ORCID Profile
0000-0001-7243-7998
Current Organisation
John Hunter Hospital
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Publisher: Springer Science and Business Media LLC
Date: 2011
Publisher: American Thoracic Society
Date: 06-2000
DOI: 10.1164/AJRCCM.161.6.9908096
Abstract: Nedocromil sodium inhibits the response to exercise-induced asthma (EIA). Mannitol given as a powder by inhalation is an osmotic stimulus that identifies EIA. We studied the acute effect of nedocromil on airway responsiveness to mannitol in 24 asthmatic subjects. After a control day, nedocromil (8 mg) or its placebo was administered randomized, double blind, 10 min before a challenge with progressively increasing doses of mannitol. Nedocromil inhibited the response to mannitol and there was a significant increase in the dose of mannitol required to cause a 15% reduction in FEV(1) (PD(15)) after nedocromil 409 (316,503) mg compared with placebo 156 (106,229) mg (p < 0.001). In the presence of nedocromil 12 subjects no longer recorded a 15% decrease in FEV(1) in response to mannitol. The remaining 12 required a significantly greater dose of mannitol to achieve a 15% decrease in FEV(1) after nedocromil. Following nedocromil, a plateau in responsiveness to mannitol was observed in 14 subjects. Nedocromil significantly inhibits the responsiveness to inhaled mannitol in asthmatic subjects.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.IJPHARM.2016.09.047
Abstract: The present study investigates the effect of DPI resistance and inhalation flow rates on the lung deposition of orally inhaled mannitol dry powder. Mannitol powder radiolabeled with
Publisher: Frontiers Media SA
Date: 2012
Publisher: Wiley
Date: 28-11-2007
DOI: 10.1111/J.1365-2222.2006.02614.X
Abstract: Bronchial provocation using methacholine, a cholinergic agonist, causes airway narrowing directly by contraction of bronchial smooth muscle. While methacholine has a high sensitivity for identifying airway hyper-responsiveness (AHR), it does not have a high specificity to diagnose asthma and false-positive responses may be observed in non-asthmatics. Mannitol is an osmotic stimulus that acts indirectly to cause airway narrowing by release of endogenous bronchoconstricting mediators. We tested the hypothesis that subjects with asymptomatic AHR to methacholine would not have AHR to mannitol. Sixteen subjects with a methacholine PD(20) <8 micro mol were challenged with mannitol. A positive response to mannitol was defined as a 15% decline in forced expiratory volume in 1 s (FEV(1)) after <635 mg (PD(15)). Expired nitric oxide (eNO) and blood eosinophils were also measured. The GM PD(20) for methacholine was 2.25 micro mol [95% confidence interval (CI): 2.19-5.29], the mean eNO was 14.7 p.p.b. (CI: 10.1-19.4) and the eosinophil count was 0.20 x 10(-9)/L (CI: 0.14-0.27 x 10(-9)/L). Only one subject (a smoker, 10 pack-years, FEV(1) 76% pred, non-allergic rhinitis, normal eNO and eosinophil count) also had a mild positive response to mannitol (PD(15): 451 mg). The response to mannitol was within the normal range in asymptomatic subjects with AHR to methacholine. Further evidence on the responsiveness to mannitol compared with methacholine in a random population s le is required to elucidate whether mannitol is a more specific test for diagnosing asthma.
Publisher: American Thoracic Society
Date: 02-2001
DOI: 10.1164/AJRCCM.163.2.9912091
Abstract: To determine predictors for failed reduction of inhaled corticosteroids (ICS), in 50 subjects with well-controlled asthma (age 43.7 [18-69] 22 males) taking a median dose of 1,000 microg ICS/d (100-3,600 microg/d), ICS were halved every 8 wk. Airway hyperresponsiveness (AHR) to a bronchial provocation test (BPT) with histamine was measured at baseline. AHR to BPT with mannitol, spirometry, exhaled nitric oxide (eNO), and, in 31 subjects, sputum inflammatory cells were measured at baseline and at monthly intervals. Thirty-nine subjects suffered an asthma exacerbation. Seven subjects were successfully weaned off ICS. Using a Kaplan- Meier survival analysis, the significant predictors of a failure of ICS reduction were being hyperresponsive to both histamine and mannitol at baseline (p = 0.039), and being hyperresponsive to mannitol during the dose-reduction phase of the study (p = 0.02). Subjects older than 40 yr of age tended to be at greater risk of ICS reduction failure (p = 0.059). Response to mannitol and percentage sputum eosinophils were significantly greater before a failed ICS reduction than before the last successful ICS reduction, whereas there were no significant differences in symptoms, spirometry, or eNO. These findings suggest that documentation of patient's AHR or sputum eosinophils may be useful in guiding the reduction of ICS doses.
Publisher: Elsevier BV
Date: 02-2015
Publisher: Springer Science and Business Media LLC
Date: 2004
DOI: 10.2165/00148581-200406030-00003
Abstract: 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 ex le, 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.
Publisher: Elsevier BV
Date: 06-2004
Abstract: To define whether coughing during mannitol challenge is a nonspecific side effect of this challenge or is associated with asthma. A prospective study. University hospital. Thirty-seven steroid-naive, asthmatic subjects and 10 healthy subjects. The participants completed a symptom questionnaire, recorded peak expiratory flows (PEFs), and underwent spirometry, skin tests, and bronchial provocations with mannitol, histamine, and cold air. Seventeen of the asthmatic subjects were treated with budesonide, 800 micro g per day, and the measurements were repeated after 3 and 6 months of treatment. Coughs were recorded during the mannitol challenges, and the cough sensitivity was expressed as the cumulative number of coughs ided by the cumulative dose of mannitol. The asthmatic subjects coughed more during the mannitol challenge than the healthy subjects (8.3 coughs per 100 mg [95% confidence interval (CI), 6.2 to 11.0] vs 1.1 coughs per 100 mg [95% CI, 0.4 to 3.0] p < 0.0001). Even those asthmatic subjects who did not develop bronchoconstriction after the maximal cumulative dose of mannitol (635 mg) coughed significantly more than the healthy subjects (53 coughs [95% CI, 34 to 72] vs 12 coughs [95% CI, 4 to 21] p = 0.003). Budesonide treatment decreased the cough sensitivity (p = 0.023), which was significantly associated with improvements in overall symptom frequency, cough frequency, diurnal PEF variation, FEV(1), and bronchial hyperresponsiveness. Coughing during mannitol challenge is associated with asthma and occurs independently of bronchoconstriction. It can be used to study the mechanisms of asthmatic cough. Furthermore, the measurement of the mannitol-provoked coughing may be useful both in the diagnosis of asthma as well as in the assessment of the effects of an anti-inflammatory therapy on this common disorder.
