotic wounds. Given this patient's presentation on admission, the nurses kept expecting the physicians to initiate end-of-life discussions with her and were surprised when this did not happen. After five days, the patient was diagnosed with calciphylaxis in the unusual presentation of normal renal and parathyroid function, and the team realized that her chances for survival were greater than expected. The nursing staff was crucial in developing and implementing an intensive treatment plan. The patient survived and made a full recovery.

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.

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.

SummaryAirway 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.

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.

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.

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.

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 FEV 1 ≥ 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

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.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.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 β(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 β(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.The recommendations in this Guideline reflect the currently available evidence. New clinical research data will necessitate a revision and update in the future.

Indirect challenges to assess bronchial hyperresponsiveness are being increasingly used both for research and for assessment in the routine pulmonary function laboratory. “Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract with or without inducing microvascular leakage. Because the responses to these challenges are modified or completely inhibited by inhaled steroids, the airway response to the challenges may be a closer reflection of active airway inflammation” (fig. 1) [1]. In contrast, the direct tests, inhaled aerosols of histamine and methacholine act directly on receptors on the bronchial smooth muscle to cause contraction. While sensitive for detecting bronchial hyperresponsiveness a positive response to these agents is not specific for identifying asthma particularly at the higher concentrations. The best known of the indirect challenges is exercise. Other indirect challenges include eucapnic voluntary hyperpnoea, mannitol, adenosine monophosphate and hyperosmolar saline. All these indirect challenges are associated with release of mediators of bronchoconstriction. For this reason they have the potential to be used to identify presence of inflammatory cells particularly mast cells [2]. Figure 1 The events that lead to airway narrowing and a reduction in forced expiratory volume in 1 s in response to different indirect challenge tests. While hyperpnoea, mannitol and 4.5% saline all act to increase osmolarity that causes mediators to be released, adenosine acts to release mast cell mediators through a specific receptor on the mast cell. ASL: airway surface liquid; FEV1: forced expiratory volume in 1 s. Modified from [2] with permission from the publisher. ### Usefulness Exercise testing is used to diagnose exercise-induced bronchoconstriction (EIB). The term EIB describes the transient increase in airways resistance that follows vigorous exercise. EIB is thought to result from transient dehydration of the airway surface in response to conditioning the inspired …

For several hours after exercise-induced bronchoconstriction, there is diminished responsiveness to repeated challenge. The mechanism causing this refractoriness is unclear. Inhalation of dry powder mannitol is a new bronchial provocation test that has been suggested as a surrogate for an exercise challenge. Refractoriness to repeated mannitol challenge has however not been established. Our objective was to investigate if repeated challenge with mannitol is associated with refractoriness and diminished release of mast cell mediators of bronchoconstriction. Sixteen subjects with asthma underwent repeated inhalation of mannitol 90 min apart. Lung function was assessed by forced expiratory volume in 1 s (FEV1). The urinary excretion (ng/mmol creatinine) of the mediators 9α,11β-prostaglandin (PG) F2 and leukotriene (LT) E4 were measured. The group mean fall in FEV1 after the second challenge was 48.5 ± 5.8% of the first ( P < 0.001). The protection afforded by the initial challenge, however, varied considerably between subjects (range 88–0%). Furthermore, the urinary excretion of the two mediators was increased after both challenges. The average excretion of mediators after the challenges was significantly higher for the six most refractory subjects. This was observed both for LTE4 (95.6 ± 5.2 vs. 58.0 ± 2.4 for the 6 least refractory) ( P < 0.001) and for 9α,11β-PGF2 (137.6 ± 6.7 vs. 50.1 ± 1.1 for the 6 least refractory) ( P = 0.002). As occurs with exercise-induced bronchoconstriction, repeated inhalation of mannitol induced refractoriness. We propose that refractoriness is due to tachyphylaxis at the level of the airway smooth muscle responsiveness to mediators of bronchoconstriction rather than due to fatigue of their release from mast cells.

Purpose of review Performing a bronchial provocation test (BPT) using a direct or indirect stimulus to identify bronchial hyper-responsiveness (BHR) reduces the possibility of over and under-diagnosis of asthma based on history and symptoms. This review discusses some long-held beliefs of BPTs to include or exclude a diagnosis of asthma or exercise-induced bronchoconstriction (EIB). Recent findings A high frequency of negative methacholine tests has been reported in 240 patients given a diagnosis of asthma at the end of the study, many of whom had documented EIB. This suggests that a negative methacholine test should not be relied upon to rule out asthma. Further, a positive methacholine test alone should be interpreted with caution as it may reflect airway injury rather than asthma or EIB. Mannitol, an indirect stimulus, identified a similar prevalence of BHR to methacholine and identified more patients than a single exercise test in three studies. However, neither mannitol nor methacholine identified all patients with EIB. Mannitol has a higher specificity for a physician diagnosis of asthma than methacholine. Summary It is likely that both a direct test and an indirect test result may be required in some patients in order to confirm or exclude a diagnosis of asthma with certainty.