Publisher: Mary Ann Liebert Inc
Date: 12-2015
Abstract: 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.
Publisher: Informa UK Limited
Date: 05-2010
DOI: 10.3109/02770900903584043
Abstract: Mannitol, inhaled as a dry powder, is used for bronchial provocation to identify bronchial hyperresponsiveness. Bronchoconstriction is associated with an increase in urinary excretion of the metabolites of prostaglandin D(2) and leukotriene E(4). Sodium cromoglycate provides about 60% protection against the fall in forced expiratory volume in one second (FEV(1)) provoked by inhaled mannitol and appears to do so by inhibiting the release of prostaglandin D(2) but not leukotriene E(4).The leukotriene receptor antagonist montelukast does not alter sensitivity to mannitol, as measured by the provoking dose to cause a 15% fall in FEV(1) to mannitol, but it significantly enhances recovery from the bronchoconstriction provoked by mannitol. The authors proposed that the combination of these two drugs would be superior to sodium cromoglycate alone and result in greater protection from the bronchoconstriction provoked by mannitol. The % fall in FEV(1) from baseline and the area under the 30-min FEV(1) time curve and time to recover to 95% baseline FEV(1) were used to express protection from 40 mg sodium cromoglycate alone, and in combination with 10 mg montelukast, in subjects with asthma. Mannitol was inhaled in the dose that caused a 20% fall in FEV(1) on the screening day. The prechallenge medications were randomised on the 3 treatment days and were (1) placebo sodium cromoglycate and placebo montelukast (2) sodium cromoglycate and placebo montelukast and (3) sodium cromoglycate and montelukast. The protection by sodium cromoglycate alone on the % fall in FEV(1) was 64.4% +/- 21.0% versus 65.8% +/- 62.8% (p = NS) on the combination. The protection on the area under the 30-min FEV(1) time curve for sodium cromoglycate was 81.8% +/- 14.0% (p <.04) and 89.3% +/- 9.8% for the combination (p <.001) compared with placebo. Recovery to 95% baseline FEV(1) by 5/10 min occurred in 58%/66% of subjects on sodium cromoglycate and 66%/83% on the combination compared with 0%/0% on placebo. The addition of montelukast to sodium cromoglycate provided only a small additional benefit against the airway response to mannitol.
Publisher: Elsevier BV
Date: 02-2011
Publisher: Wiley
Date: 23-07-2022
DOI: 10.1111/ALL.15431
Abstract: Allergy and respiratory disorders are common in young athletic in iduals. In the context of elite sport, it is essential to secure an accurate diagnosis in order to optimize health and performance. It is also important, however, to consider the potential impact or consequences of these disorders, in recreationally active in iduals engaging in structured exercise and/or physical activity to maintain health and well‐being across the lifespan. This EAACI Task Force was therefore established, to develop an up‐to‐date, research‐informed position paper, detailing the optimal approach to the diagnosis and management of common exercise‐related allergic and respiratory conditions. The recommendations are informed by a multidisciplinary panel of experts including allergists, pulmonologists, physiologists and sports physicians. The report is structured as a concise, practically focussed document, incorporating diagnostic and treatment algorithms, to provide a source of reference to aid clinical decision‐making. Throughout, we signpost relevant learning resources to consolidate knowledge and understanding and conclude by highlighting future research priorities and unmet needs.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.RMED.2019.09.011
Abstract: Citric acid has been used as a cough provocation test for decades. However, the methods of administration have not been standardized. Inhaled mannitol is a novel cough provocation test, which has regulatory approval and can be performed utilizing a simple disposable inhaler in a standardized manner. To compare the mannitol and citric acid cough provocation tests with respect to their ability to identify subjects with chronic cough and their tolerability. Subjects with chronic cough (n = 36) and controls (n = 25) performed provocation tests with mannitol and citric acid. Both tests were video recorded. Cough sensitivity was expressed as coughs-to-dose ratios (CDR) and the cumulative doses to mannitol or concentration to citric acid evoking 5 coughs (C5). Forced expiratory volume in 1 s (FEV Mannitol and citric acid CDR both effectively separated those with cough and the control subjects (AUC 0.847 and 0.803, respectively) as did C5 (AUC 0.823 and 0.763, respectively). There was a good correlation between the cough sensitivity provoked by the two stimuli, either expressed as CDR (r = 0.65, p < 0.001) or C5 (r = 0.53, p = 0.001). Both tests were similarly tolerated in terms of VAS, although more patients discontinued the mannitol test early, primarily due to cough. Mannitol and citric acid tests correlated well, equally identified subjects with chronic cough and their tolerability was similar. The feasibility issues, strict standardisation and regulatory approval may favour mannitol to be used in clinical cough research.
Publisher: Public Library of Science (PLoS)
Date: 24-02-2020
Publisher: Elsevier BV
Date: 10-2003
Abstract: To compare the sensitivity and validity of mannitol, histamine, and cold air challenges to demonstrate the effect of inhaled corticosteroids (ICS) in asthma. A prospective study. Seventeen patients with recently diagnosed, steroid-naive asthma who fulfilled the diagnostic criteria of Finnish Social Insurance Institution and were hyperresponsive to both mannitol and histamine. The following procedures were carried out at baseline and after 3 months and 6 months of treatment with inhaled budesonide, 800 microg/d: symptom assessment with a questionnaire, ambulatory peak expiratory flow (PEF) measurements twice daily for 2 weeks, and bronchial challenges with mannitol, histamine, and cold air. Budesonide decreased the sum symptom score, daily use of bronchodilating drugs, and diurnal PEF variation, but did not change FEV(1) percentage of predicted significantly. In addition, budesonide significantly decreased mannitol (p = 0.005) and histamine (p = 0.002) response dose ratios. The magnitude of the budesonide-induced change in responsiveness to these two challenges did not differ significantly. The effect of budesonide on cold air responsiveness did not reach statistical significance (p = 0.064). Change in mannitol responsiveness correlated significantly with the changes in sum symptom score and in FEV(1). Change in cold air responsiveness correlated with the changes in sum symptom score and in diurnal PEF variation. Change in histamine responsiveness correlated only with change in FEV(1). Mannitol challenge is both a sensitive and valid test to demonstrate the effects of ICS in asthma. Histamine challenge is equally sensitive for this purpose, but its validity may be lower than that of mannitol challenge. Cold air challenge seems to be a valid test to demonstrate the effects of ICS, but its sensitivity may be lower than that of mannitol and histamine challenges.