Background and objective: Dry powder mannitol has the potential to be used to enhance clearance of mucus in subjects with bronchiectasis. A reduction in FEV1 has been recorded in some subjects with bronchiectasis after inhaling mannitol. The aim of this study was to investigate if pre-medicating with either sodium cromoglycate (SCG) or eformoterol could inhibit this reduction in FEV1. Methods: A double-blind, placebo-controlled, randomized cross-over study was conducted. Lung function and airway response to mannitol was assessed on a control day and then re-assessed after pre-medication with placebo, SCG and eformoterol in nine subjects. Sensitivity to mannitol, expressed as the dose required to induce a 15% fall in FEV1 (PD15), and reactivity to mannitol, expressed as the % fall in FEV1 per mg of mannitol (response–dose ratio, RDR), are reported. Results: Subjects had an FEV1 of 68 ± 14% predicted, FVC of 97 ± 15% predicted and FEV1/FVC of 71 ± 8%. They were mildly hypoxemic and the SpO2 was 95 ± 2%.They had a PD15 to mannitol of 235 mg (95% CI: 150–368 mg) and a RDR of 0.057% fall in FEV1 per mg (95% CI: 0.038–0.085). After pre-medication with SCG, PD15 increased (773 mg, P

Chief Editors: John M. Weiler, MD, MBA, President, CompleWare Corporation, Professor Emeritus, University of Iowa, Iowa City, Iowa; Sandra D. Anderson, PhD, DSc, Clinical Professor, Sydney Medical School, Royal Prince Alfred Hospital, Department of Respiratory and Sleep Medicine, Camperdown NSW 2050, Australia; Christopher Randolph, MD, Clinical Professor of Pediatrics, Yale Affiliated Programs, Waterbury Hospital, Center for Allergy, Asthma and Immunology, Waterbury, Connecticut

SummaryAsthmatics with overproduction of mucus that is viscous and sticky have impaired mucociliary clearance (MCC) leading to mucus plugs, and airway obstruction. Inhaled mannitol improves mucus clearance in other hypersecretory diseases. This study investigated the effect of mannitol and cough in asthmatics with mucociliary dysfunction.Seven stable asthmatics, age 52 ± 20 yr, lifelong non-smokers, without the diagnosis of bronchiectasis, with chronic cough and sputum production, treated with inhaled corticosteroids participated in the study. MCC and cough clearance (CC) was measured on 4 visits: at baseline (no cough or mannitol), with mannitol (240 and 480 mg) and cough control (no mannitol) over total 90 min using a radioaerosol technique and imaging with a gamma camera. Cough clearance was assessed after MCC by asking subjects to cough 100 times over 30 min. Premedication with eformoterol (12 μg) on all visits protected all subjects from bronchoconstriction (fall in FEV1 > 15%) in response to mannitol.Mean (±SD) clearance over 60 min increased from 5.5 ± 5.6% at baseline and 7.3 ± 6.6% with cough control to 19.5 ± 14.6% and 26.4 ± 11.5% with 240 mg (p 0.05). Mannitol improved clearance in all lung regions (p

Indirect challenges cause the release of endogenous mediators that cause the airway smooth muscle to contract and the airways to narrow. Airway sensitivity to indirect challenges is reduced or even totally inhibited by treatment with inhaled corticosteroids (ICS), so a positive response to an indirect stimulus is believed to reflect active airway inflammation. The indirect challenges commonly used in pulmonary function laboratories include exercise, eucapnic voluntary hyperpnea, hypertonic (4.5%) saline, and mannitol. Exercise was the first test to be standardized and was used to identify exercise-induced bronchoconstriction (EIB). The inhibition of EIB in young children by sodium cromoglycate led to the concept that mast cells were important very early in the onset of asthma. All of these indirect challenges are associated with the release of mast cell mediators (eg, prostaglandins, leukotrienes, and histamine). The hypertonic saline and mannitol challenges arose from the concept that EIB was caused by an increased osmolarity of the airway surface with release of mediators. These osmotic aerosols simplified testing with indirect challenges in the laboratory, improving the potential to identify currently active asthma. Although hyperresponsiveness to indirect challenges is frequently associated with a sputum eosinophilia, it is not a prerequisite because the mast cell is the most important source of mediators. The mechanism for ICS reducing hyperresponsiveness to indirect challenges likely involves both mast cells and eosinophils. Indirect challenges are appropriate to inform further on both the pathogenesis of asthma and the role of antiinflammatory agents in its treatment.