Publisher: Springer Science and Business Media LLC
Date: 2006
Publisher: Elsevier BV
Date: 03-2012
Publisher: Wiley
Date: 19-11-2007
DOI: 10.1111/J.1365-2222.2007.02878.X
Abstract: Airway hyperresponsiveness (AHR) to stimuli that cause bronchial smooth muscle (BSM) contraction indirectly through the release of endogenous mediators is thought to reflect airway inflammation more closely compared with AHR measured by stimuli that act directly on BSM. Fifty-three adult non-smoking asthmatics (28 females, 18-56 years) who were not taking inhaled steroids were challenged with mannitol (up to 635 mg) and methacholine (up to 8 mumol). Induced sputum eosinophils, exhaled nitric oxide (eNO), peak flow variation and clinical severity of asthma according to the Global Initiative for Asthma guidelines were measured in addition to the health-related quality-of-life score using the Juniper asthma quality-of-life questionnaire. Both AHR to mannitol as well as to methacholine was associated with elevated markers of airway inflammation: in 83% of asthma patients with AHR to mannitol, and in 88% of asthma patients with AHR to methacholine, the eNO level was >20 p.p.b. Sputum% eosinophils >1% was measured in 70% of asthma patients with AHR to mannitol and in 77% of asthma patients with AHR to methacholine. In asthma patients without AHR, 15% had an eNO level >20 p.p.b., but none had sputum% eosinophils >1%. AHR to mannitol was more closely associated with the percentage of sputum eosinophils (PD(15) to mannitol vs. sputum% eosinophils: r: -0.52, P<0.05), compared with AHR to methacholine (PD(20) to methacholine vs. sputum% eosinophils: r: -0.28, NS). Furthermore, there was a stronger correlation between AHR to mannitol and the level of eNO [PD(15) to mannitol vs. eNO (p.p.b.): r: -0.63, P<0.001], compared with AHR to methacholine [PD(20) to methacholine vs. eNO (p.p.b.): r: -0.43, P<0.05]. In asthma patients not being treated with steroids, AHR to mannitol and to methacholine indicated the presence of airway inflammation. AHR to mannitol reflected the degree of airway inflammation more closely when compared with methacholine.
Publisher: American Thoracic Society
Date: 10-1998
DOI: 10.1164/AJRCCM.158.4.9802087
Abstract: We investigated airway responsiveness to mannitol, a new hyperosmolar challenge, in persons hyperresponsive to airway drying. We studied 36 asthmatic subjects, 18 to 40 yr of age, responsive to exercise (n = 23) and eucapnic hyperventilation (n = 28) defined by a 10% fall in FEV1. Fifteen subjects performed both challenges. All subjects performed a challenge with dry powder mannitol, encapsulated and delivered via a Dinkihaler until a 15% decrease in FEV1 was documented or a cumulative dose of 635 mg was delivered. All subjects responsive to eucapnic hyperventilation and all but one subject responsive to exercise were responsive to mannitol. Sixty-nine percent of subjects had a positive response to mannitol after less than 155 mg (6 capsules) and 94% less than 320 mg (10 capsules). The provoking dose of mannitol required to cause a 15% fall in FEV1 (PD15) was related to the severity of the response to exercise (Pearson's correlation coefficient [rp] = 0.68, p < 0.01) and eucapnic hyperventilation (rp = 0.68, p < 0.01) in subjects who were not taking inhaled corticosteroids. The mean (+/- SD) maximum percent fall in FEV1 after mannitol was 24.4 +/- 6.2% and recovery to bronchodilator occurred within 10 min in most subjects. The mannitol test is simple, inexpensive, faster to perform than hyperpnea with dry air and could become an office-based test. Further studies are now required to determine the sensitivity of mannitol to identify exercise-induced asthma in a random population.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2011
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.IAC.2018.01.010
Abstract: Exercise-induced bronchoconstriction (EIB) is a form of airway hyperresponsiveness that occurs with or without current symptoms of asthma. EIB is an indicator of active and treatable pathophysiology in persons with asthma. The objective documentation of EIB permits the identification of an in idual who may be at risk during a recreational sporting activity or when exercising as an occupational duty. EIB can be identified with laboratory exercise testing or surrogate tests for EIB. These include eucapnic voluntary hyperpnea and osmotic stimuli (eg, inhaled mannitol) and offer improved diagnostic sensitivity to identify EIB and improved standardization when compared with laboratory exercise.
Publisher: BMJ
Date: 04-10-2012
Publisher: Springer Science and Business Media LLC
Date: 2003
Publisher: Informa UK Limited
Date: 10-2009
DOI: 10.1586/ERS.09.38
Abstract: 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.
Publisher: Wiley
Date: 14-05-2007
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2010
Publisher: S. Karger AG
Date: 2005
DOI: 10.1159/000083401
Abstract: i Background: /i 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. i Objectives: /i To investigate if responsiveness to HS can be estimated by questionnaire items investigating asthma symptoms of the last 3 months. i Methods: /i 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 FEV sub /sub (PD sub /sub ) and the response-dose ratio (RDR). i Results: /i 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 PD sub /sub 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 PD sub /sub , 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. i Conclusions: /i 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.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.ADDR.2018.04.003
Abstract: 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.
Publisher: Springer Science and Business Media LLC
Date: 12-2005
Abstract: Inhaled mannitol is a new bronchial provocation test (BPT) developed to improve portability and standardisation of osmotic challenge testing. Osmotic challenge tests have an advantage over the traditional methods of measuring airway hyperresponsiveness using methacholine as they demonstrate higher specificity to identify asthma and thus the need for treatment with inhaled corticosteroids (ICS). The safety and the efficacy of mannitol (M) as a BPT to measure airway hyperresponsiveness were compared to hypertonic (4.5%) saline (HS) in people both with and without signs and symptoms of asthma. A phase III, multi-centre, open label, operator-blinded, crossover design, randomised trial, with follow-up. Asthmatics and non-asthmatics (6–83 yr) were recruited and 592 subjects completed the study. Mannitol was delivered using a low resistance dry powder inhaler and HS was delivered using an ultrasonic nebuliser. The FEV 1 was measured 60 seconds after each dose of mannitol (5,10,20,40,80,160,160,160 mg) and after each exposure to HS (0.5,1.0,2.0,4.0,8.0 minutes). A 15% fall in FEV 1 defined a positive test. Adverse events were monitored and diaries kept for 7 days following the tests. Mean pre-test FEV1 (mean ± SD) was 95.5 ± 14% predicted. 296 were positive to mannitol (M+) and 322 positive to HS (HS+). A post study physician conducted clinical assessment identified 82.3% asthmatic (44% classified mild) and 17.7% non-asthmatic. Of those M+, 70.1% were taking ICS and of those mannitol negative (M-), 81.1 % were taking ICS. The % fall in FEV1 for mannitol in asthmatics was 21.0% ± 5.7 and for the non-asthmatics, 5.5% ± 4.8. The median PD15 M was 148 mg and PD15 HS 6.2 ml. The sensitivity of M to identify HS+ was 80.7% and the specificity 86.7%. The sensitivity of M compared with the clinical assessment was 59.8% and specificity 95.2% and increased to 88.7% and 95.0% respectively when the M- subjects taking ICS were excluded. Cough was common during testing. There were no serious adverse events. The diarised events were similar for mannitol and HS, the most common being headache (17.2%M, 19%HS), pharyngolaryngeal pain (5.1%M, 3%HS), nausea (4.3%M, 3%HS), and cough (2.2%M, 2.4%HS). The efficacy and safety of mannitol was demonstrated in non-asthmatic and clinically diagnosed asthmatic adults and children.
Publisher: Wiley
Date: 11-01-2009
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.JACI.2016.05.029
Abstract: The first practice parameter on exercise-induced bronchoconstriction (EIB) was published in 2010. This updated practice parameter was prepared 5 years later. In the ensuing years, there has been increased understanding of the pathogenesis of EIB and improved diagnosis of this disorder by using objective testing. At the time of this publication, observations included the following: dry powder mannitol for inhalation as a bronchial provocation test is FDA approved however not currently available in the United States if baseline pulmonary function test results are normal to near normal (before and after bronchodilator) in a person with suspected EIB, then further testing should be performed by using standardized exercise challenge or eucapnic voluntary hyperpnea (EVH) and the efficacy of nonpharmaceutical interventions (omega-3 fatty acids) has been challenged. The workgroup preparing this practice parameter updated contemporary practice guidelines based on a current systematic literature review. The group obtained supplementary literature and consensus expert opinions when the published literature was insufficient. A search of the medical literature on PubMed was conducted, and search terms included pathogenesis, diagnosis, differential diagnosis, and therapy (both pharmaceutical and nonpharmaceutical) of exercise-induced bronchoconstriction or exercise-induced asthma (which is no longer a preferred term) asthma and exercise and asthma. References assessed as relevant to the topic were evaluated to search for additional relevant references. Published clinical studies were appraised by category of evidence and used to document the strength of the recommendation. The parameter was then evaluated by Joint Task Force reviewers and then by reviewers assigned by the parent organizations, as well as the general membership. Based on this process, the parameter can be characterized as an evidence- and consensus-based document.
Publisher: Wiley
Date: 03-2002
DOI: 10.1046/J.1440-1843.2002.00357.X
Abstract: The aim of the study was to investigate whether treatment using inhaled corticosteroids decreases airway responsiveness to inhaled mannitol in asthmatic subjects. Before treatment or a change in treatment with inhaled corticosteroids, 18 asthmatic subjects had measurements of lung function and airway sensitivity to mannitol taken and they completed a self-administered questionnaire on asthma symptoms. The procedure was repeated 6-9 weeks after taking 800-2400 microg/day of budesonide. There were significant reductions in airway sensitivity (provoking dose to induce a 15% fall in FEV1 (PD15)) and airway reactivity measured by the response dose ratio (RDR final percentage fall FEV1/total dose of mannitol administered). The PD15 (Gmean (95%CI)) increased from 78 mg (51, 117) before treatment to 289 mg (202, 414) following treatment (P < 0.001). All subjects had a significant increase beyond the repeatability of 0.9 doubling doses with seven subjects becoming unresponsive. There was a 4.2 (3.4, 4.9)-fold improvement in the RDR with the value before the treatment period 0.18 (0.12, 0.28) decreasing to 0.04 (0.03, 0.08) following treatment (P < 0.001). These improvements were associated with significant improvements in lung function and symptom severity. Treatment with the inhaled corticosteroid budesonide caused a decrease in airway sensitivity and reactivity to inhaled mannitol and this was associated with expected improvements in lung function and symptoms.
Publisher: Springer Science and Business Media LLC
Date: 21-09-2012
Publisher: Wiley
Date: 26-08-2005
DOI: 10.1111/J.1440-1843.2005.00724.X
Abstract: 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. 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. 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). 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.
Publisher: BMJ
Date: 10-05-2010
Publisher: European Respiratory Society (ERS)
Date: 15-03-2018
Publisher: Elsevier BV
Date: 05-2002
Publisher: European Respiratory Society (ERS)
Date: 05-2006
DOI: 10.1183/09031936.06.00078205
Abstract: Mannitol inhalation increases urinary excretion of 9alpha,11beta-prostaglandin F2 (a metabolite of prostaglandin D2 and marker of mast cell activation) and leukotriene E4. The present study tested the hypothesis that beta2-adrenoreceptor agonists and disodium cromoglycate (SCG) protect against mannitol-induced bronchoconstriction by inhibition of mast cell mediator release. Fourteen asthmatic subjects inhaled mannitol (mean dose 252+/-213 mg) in order to induce a fall in forced expiratory volume in one second (FEV1) of > or = 25%. The same dose was given 15 min after inhalation of formoterol fumarate (24 microg), SCG (40 mg) or placebo. Pre- and post-challenge urine s les were analysed by enzyme immunoassay for 9alpha,11beta-prostaglandin F2 and leukotriene E4. The maximum fall in FEV1 of 32+/-10% on placebo was reduced by 95% following formoterol and 63% following SCG. Following placebo, there was an increase in median urinary 9alpha,11beta-prostaglandin F2 concentration from 61 to 92 ng.mmol creatinine(-1), but no significant increase in 9alpha,11beta-prostaglandin F2 concentration in the presence of either formoterol (69 versus 67 ng.mmol creatinine(-1)) or SCG (66 versus 60 ng.mmol creatinine(-1)). The increase in urinary leukotriene E4 following placebo (from 19 to 31 ng.mmol creatinine(-1)) was unaffected by the drugs. These results support the hypothesis that the drug effect on airway response to mannitol is due to inhibition of mast cell prostaglandin D2 release.