Background Methacholine hyperresponsiveness is prevalent in elite athletes. Comparative studies have hitherto been limited to methacholine, eucapnic voluntary hyperpnoea and exercise. This study investigated airway responsiveness to these stimuli as well as to adenosine 5′-monophosphate (AMP) and mannitol, in 58 cross-country ski athletes. Methods Exhaled nitric oxide concentration (F E NO), spirometry and bronchial challenge in random order with methacholine, AMP and mannitol were consecutively performed on three study days in the autumn. Specifi c IgE to eight aeroallergens and a self-completed questionnaire about respiratory symptoms, allergy and asthmatic medication were also performed on day 1. Eucapnic voluntary hyperventilation (EVH) and fi eld exercise tests were randomly performed in 33 of the skiers on two study days in the following winter. Results Of 25 (43%) skiers with airway hyperresponsiveness (AHR), 23, fi ve and three skiers were hyperresponsive to methacholine, AMP and mannitol, respectively. Methacholine hyperresponsiveness was more prevalent in subjects without asthma-like symptoms. The F E NO was not signifi cantly different in skiers with and without methacholine hyperresponsiveness. Four of 14 skiers with and four of 19 skiers without methacholine hyperresponsiveness were hyperresponsive to EVH or exercise challenge. AHR to any stimulus was present in 16 asymptomatic and nine symptomatic skiers. Asthma-like symptoms were not correlated with AHR to any stimulus. Conclusions Methacholine hyperresponsiveness is more common in asymptomatic skiers and is a poor predictor of hyperresponsiveness to mannitol and hyperpnoea. The low prevalence of hyperresponsiveness to indirect stimuli may suggest differences in the pathogenesis of methacholine hyperresponsiveness in elite skiers and non-athletes.

The airway mucus in patients with cystic fibrosis (CF) is dehydrated and adhesive and accumulates in the airways, resulting in chronic inflammation, infection, and progressive loss of lung function. Inhaled mannitol improves mucus clearance and, when administered over 2 weeks, it improves lung function in CF (Jaques et al. Chest. 2008;133(6):1388-1396). The changes in the physical properties of sputum after a 2-week treatment with mannitol were investigated in the same subjects with CF.Sputum was collected before and at the end of the 2-week treatment period from 28 subjects with CF who participated in the double-blind crossover study. Mannitol or placebo 420 mg bid was inhaled over 2 weeks. The solids content, surface tension, contact angle, and viscoelasticity were measured.Two-week treatment with mannitol reduced the solids from 7.3% +/- 3.0% to 5.7% +/- 3.0% (P = .012), surface tension from 83.1 +/- 7.2 to 78.6 +/- 8.0 mN/m (P.039), and contact angle from 52.4 +/- 7.7 to 47.9 +/- 7.3 degrees. There was no significant change in the viscoelastic properties of sputum (P.1). Placebo treatment had no significant effect on the sputum properties. The change in solids content correlated with the change in both FEV(1) (r = -0.78, P = .004) and forced expiratory flow in the middle half of the FVC (r = -0.80, P = .003), and the percentage change in surface tension and contact angle correlated with the percentage change in the FEV(1) (r = -0.73, P = .012 and r = -0.63, P = .03, respectively) in these subjects.Treatment with inhaled mannitol over 2 weeks improved the hydration and surface properties of sputum in patients with CF. This effect was sustained and correlated with airway function changes.clinicaltrials.gov; Identifier: NCT00455130.

SummaryMucociliary clearance increases with increasing doses of mannitol and clearance is enhanced when mannitol inhalation is followed by repetitive voluntary coughing.The aim of the study was to investigate: 1) the effect of increasing doses of mannitol and repetitive coughing on the sputum physical properties; 2) if the changes in sputum properties can predict the efficacy of mucus clearance measured by radioaerosol technique in bronchiectasis patients.Sputum was collected from 14 patients, age: 63±6yr, who participated on the mucociliary and cough clearance studies at baseline, with mannitol (160, 320 and 480mg) and control (Daviskas et al. ERJ 2008; 31:765-772). Sputum was collected: 1) on the screening visit before and after mannitol challenge (635mg); 2) at the start and end of each clearance study after 100 repetitive voluntary coughs except on the control study (no mannitol or repetitive coughing). The sputum solids content, surface tension, contact angle and rheology were measured.Mannitol in association with coughing and coughing alone reduced the solids content, surface tension, contact angle and viscoelastic sputum properties (p

Cite this as: S. D. Anderson and J. D. Brannan, Clinical & Experimental Allergy, 2010 (40) 193–196.

Educational aims To describe the stimulus for exercise-induced bronchoconstriction. To describe the different mechanisms whereby this stimulus may act to cause the airways to narrow in asthmatics and athletes. To describe the relevance of the stimulus and mechanism to protocols to diagnose exercise-induced bronchoconstriction. To describe the inflammatory mediators involved in exercise-induced bronchoconstriction. To describe how and why airway injury could contribute to the pathogenesis of airway hyperresponsiveness and exercise-induced bronchoconstriction in athletes. Summary The stimulus for exercise-induced bronchoconstriction (EIB) is the loss of water by humidifying large volumes of air during exercise. The mechanism for EIB relates to the thermal and osmotic effects of water loss. The thermal theory proposes that EIB is a vascular event comprising vasoconstriction during exercise followed by rapid rewarming and a reactive hyperaemia at the end of exercise. The osmotic theory proposes that water loss induces an increase in osmolarity in the airways, which causes the release of mediators that cause bronchial smooth muscle to contract. Increased vascular permeability and leakage are common to both theories.

Bronchial provocation tests (BPTs) are useful for identifying one of the key features of asthma: bronchial hyper-responsiveness (BHR). The symptoms of asthma are not always reflective of the underlying pathophysiology of asthma and there is a need for objective tests to identify the presence and severity of BHR. A new BPT, involving the inhalation of dry powder mannitol, has recently been approved to identify BHR and is now in use as a diagnostic tool for currently active asthma. Airway sensitivity to mannitol identifies BHR that is dependent upon the presence of airway inflammation and would probably benefit from treatment with inhaled corticosteroids. The mannitol BPT is available commercially as a (single-use) test kit (Aridol™/Osmohale™), with the only additional requirement to perform the test being a spirometer. Accordingly, the mannitol BPT provides a point-of-need tool to identify BHR to assist in the diagnosis of asthma.

Asthma is frequent in elite athletes and clinical studies in athletes have found increased airway inflammation.To investigate asthma-like symptoms, airway inflammation, airway reactivity (AR) to mannitol and use of asthma medication in Danish elite athletes.The study group consisted of 54 elite athletes (19 with doctor-diagnosed asthma), 22 non-athletes with doctor-diagnosed asthma (steroid naive for 4 weeks before the examination) and 35 non-athletes without asthma; all aged 18-35 years. Examinations (1 day): questionnaires, exhaled nitric oxide (eNO) in parts per billion, spirometry, skin prick test, AR to mannitol and blood samples. Induced sputum was done in subjects with asthma.No significant difference was found in values for eNO, AR and atopy between 42 elite athletes with and 12 without asthma-like symptoms. Elite athletes with doctor-diagnosed asthma had less AR (response dose ratio 0.02 (0.004) vs 0.08 (0.018) p0.01) and fewer sputum eosinophils (0.8% (0-4.8) vs 6.0% (0-18.5), p0.01) than non-athletes with doctor-diagnosed asthma. Use of inhaled corticosteroids was similar in the two groups (not significant). In all, 42 elite athletes had asthma-like symptoms but only 12 had evidence of current asthma. Elite athletes without asthma had asthma-like symptoms more frequently than non-athletes without asthma (68.6% vs 25.7%, p0.001).Asthma-like symptoms in elite athletes are not necessarily associated with classic features of asthma and alone should not give a diagnosis of asthma. More studies are needed to further investigate if and how the asthma phenotype of elite athletes differs from that of classical asthma.