Publisher: Springer Science and Business Media LLC
Date: 10-05-2018
Publisher: Wiley
Date: 04-2000
DOI: 10.1002/(SICI)1099-0496(200004)29:4<291::AID-PPUL9>3.0.CO;2-A
Abstract: Inhaled mannitol has been developed for bronchial challenge testing in adults. This study determined if mannitol could identify children with active asthma and responsive to methacholine, and whether mannitol challenge was faster to complete than methacholine challenge. Twenty-five children (aged 6-13 years) responsive to methacholine and 10 nonasthmatic children unresponsive to methacholine were studied. The methacholine challenge (Cockcroft protocol) was followed by a mannitol challenge on separate days. Twenty-one asthmatic children were positive to mannitol. Three taking inhaled corticosteroids with borderline methacholine responsiveness did not respond to mannitol, and one could not complete the mannitol challenge due to cough. The geometric mean (GM) and 95% confidence interval (CI) for PD(15) for mannitol was 39 mg (19, 78), and PC(20) for methacholine was 0.6 mg/mL (0.35-1.02) (r(p) = 0.75, p < 0.001, n = 21). Responses to mannitol were repeatable: GM PD(15) for the first challenge was 29 mg (CI: 17,50), and for the second challenge, 33 mg (CI: 20, 55) (P = 0.44, n = 9). Mannitol was faster to administer than methacholine (median (range)) 14 min (5-32) vs. 29 min (19-49), respectively (P < 0.001). Time to recover to baseline FEV(1) spontaneously and after bronchodilator administration was similar for both challenges. There were no significant falls in arterial oxygen saturations. During mannitol challenge, the mean (SD) fall in FEV(1) in nonasthmatic children was 3.1% (2.9). We conclude that mannitol identifies children with airway hyperresponsiveness and is faster to perform than the methacholine challenge.
Publisher: Wiley
Date: 04-07-2013
Publisher: American Thoracic Society
Date: 05-2001
DOI: 10.1164/AJRCCM.163.6.2006019
Abstract: We studied, separately, the effects of the histamine antagonist, fexofenadine hydrochloride, and the leukotriene antagonist, montelukast sodium, and their placebos on airway sensitivity to and recovery from inhaled mannitol in subjects with asthma. Two 180-mg doses of fexofenadine were taken over 14 h, and three 10-mg doses of montelukast over 36 h, with the last dose 5 h before challenge. Fexofenadine reduced sensitivity to mannitol and the PD(15) was (mean [95% confidence interval] 138 [95, 201]) mg versus placebo (51 [25, 106] mg) (p < 0.001). The final percent reduction in FEV(1) with fexofenadine was 20.8 +/- 5.4% and not different from placebo (20.1 +/- 5.3%) (p = 0.7) however, recovery was slower with fexofenadine compared with placebo (p < 0.001). By contrast, montelukast had no effect on sensitivity to mannitol and the PD(15) was 71 [36, 144] mg versus placebo (87 [51, 148] mg (p = 0.35). The total dose of mannitol delivered and the final percent reduction in FEV(1) with montelukast were 171 +/- 142 mg and 21 +/- 4% and for placebo were 182 +/- 144 mg and 20 +/- 5% (p = 0.35, p = 0.59, respectively). However, recovery of FEV(1) to baseline was faster with montelukast, with the area under the percent reduction FEV(1)-versus-time curve reduced (220 +/- 121% change.min) compared with placebo (513 +/- 182% change.min) (p < 0.001). We conclude that whereas histamine is important for the initial airway response, leukotrienes are important in sustaining the airway response to inhaled mannitol.
Publisher: Elsevier BV
Date: 08-2010
Abstract: The two key pathophysiologic features of asthma are bronchial hyperresponsiveness (BHR) and airway inflammation. Symptoms and lung function are the most accessible clinical markers for the diagnosis of asthma as well as for assessing asthma control using the most effective treatment of asthma, inhaled corticosteroids (ICS). However, BHR and inflammation usually take longer to resolve using ICS compared with symptoms and lung function. BHR can be assessed using "direct" stimuli that act on the airway smooth muscle (eg, methacholine) or "indirect" stimuli that require the presence of airway inflammation (eg, exercise, osmotic stimuli). Although there are practical limitations in using BHR to assess asthma control, efforts have been made to make BHR more accessible and standardized. Some studies have demonstrated that treatment aimed to decrease BHR with direct stimuli can lead to improved asthma control however, it often results in the use of higher doses of ICS. Furthermore, BHR to direct stimuli does not usually resolve using ICS because of a fixed component. By contrast, BHR with an indirect stimulus indicates a responsive smooth muscle that occurs only in the presence of inflammation sensitive to ICS (eg, mast cells, eosinophils). BHR to indirect stimuli does resolve using ICS. Because ICS target both key pathophysiologic features of asthma, assessing indirect BHR in the presence of ICS will identify resolution or persistence of BHR and airway inflammation. This may provide a more clinically relevant marker for asthma control that may also lead to improving the clinical usefulness of ICS.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2010
Publisher: Wiley
Date: 22-01-2009
DOI: 10.1111/J.1365-2222.2008.03172.X
Abstract: Asthma is a chronic inflammatory disease of the airways characterized by physiological abnormalities of variable airflow obstruction and airway hyperresponsiveness (AHR) to a wide variety of physical and inhaled chemical stimuli and the presence of symptoms. AHR is measured by challenging the airways with a variety of agonists and naturally occurring stimuli, which results in constriction of the airway smooth muscle, leading to airway narrowing and airflow limitation. There are two distinct mechanisms by which the airways can narrow to a constrictor stimulus and these are defined by the pathways they take to induce AHR. Direct stimuli are pharmacological agents administered exogenously (such as histamine or methacholine) that act 'directly' on specific receptors on the bronchial smooth muscle to cause constriction. The other mechanism by which the airway can narrow is via the inhalation of indirect stimuli, which include natural stimuli, such as allergen or exercise, and pharmacological agents such as adenosine monophosphate and hyper-osmotic agents (e.g. hypertonic saline or dry powder mannitol). These stimuli induce airway narrowing 'indirectly' by causing the endogenous release of mediators of bronchoconstriction from airway inflammatory cells. Provoked models of asthma have been extremely valuable in understanding the pathobiology of asthma, in aiding diagnosis, in helping to clarify the mechanisms of actions of effective drugs and in the development of new entities to treat asthma. Some provoked models are valuable clinically, particularly those that measure direct AHR, while others, particularly allergen challenge, have been used in animal models and in humans to study the mechanisms of allergen-induced airway inflammation and the associated physiological changes, as well in the development of new drugs for asthma. An emerging role for measurements of AHR is in the evaluation of the optimal treatment for patients with asthma.
Publisher: European Respiratory Society (ERS)
Date: 09-2003
DOI: 10.1183/09031936.03.00113403
Abstract: The aim of this study was to investigate if mannitol inhalation, as a model of exercise-induced bronchoconstriction (EIB), causes mast cell activation and release of mediators of bronchoconstriction. Urinary excretion of previously identified mediators of EIB was investigated in association with mannitol-induced bronchoconstriction. Twelve asthmatic and nine nonasthmatic subjects inhaled mannitol and urine was collected 60 min before and for 90 min after challenge. The urinary concentrations of leukotriene (LT)E4, the prostaglandin (PG)D2 metabolite and the mast cell marker 9alpha,11beta-PGF2 were measured by enzyme immunoassay. N(tau)-methylhistamine was measured by radioimmunoassay. In asthmatic subjects, inhalation of a mean+/-SEM dose of 272+/-56 mg mannitol induced a reduction in forced expiratory volume in one second (FEV1) of 34.5+/-2.1%. This was associated with increases in urinary 9alpha,11beta-PGF2 (91.9+/-8.2 versus 66.9+/-6.6 ng x mmol creatinine(-1), peak versus baseline) and LTE4 (51.3+/-7.5 versus 32.9+/-4.7). In nonasthmatic subjects, the reduction in FEV1 was 1.0+/-0.5% after inhaling 635 mg of mannitol. Although smaller than in the asthmatics, significant increases of urinary 9alpha,11beta-PGF2 (68.4+/-6.9 versus 56.0+/-5.8 ng x mmol creatinine(-1)) and LTE4 (58.5+/-5.3 versus 43.0+/-3.3 ng x mmol creatinine(-1)) were observed in the nonasthmatic subjects. There was also a small increase in urinary excretion of N(tau)-methylhistamine in the nonasthmatics, but not in the asthmatics. The increased urinary levels of 9alpha,11beta-prostaglandin F2 support mast cell activation with release of mediators following inhalation of mannitol. Increased bronchial responsiveness to the released mediators could explain the exclusive bronchoconstriction in asthmatic subjects.
Publisher: Wiley
Date: 28-03-2019
DOI: 10.1111/RESP.13540
Abstract: Publicly funded therapy for idiopathic pulmonary fibrosis (IPF) relies on percentage predicted values from pulmonary function testing, for ex le Australian patients must have a forced vital capacity ≥50% (%FVC), transfer factor of the lung for carbon monoxide ≥ 30% (%TLco) and forced expiratory volume in 1 s (FEV FVC and TLco measurements from a large general respiratory laboratory and the Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR) database were analysed using multiple equations. Differences between %FVC and %TLco for each equation were calculated, with particular interest in classification of patients (%) at the threshold for subsidized treatment. A total of 20 378 general respiratory database results were analysed. The %FVC ≥ 50% increased from 86% with the Roca equation to 96% with Quanjer (European Coal and Steal Community, ECSC) and %TLco≥30% increased from 91% with Paoletti to 98% with Thompson. However, overall increase in eligibility for subsidized treatment was modest, varying from 48.2% to 49.2%. A total of 545 AIPFR database results were analysed. The %FVC ≥ 50% increased from 73% with Roca to 94% with Quanjer (ECSC) and %TLco≥30% increased from 87% with Paoletti to 96% with Miller. Overall eligibility for subsidized treatment in the AIPFR group varied from 73.6% to 82.8% between surveyed interstitial lung disease (ILD) centres based entirely on the equation used. Substantial variability exists between reference equations, impacting access to subsidized treatment. Treating clinicians should be aware of this when assessing patients around public funding thresholds.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2001
DOI: 10.1097/00005768-200106000-00007
Abstract: As new delivery devices and formulations are being introduced for drugs given by inhalation, there is a need to evaluate their equivalence with old preparations. One way to do this is to investigate their equivalence in protecting from exercise-induced asthma (EIA). We used a protocol for EIA to compare the protective effect of salbutamol delivered by the pressurised metered dose inhaler (pMDI) and the new Diskus dry powder device. Twenty-seven asthmatic subjects with moderately severe EIA completed an exercise test on four separate days at two study centers. Exercise was performed by cycling for 8 min while inhaling dry air (0% RH, 20-24 degrees C). The target workload in W was predicted as (53.76 x predicted FEV1) - 11.07 and 95% of this target was achieved at 4 min of exercise. This target was chosen in order to achieve ventilation between 50 and 60% of predicted maximum in the last 4 min. There was no significant difference in the workload, ventilation, or heart rate achieved on the study days. The severity of EIA was measured as the % fall in FEV1. EIA severity was similar on the placebo and control day and the coefficient of variation was 19.4%. The mean +/- SD % fall on the control, placebo, salbutamol by Diskus, and pMDI were 42.0% +/- 15, 39.4% +/-17.6, 13.4% +/- 13.2, and 8.5% +/- 13.8, respectively. Salbutamol significantly inhibited the % fall in FEV1 after exercise, and there was no difference between the preparations. The protocol described here is suitable for evaluating equivalence of salbutamol preparations in protecting against EIA and could be used to evaluate the protective effect of other medications.
Publisher: Wiley
Date: 06-2003
DOI: 10.1046/J.1365-2222.2003.01688.X
Abstract: 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. 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. 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. Compared to placebo, montelukast/desloratadine conferred improvements (P < 0.05) in adenosine monophosphate (AMP) threshold concentration and mannitol threshold dose: a 3.2-fold (95% CI 2.2-4.6) and 2.4-fold (95% CI 1.7-3.3) difference, respectively, while compared to montelukast this amounted to a 2.0-fold (95% CI 1.2-3.4) and 1.5-fold (95% CI 1.1-2.4) improvement, respectively. Montelukast was not significantly different from placebo. Both montelukast/desloratadine and montelukast compared to placebo, shortened recovery following both challenges (P < 0.05): a 27-min (95% CI 17-37) and 29-min (95% CI 20-36) reduction, respectively, for AMP, and a 27-min (95% CI 17-37) and 26-min (95% CI 17-35) reduction, respectively for mannitol. The dissociated effects of single doses of montelukast alone but not montelukast/desloratadine combination on AHR and recovery time, highlights the relative roles of histamine in initiating the bronchoconstrictor response and cysteinyl leukotrienes in sustaining it. Similar improvements in AHR and recovery time were observed following both indirect bronchoconstrictor stimuli.