The International Olympic Committee Medical Commission (IOC-MC) requires athletes to provide the result of an objective test to support a diagnosis of asthma or exercise-induced bronchoconstriction (EIB) if they want to inhale a beta-2-agonist. The purpose of the study was to evaluate the airway response to a methacholine challenge and to hyperpnea induced by exercise in the field and in the laboratory or that induced voluntarily by eucapnic hyperpnea in a group of female elite swimmers.Sixteen female nonasthmatic elite swimmers performed a eucapnic voluntary hyperpnea (EVH) test, a field-based exercise test (FBT), a laboratory-based exercise test (LBT), and a methacholine challenge. The criteria suggested by the IOC-MC were used to define a positive response to the challenges (EVH, field test, and laboratory test: minimum 10% decrease in FEV1; methacholine: PD20or = 2 micromol).Eight swimmers (50%) had at least one positive test to hyperpnea. Five were identified with the EVH test, four with FBT, and four with LBT. None were identified using methacholine. Three swimmers with airway hyperresponsiveness to exercise would have been identified using a higher cutoff for methacholine (PD20or = 8 micromol).The EVH test is the test that diagnoses most swimmers with an abnormal response to hyperpnea, but not all cases of EIB are identified with the EVH test. Performing a methacholine test using IOC-MC's cutoff value does not improve the chances of diagnosing EIB. We recommend performing the EVH test when diagnosing and evaluating EIB in elite swimmers and if EVH test negative then proceeding to a strenuous LBT.

Smoking induces airway hyperresponsiveness (AHR). Bronchial provocation with mannitol is used to identify AHR in subjects with asthma. This study aimed to determine the prevalence of airway hyperresponsiveness to mannitol in asymptomatic smokers compared to non-smokers and to assess if airway responsiveness to mannitol changes after smoking cessation. Airway responsiveness to inhaled mannitol was measured in smokers (n=42), and non-smokers (n=45). In smokers, the mannitol test was repeated 3 months after smoking cessation. Demographics including age, lung function and atopy status were similar for smokers and non-smokers (p=ns). Compared with non-smokers (2.2%), AHR to mannitol expressed by 15%> or = fall in FEV(1) was significantly more common in smokers (26.2%) (p=0.001). The provoking dose to induce a 15%> or = fall in FEV(1) (PD(15)), a measure of sensitivity, was median [IQR] 291 mg [207-377] in the 11 positive smokers. The response-dose ratio (RDR) (% fall in FEV(1)/cumulative dose), a measure of reactivity, was significantly higher in smokers (0.013 [0.006-0.029]) compared with non-smokers (0.004 [0.002-0.007]), (p

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.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.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.A prototype aerosol delivery system has been developed that is consistently able to deliver doubling doses suitable for bronchial provocation testing in young children.

Mannitol as a dry powder aerosol is used for bronchoprovocation testing and to enhance mucus clearance in people with excessive airway secretions. The dose and distribution of the deposited aerosol in the lung was investigated using fast single photon emission tomography (SPECT) imaging. Mannitol powder (3 microm particle size) was produced by spray drying and radiolabeled with (99m)Tc-DTPA. Approximately 60 mg of radiolabeled mannitol (containing 52-68 MBq of (99m)Tc-DTPA) was administered to 10 healthy subjects using the Inhalator dry powder inhaler (DPI), and SPECT images (1 min each) were collected. Thirteen percent to 31% of the dose of mannitol loaded in the inhaler deposited in the lungs and the deposited dose correlated positively with the peak inhalation air flow. The regional aerosol lung distribution, as expressed by the penetration index (i.e., ratio of peripheral to central deposition in the lung) varied from 0.31 to 0.88, which however showed no dependency on any flow parameters. The variation in response to the same dose of mannitol within the asthmatic population may in part be explained by these findings.

Background The International Olympic Committee Medical Commission required a medical justification for athletes to inhale a β 2 -agonist before an event at the Summer Games in Athens in 2004. Objective We sought to establish the percentage of athletes applying to use an inhaled β 2 -agonist on the basis of the results of objective tests to establish a diagnosis of asthma or exercise-induced bronchoconstriction. We also sought to compare this percentage with the percentage of athletes simply notifying the intention to use a β 2 -agonist at the previous Summer Games in Sydney in 2000. Methods An analysis was made of tests that measured the change in FEV 1 in response to a bronchodilator or in response to a provoking stimulus, such as exercise, eucapnic voluntary hyperpnea, hypertonic saline, or methacholine. Results Ten thousand six hundred fifty-three athletes competed in Athens; 4.2% were approved to use a β 2 -agonist, and 0.4% were rejected. This approval rate was 26% less than the notifications in 2000 in Sydney (5.7%). Compared with Sydney 2000, there was a significant reduction of submissions and approvals for athletes from the United States, New Zealand, Australia, and Canada and in triathlon and swimming sports. Conclusion The need to provide objective testing has resulted in a reduction in the number of athletes seeking approval to use an inhaled β 2 -agonist. Objective evidence has provided information for the doctor that is likely to improve the health of the athlete because many athletes appeared to be undertreated at the time of testing. Clinical implications We show that documentation of airway narrowing in athletes, particularly in response to exercise or surrogate stimuli for exercise, aids in the diagnosis and management of asthma by providing evidence of bronchial hyperresponsiveness that will respond to treatment with inhaled corticosteroids and is usually associated with a reduction in respiratory symptoms on exercise.

β2-Agonists taken immediately before exercise provide significant protection against exercise-induced asthma (EIA) in most patients. However, when they are taken daily, there are some negative aspects regarding severity, control, and recovery from EIA. First, there is a significant minority (15–20%) of asthmatics whose EIA is not prevented by β2-agonists, even when inhaled corticosteroids are used concomitantly. Second, with daily use, there is a decline in duration of the protective effect of long-acting β2-agonists. Third, if breakthrough EIA occurs, recovery of lung function is slower in response to a β2-agonist, and additional doses are often required to achieve pre-exercise values. If a person who takes a β2-agonist daily experiences problems with exercise, then the physician should consider changing the treatment regimen to achieve better control of EIA. These problems likely result from desensitization of the β2-receptor on the mast cell, which enhances mediator release, and on the bronchial smooth muscle, which enhances the bronchoconstrictor response and delays recovery from EIA. These effects are reversed within 72 h after cessation of a β2-agonists. The important clinical question is: Are we acutally compromising the beneficial effects of β2-agonists on the prevention and recovery from EIA by prescribing them daily? Patients with EIA need to ensure that their doses of inhaled corticosteroid or other anti-inflammatory therapy are optimized so that, if necessary, a β2-agonist can be used intermittently as prophylactic medication with greater confidence in the outcome.

Chronic asthma is characterized by airway inflammation, mucus hypersecretion and impaired mucociliary clearance (MCC). We investigated baseline MCC and the acute effect of terbutaline in chronic asthmatics with sputum production while on long-term treatment with salmeterol in combination with inhaled corticosteroids (ICS). MCC was measured at baseline and in response to 1 mg terbutaline (or placebo) on three visits over 80 min in 16 asthmatics (52 +/- 13 years of age). Subjects who had greater than 10% absolute increase in MCC above baseline and placebo, after terbutaline, were categorized in group A and subjects who had less than 10% in group B. In group A subjects (n = 6), MCC increased from 23.7 +/- 4.0% at baseline to 43.7 +/- 4.9% with terbutaline (P 0.05). Group B subjects withdrew from all beta(2) agonists for a week and MCC was remeasured. After withdrawal, baseline MCC (7.0 +/- 1.8%) was similar to the initial baseline value (P > 0.1) and MCC with terbutaline (15.8 +/- 4.9%) was greater than baseline (P < 0.005) but remained abnormal in most subjects. Baseline percentage predicted FEV1 and FEF25-75% were 77.3 +/- 7.2 and 41.7 +/- 5.6 in group A and 59.9 +/- 8.1 and 29.5 +/- 8.4 in group B subjects, respectively. MCC was impaired in most of these asthmatics with persistent airway obstruction and sputum production, despite regular treatment with ICS and salmeterol. In addition, there was little or no stimulation of MCC acutely after terbutaline in most of these asthmatics.

Objective: Inhaled mannitol induces both bronchoconstriction and cough. Nedocromil sodium greatly attenuates mannitol-induced bronchoconstriction. Knowledge about the effect of nedocromil on mannitol-provoked cough might, therefore, clarify the mechanisms of this response. Methodology: Inhalation challenges with mannitol powder were performed after inhalation of 8 mg of nedocromil or its placebo in 24 subjects with asthma. The study was double-blind, randomised, and placebo-controlled. The mannitol-provoked coughs were manually recorded and the mannitol-induced bronchoconstriction was measured with a spirometer. Results: The cumulative dose of mannitol that provoked at least two coughs tended to be higher on the nedocromil day than on the placebo day (34 (22–53) mg vs 26 (18–37) mg, P = 0.051). The cumulative number of coughs per dose of mannitol was slightly, but significantly, lower on the nedocromil than on the placebo day (4.2 (2.8–6.3) coughs/100 mg vs 6.1 (4.0–9.4) coughs/100 mg, P = 0.037). However, when analysed on a constant-dose basis, nedocromil provided no protection for coughing (−1% protection), whereas the protection for bronchoconstriction was clear (55% protection). Conclusions: Nedocromil strongly attenuates mannitol-induced bronchoconstriction but has a negligible effect on mannitol-provoked cough. Therefore, these responses seem to have different pathways in asthma. Recording of both provoked coughs and induced bronchoconstriction during mannitol challenge may provide supplementary information about a patient's disease.