Publisher: Mary Ann Liebert Inc
Date: 09-2002
DOI: 10.1089/089426802760292663
Abstract: Bronchial provocation testing with pharmacological agents that act directly on airway smooth muscle has important limitations. These include the inability to identify exercise-induced asthma (EIA), to differentiate the airway hyperresponsiveness (AHR) of airway remodelling from the AHR of active inflammation and to differentiate between doses of steroids. Recent studies show that tests that act indirectly to narrow airways are more sensitive than pharmacological agents for identifying airway inflammation and response to treatment. Adenosine monophosphate (AMP) is an indirect challenge that acts on mast cells to cause release of mediators. Hypertonic saline is another and, since its development in the 1980s, has become widely used in Australia. Hypertonic (4.5%) saline is used to identify those with active asthma, those with EIA and those who wish to enter certain occupations or sports (e.g., ing). The recent development, again in Australia, of a test that uses dry powder mannitol has promise for use in the laboratory, the office, or for testing in the field. AHR to mannitol identifies people with EIA and is an estimate of its severity. The mannitol response is modified by drugs used to prevent EIA, implying that similar mediators are involved. A mannitol test can be used to monitor response to steroids and is more sensitive than histamine for identifying persistent airway hyperresponsiveness in asthmatics well controlled on steroids. These findings suggest that indirect challenges give more useful clinical information about currently active asthma and the response to treatment than direct challenge and they will become more widely used.
Publisher: European Respiratory Society (ERS)
Date: 11-1997
DOI: 10.1183/09031936.97.10112449
Abstract: Inhalation of hypertonic saline stimulates mucociliary clearance (MCC) in healthy subjects and those with obstructive lung disease. We investigated the effect of inhaling the osmotic agent mannitol on MCC. We used a dry-powder preparation of mannitol British Pharmacopea (BP) which was encapsulated and delivered using a Dinkihaler. MCC was measured for 75 min in six asthmatic and six healthy subjects on two occasions before and after the mannitol inhalation or its control, using 99mTc-sulphur colloid and a gamma camera. The inhaled dose of mannitol was 267+/-171 mg (mean+/-SD) and 400 mg and the percentage fall in forced expiratory volume in one second (FEV1) was 22+/-3 and 4+/-2% in the asthmatic and healthy subjects, respectively. The total clearance in the whole right lung for the 60 min from the start of inhalation of mannitol was greater by 263+/-11.9% in the asthmatic and 18.1+/-4.9% in the healthy subjects compared to the control. The total clearance over 75 min was 54.7+/-9.6% and 33.6+/-9.4% on the mannitol and control day (p .002), respectively, in the asthmatic subjects and 40.5+/-7.1% and 24.8+/-7.8% (p .002) in the healthy subjects. In conclusion, inhalation of dry-powder mannitol increases mucociliary clearance in asthmatic and healthy subjects and may benefit patients with abnormal mucociliary clearance.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.JACI.2009.08.047
Abstract: Long-acting ss(2)-agonists are an established controller medication in asthma. BI 1744 is a novel L\\long-acting ss(2)-agonist with a preclinical profile that suggests 24-hour bronchodilation and bronchoprotection may be achieved. To examine the bronchoprotective effects of single doses of BI 1744 against methacholine provocation in subjects with mild asthma. Thirty-one subjects with mild asthma were randomized to receive single doses of BI 1744 (2, 5, 10, 20 microg) or placebo on separate days according to a double-blind, 5-way crossover design. Methacholine challenges were performed at 30 minutes and at 4, 8, 24, and 32 hours after each single dose of medication, and the results were expressed as PC(20) FEV(1). All doses of BI 1744 produced statistically significant increases in the methacholine PC(20) compared with placebo as long as 32 hours. The mean (geometric SEM) methacholine PC(20) 24 hours after dosing with placebo was 1.73 (1.13) mg/mL, which increased after 2 microg to 3.86 (1.14) mg/mL, after 5 microg to 5.67 (1.14) mg/mL, after 10 microg to 9.42 (1.13) mg/mL, and after 20 microg to 13.71 (1.14) mg/mL (all P < .0001). After 32 hours, the methacholine PC(20) value remained significantly increased for all doses. No safety or tolerability concerns were identified. BI 1744 provides significant bronchoprotection against inhaled methacholine for up to 32 hours after single-dose administration.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2018
Publisher: Informa UK Limited
Date: 10-02-2017
DOI: 10.1080/02770903.2016.1258076
Abstract: This study aimed to evaluate the effectiveness of an asthma first-aid training tool for childcare staff in Australia. The effects of training on both asthma knowledge and skills were assessed. A pre ost-study design was utilised to assess changes in asthma knowledge and asthma first-aid skills in childcare staff before and after an educational intervention. Asthma first-aid skills were assessed from the participant's response to two scenarios in which a child was having a severe exacerbation of asthma. Asthma knowledge and asthma skills scores were collected at base-line and 3 weeks post the education session, which involved feedback on each in idual's skills and a brief lecture on asthma delivered via PowerPoint presentation. There was a significant improvement after intervention in asthma knowledge (Z = -3.638, p < 0.001) and asthma first-aid skills for both scenario 1 (Z = -6.012, p < 0.001) and scenario 2 (Z = -6.018, p < 0.001). In scenario 1 and 2, first-aid skills improved by 65% (p < 0.001) and 57% (p < 0.001), respectively. Asthma knowledge was high at baseline (79%) and increased by 7% (p < 0.001) after the educational intervention. These asthma knowledge results were not significant when adjusted for prior knowledge. Results suggest that knowledge assessment alone may not predict the practical skills needed for asthma first-aid. Skills assessment is a useful adjunct to knowledge assessment when gauging the ability of childcare staff to manage acute asthma exacerbation. Skills assessment could be considered for incorporation into future educational interventions to improve management of acute asthma exacerbation.