Background: Airway hyperresponsiveness to hypertonic saline (HS) is associated with airway inflammation. We investigated if responsiveness to HS was predicted by asthma symptoms in the last 3 months. Objectives: To investigate if responsiveness to HS can be estimated by questionnaire items investigating asthma symptoms of the last 3 months. Methods: Six hundred and four patients with physician-diagnosed asthma being assessed for asthma severity were studied. Bronchial provocation with 4.5% saline was performed, and a questionnaire was administered. The response to 4.5% saline was reported as the provoking dose to cause a 15% fall in the forced expiratory volume in 1 s FEV1 (PD15) and the response-dose ratio (RDR). Results: Based on the GINA guidelines, asthma severity was intermittent in 497 patients, mild in 107 patients, moderate in 3 patients and severe in 1 patient. A PD15 to 4.5% saline was recorded in 234 of the 604. Questions on self-recognition of asthma, dust as a trigger, food as a trigger, and frequency of bronchodilator use were significant predictors for a PD15, and currently taking steroids decreased the likelihood of a positive response to 4.5% saline. Using a multiple-linear regression model, a difference in the RDR could be calculated between those who answered positively compared with the reference group, who answered negatively. This difference could be used as a guide for predicting abnormal reactivity. An increase in RDR in response to 4.5% saline, compared with the reference group, was demonstrated in the presence of self-recognition of asthma severity, dust and cats as a trigger or use of bronchodilator during sleep hours. Conclusions: Because of the high positive predictive value of HS for identifying patients with asthma it might be that the need for bronchodilator use at night not only predicts airway hyperresponsiveness to HS, it also could reflect the severity of asthma.

Inhaled mannitol increases mucus clearance in patients with bronchiectasis by an unclear mechanism. The effect of mannitol on lung function, health status and sputum properties was investigated.Nine patients with bronchiectasis inhaled 400 mg of mannitol once daily for 12 days. Health status was assessed using the St George's Respiratory Questionnaire (SGRQ). Sputum was analysed for viscosity, elasticity, spinnability, surface tension, contact angle, solids, mucociliary transportability (MCTR) on a frog palate, and cough transportability (CTR) on a simulated cough machine.Lung function was unchanged with treatment (baseline FEV1 82.0 +/- 16.2%) apart from an improvement in FEF from 85.4 +/- 13% (baseline) to 90.7 +/- 14.4% (P0.05; 12th treatment; visit 7). The total SGRQ score (mean +/- SD) of 49.3 +/- 13.8 at baseline, decreased by 12.4 +/- 10.2 (P0.01; visit 7) and 10.1 +/- 9.4 units (P0.02) 6-10 days after treatment cessation. The baseline subscores for symptoms (72.9 +/- 11.8), activity (44.7 +/- 20.9) and impact (44.4 +/- 14.3) were reduced by 0.8 +/- 9.1 (P0.7), 8.4 +/- 16.0 (P0.1) and 19.2 +/- 13.7 (P0.005) units, respectively (visit 7). Mannitol reduced the baseline (mean +/- SE) surface tension from 94.5 +/- 1.4 to 84.7 +/- 2.1 mN/m (P0.0001), contact angle from 51.1 +/- 2.8 to 33.2 +/- 2.4 degrees (P0.0001), spinnability from 11.6 +/- 0.4 to 10.0 +/- 0.2 mm (P0.005), and solids from 5.7 +/- 0.4 to 4.3 +/- 0.7% (P0.02), acutely (visit 7). Viscosity, elasticity and MCTR did not change significantly, while CTR was increased from 25.8 +/- 1.0 to 34.1 +/- 2.7 mm (P0.003).Mannitol significantly improved the health status over 12 days and this improvement was maintained for 6-10 days after cessation of treatment. In addition, mannitol reduced the tenacity, increased the hydration of mucus acutely and improved cough clearability in patients with bronchiectasis.

Study objective: For the 2002 Winter Olympic Games, athletes were required to submit objective evidence of asthma or exercise-induced bronchoconstriction (EIB) for approval to inhale a 2-agonist. Eucapnic voluntary hyperventilation (EVH) was recommended as a laboratory challenge that would identify airway hyperresponsiveness (AHR) consistent with EIB. The objective was to compare the change in FEV1 provoked by EVH with that provoked by exercise in cold weather athletes. Design: Spirometry was measured before and for 15 min after challenges. The two challenges were performed in random order at least 24 h apart. Setting: EVH was performed in the laboratory at 19°C, and exercise took place in the field in the cold (2°C, 45% relative humidity). Participants: Thirty-eight athletes (25 female subjects; median age, 16 years). Interventions: For the EVH, athletes inhaled dry air containing 5% carbon dioxide for 6 min at a target ventilation equivalent to 30 times baseline FEV1. Exercise was performed by cross-country skiing, ice skating, or running for 6 to 8 min. Measurements and results: AHR consistent with EIB was defined as > 10% fall in FEV1 from baseline after challenge. Eleven athletes were exercise positive (EX) [FEV1 fall, 20.5 7.3%], and 17 athletes were EVH positive (FEV1 fall, 14.5 4.5%) [mean SD]. Of 19 subjects with AHR, 58% were identified by exercise and 89% were identified by EVH. EVH identified 9 of 11 subjects who were EX and a further 8 subjects with potential for EIB. The average ventilation during EVH was 28 times FEV1. Conclusion: Performing EVH for 6 min in the laboratory had a greater chance of identifying AHR in these athletes compared with 6 to 8 min of field exercise in the cold. The EVH test will be useful to evaluate elite summer sports athletes whose widely different forms of exercise provide an “equipment” challenge to any laboratory.

The safety and efficacy of long-acting beta(2)-adrenoceptor agonists (LABAs) taken intermittently for the prevention of exercise-induced asthma (EIA) in children is well established. However, the safety and efficacy of LABAs taken twice daily, either alone or in combination with inhaled corticosteroids, for the prevention of EIA is not as clear because of issues of tolerance (defined as being less responsive to the influence of LABAs). There have been many observations on short-acting beta(2)-adrenoceptor agonists (SABAs) and EIA that should have alerted us to the potential for tolerance and desensitization to occur with LABAs. For example, we expected that the use of LABAs for EIA would overcome the problem of the short duration of protection of SABAs, and to some extent they have. The protective period of a LABA is two to three times longer in duration than that of a SABA. However, when a LABA is taken daily it is apparent that the duration of its protective effect is reduced and there is a risk of EIA occurring well within the 12-hour administration schedules. Furthermore, daily use of LABAs attenuates the bronchodilator effect of SABAs, an effect that is greater the more severe the bronchoconstriction. This 'tolerance' increases both the time and the amount of therapy that is needed to recover from bronchoconstriction, and thus, could potentially impact on the success of rescue therapy should severe EIA occur. The daily use of LABAs also increases the sensitivity of the bronchial smooth muscle to contractile agents. This increase in sensitivity is almost equivalent to the extent to which inhaled corticosteroids reduce sensitivity to the same contractile agents. The increased sensitivity to contractile agents may occur either by a reduction in the inhibitory effect of beta(2)-adrenoceptor agonists on release of mediators from mast cells or by a direct effect on the bronchial smooth muscle. These unwanted effects of LABAs are not necessarily reduced by concomitant treatment with inhaled corticosteroids. As the number of children being treated with LABAs increases, it is predicted that problems with breakthrough EIA will also increase. We need to know the percentage of children taking a LABA daily who are requiring either extra doses of a beta(2)-adrenoceptor agonist to prevent (or reverse) EIA or other provocative stimuli. If this percentage is significant then we may need to reconsider the position of LABAs in the treatment of children with asthma who regularly perform strenuous physical activity.

Background: Assessment of airway hyperresponsiveness (AHR) to indirect bronchoconstrictor stimuli is a useful noninvasive tool in the evaluation of asthma and its treatment. We investigated the putative relationship in AHR between inhaled adenosine monophosphate and mannitol. Methods: Fifteen mild-to-moderate atopic asthmatics were evaluated. On two separate screening days, the threshold AMP concentration and threshold mannitol dose to provoke a given fall in FEV1 were measured. Results: For AMP PC20vs. mannitol PD15, the Pearsons correlation coefficient was 0.80, P

Summary Background Airway hyper-responsiveness (AHR) to indirect stimuli is a useful non-invasive surrogate inflammatory marker in the evaluation of asthma, while histamine and cysteinyl leukotrienes are important inflammatory mediators. Objective To evaluate AHR to indirect bronchoconstrictor stimuli and time taken to recover following single doses of montelukast 10 mg and desloratadine 5 mg in combination, montelukast 10 mg alone and placebo. Methods Fifteen mild-to-moderate persistent asthmatics completed a randomized, double-blind, cross-over study. Patients received encapsulated montelukast 10 mg/desloratadine 5 mg combination, montelukast 10 mg alone and placebo, 10–14 h prior to challenge on two separate occasions. The mannitol threshold dose, AMP threshold concentration and recovery times after challenge were measured along with lung function. Results Compared to placebo, montelukast/desloratadine conferred improvements (P