Publisher: European Respiratory Society (ERS)
Date: 09-2001
DOI: 10.1183/09031936.01.00058601
Abstract: In steroid-naïve asthmatics, airway hyperresponsiveness correlates with noninvasive markers of airway inflammation. Whether this is also true in steroid-treated asthmatics, is unknown. In 31 stable asthmatics (mean age 45.4 yrs, range 22–69 17 females) taking a median dose of 1,000 µg inhaled corticosteroids (ICS) per day (range 100–3,600 µg·day −1 ), airway responsiveness to the “direct” agent histamine and to the “indirect” agent mannitol, lung function (forced expiratory volume in one second (FEV 1 ), forced vital capacity (FVC), peak expiratory flow (PEF)), exhaled nitric oxide (eNO), and number of inflammatory cells in induced sputum as a percentage of total cell count were measured. Of the 31 subjects, 16 were hyperresponsive to mannitol and 11 to histamine. The dose-response ratio (DRR: % fall in FEV 1 /cumulative dose) to both challenge tests was correlated (r=0.59, p=0.0004). However, DRR for histamine and DRR for mannitol were not related to basic lung function, eNO, per cent sputum eosinophils and ICS dose. In addition, NO was not related to basic lung function and per cent sputum eosinophils. In clinically well-controlled asthmatics taking inhaled corticosteroids, there is no relationship between markers of airway inflammation (such as exhaled nitric oxide and sputum eosinophils) and airway responsiveness to either direct (histamine) or indirect (mannitol) challenge. Airway hyperresponsiveness in clinically well-controlled asthmatics appears to be independent of eosinophilic airway inflammation.
Publisher: Wiley
Date: 10-07-2003
DOI: 10.1034/J.1398-9995.2003.00226.X
Abstract: 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. 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. For AMP PC20vs. mannitol PD15, the Pearsons correlation coefficient was 0.80, P < 0.001. For AMP PC15vs. mannitol PD15 and AMP PC10vs. mannitol PD10 corresponding values were 0.83, P < 0.001 and 0.68, P = 0.005. There was a highly significant association between the threshold concentration of AMP and dose of mannitol causing a given fall in FEV1. Further studies are required to evaluate the relationship between inhaled mannitol and other surrogate inflammatory markers.
Publisher: Wiley
Date: 07-08-2020
DOI: 10.1111/BPH.15197
Publisher: Elsevier BV
Date: 12-2003
Abstract: To compare a new bronchial provocation test, the mannitol challenge, with cold air and histamine challenges to demonstrate airway hyperresponsiveness (AHR) in patients with difficult-to-diagnose asthma. A prospective study. Thirty-seven consecutive patients with recently diagnosed, steroid-naive, mild, or atypical asthma fulfilling the diagnostic criteria of Finnish Social Insurance Institution, and 10 healthy control subjects. Each subject completed a symptom questionnaire and underwent spirometry, diffusion capacity measurement, skin-prick tests, and bronchial provocations with mannitol, histamine, and cold air. The severity of asthma was classified according to the Global Initiative for Asthma (GINA). Fifty-one percent of the asthmatic patients responded to mannitol (> or =15% fall in FEV(1)), 24% to cold air (> or =9% fall in FEV(1)), and 81% or 49% to histamine (provocative dose causing a 15% fall in FEV(1) [PD(15)] < 1.0 mg or < 0.4 mg, respectively). None of the healthy control subjects responded. The GINA classification was not associated with responsiveness to any of the challenges. Mannitol is more sensitive than cold air in demonstrating AHR in patients with mild or atypical asthma. Histamine was more sensitive than both mannitol and cold air if 1.0 mg was used as a cut-off value for histamine PD(15). However, if the cut-off value for histamine PD(15) is lowered to 0.4 mg, which represents a specific diagnosis of asthma according to previous studies, the sensitivity values of mannitol and histamine challenges are comparable.
Publisher: Informa UK Limited
Date: 12-2010
Abstract: Exercise-induced bronchoconstriction (EIB) is common in in iduals with asthma, and may be observed even in the absence of a clinical diagnosis of asthma. Exercise-induced bronchoconstriction can be diagnosed via standardized exercise protocols, and anti-inflammatory therapy with inhaled corticosteroids (ICS) is often warranted. Exercise-related symptoms are commonly reported in primary care however, access to standardized exercise protocols to assess EIB are often restricted because of the need for specialized equipment, as well as time constraints. Symptoms and lung function remain the most accessible indicators of EIB, yet these are poor predictors of its presence and severity. Evidence suggests that exercise causes the airways to narrow as a result of the osmotic and thermal consequences of respiratory water loss. The increase in airway osmolarity leads to the release of bronchoconstricting mediators (eg, histamine, prostaglandins, leukotrienes) from inflammatory cells (eg, mast cells and eosinophils). The objective assessment of EIB suggests the presence of airway inflammation, which is sensitive to ICS in association with a responsive airway smooth muscle. Surrogate tests for EIB, such as eucapnic voluntary hyperpnea or the osmotic challenge tests, cause airway narrowing via a similar mechanism, and a response indicates likely benefit from ICS therapy. The complete inhibition of EIB with ICS therapy in in iduals with asthma may be a useful marker of control of airway pathology. Furthermore, inhibition of EIB provides additional, useful information regarding the identification of clinical control based on symptoms and lung function. This article explores the inflammatory basis of EIB in asthma as well as the effect of ICS on the pathophysiology of EIB.
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.IAC.2013.02.010
Abstract: The role of epithelial injury is an unanswered question in those with established asthma and in elite athletes who develop features of asthma and exercise-induced bronchorestriction (EIB) after years of training. The movement of water in response to changes in osmolarity is likely to be an important signal to the epithelium that may be central to the onset of EIB. It is generally accepted that the mast cell and its mediators play a major role in EIB and the presence of eosinophils is likely to enhance EIB severity.
Publisher: American Physiological Society
Date: 04-2011
DOI: 10.1152/JAPPLPHYSIOL.00978.2010
Abstract: 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 (FEV 1 ). The urinary excretion (ng/mmol creatinine) of the mediators 9α,11β-prostaglandin (PG) F 2 and leukotriene (LT) E 4 were measured. The group mean fall in FEV 1 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 LTE 4 (95.6 ± 5.2 vs. 58.0 ± 2.4 for the 6 least refractory) ( P 0.001) and for 9α,11β-PGF 2 (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.
No related grants have been discovered for John Brannan.