Publications by authors named "John D Brannan"

46 Publications

Cough as an adverse effect on inhalation pharmaceutical products.

Br J Pharmacol 2020 09 7;177(18):4096-4112. Epub 2020 Aug 7.

Advanced Drug Delivery Group, Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.

Cough is an adverse effect that may hinder the delivery of drugs into the lungs. Chemical or mechanical stimulants activate the transient receptor potential in some airway afferent nerves (C-fibres or A-fibres) to trigger cough. Types of inhaler device and drug, dose, excipients and formulation characteristics, including pH, tonicity, aerosol output and particle size may trigger cough by stimulating the cough receptors. Release of inflammatory mediators may increase the sensitivity of the cough receptors to stimulants. The cough-provoking effect of aerosols is enhanced by bronchoconstriction in diseased airways and reduces drug deposition in the target pulmonary regions. In this article, we review the factors by which inhalation products may cause cough.
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http://dx.doi.org/10.1111/bph.15197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443471PMC
September 2020

Bronchial Provocation Testing for the Identification of Exercise-Induced Bronchoconstriction.

J Allergy Clin Immunol Pract 2020 Jul - Aug;8(7):2156-2164

Centre for Human Performance, Exercise and Rehabilitation, Brunel University London, Uxbridge, United Kingdom; Division of Sport, Health and Exercise Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom.

Exercise-induced bronchoconstriction (EIB) occurs in patients with asthma, children, and otherwise healthy athletes. Poor diagnostic accuracy of respiratory symptoms during exercise requires objective assessment of EIB. The standardized tests currently available are based on the assumption that the provoking stimulus to EIB is dehydration of the airway surface fluid due to conditioning large volumes of inhaled air. "Indirect" bronchial provocation tests that use stimuli to cause endogenous release of bronchoconstricting mediators from airway inflammatory cells include dry air hyperpnea (eg, exercise and eucapnic voluntary hyperpnea) and osmotic aerosols (eg, inhaled mannitol). The airway response to different indirect tests is generally similar in patients with asthma and healthy athletes with EIB. Furthermore, the airway sensitivity to these tests is modified by the same pharmacotherapy used to treat asthma. In contrast, pharmacological agents such as methacholine, given by inhalation, act directly on smooth muscle to cause contraction. These "direct" tests have been used traditionally to identify airway hyperresponsiveness in clinical asthma but are less useful to diagnose EIB. The mechanistic differences between indirect and direct tests have helped to elucidate the events leading to airway narrowing in patients with asthma and elite athletes, while improving the clinical utility of these tests to diagnose and manage EIB.
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http://dx.doi.org/10.1016/j.jaip.2020.03.034DOI Listing
December 2019

Prevalence and effects of gastro-oesophageal reflux during spirometry in subjects undergoing reflux assessment.

PLoS One 2020 24;15(2):e0229250. Epub 2020 Feb 24.

Department of Respiratory & Sleep Medicine, John Hunter Hospital, New Lambton, NSW, Australia.

Variability during spirometry can persist despite control of technical and personal factors. We postulate spirometry induces gastro-oesophageal reflux (GOR), which may cause variability and affect results of spirometry. Fifty-eight (58) subjects undergoing GOR investigation with oesophageal manometry and 24hr pH monitoring were recruited. Oesophageal dysmotility and GOR were assessed as part of clinical care. Subjects performed 2 sets of spirometry separated by a 10-minute rest period. The assessment of GOR during spirometry procedure (defined by a lower oesophageal pH<4) started from the first set of spirometry and concluded when the second set of spirometry was completed. We calculated variability (%) of FEV1, FVC and PEFR within each set as well as changes over 10-minutes. Twenty-six subjects (45%) recorded GOR during assessment. Of these, 23 subjects recorded GOR during the 10-minute rest period. Four subjects had GOR recorded only during spirometry tests. We did not find variability of spirometry parameters between the groups with and without GOR during spirometry procedure. However, in subjects with GOR, we found small but significant reductions of PEFR (0.5L/s, 8%, p<0.001) and FEV1 (84 mL, 3%, p = 0.048) in the second set of spirometry compared to the first spirometry set. This pilot study demonstrates that GOR can occur during and following spirometry. Presence of GOR during spirometry in this patient population caused small decreases in PEFR and FEV1 when it is repeated 10-minutes later however not increase variability in a single series of measurements.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229250PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039503PMC
June 2020

Comparison of mannitol and citric acid cough provocation tests.

Respir Med 2019 Oct - Nov;158:14-20. Epub 2019 Sep 16.

Division of Respiratory Medicine, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, POB 1627, 70211, Kuopio, Finland; Center of Medicine and Clinical Research, Division of Respiratory Medicine, Kuopio University Hospital, POB 100, 70029, Kuopio, Finland.

Rationale: 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.

Objective: To compare the mannitol and citric acid cough provocation tests with respect to their ability to identify subjects with chronic cough and their tolerability.

Methods: 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), visual analogue scales (VAS), test completion rates and the total cough frequencies were analysed.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.rmed.2019.09.011DOI Listing
August 2020

Eligibility for anti-fibrotic treatment in idiopathic pulmonary fibrosis depends on the predictive equation used for pulmonary function testing.

Respirology 2019 10 28;24(10):988-995. Epub 2019 Mar 28.

Respiratory Department, John Hunter Hospital (JHH), Newcastle, NSW, Australia.

Background And Objective: Publicly funded therapy for idiopathic pulmonary fibrosis (IPF) relies on percentage predicted values from pulmonary function testing, for example 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 ratio > 0.7. Despite defined cut-off values, no jurisdiction prescribes a reference equation for use; multiple equations exist. We hypothesized that access to subsidized treatment varies depending on the chosen equation. The %FVC and %TLco from different commonly used reference equations across general respiratory patients, and IPF-specific patients, were compared.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1111/resp.13540DOI Listing
October 2019

Loss of bronchoprotection to Salbutamol during sputum induction with hypertonic saline: implications for asthma therapy.

Allergy Asthma Clin Immunol 2018 10;14:26. Epub 2018 May 10.

1Firestone Institute for Respiratory Health, St. Joseph's Healthcare, 50 Charlton Avenue East, Hamilton, ON L8N 4A6 Canada.

Background: Sputum induction with hypertonic saline in obstructive airway diseases is generally safe. However, saline induces bronchoconstriction in some patients despite pre-medication with Salbutamol. Our objectives were to investigate the predictors of failure of Salbutamol to protect against saline-induced-bronchoconstriction in patients with asthma and COPD and to evaluate implications for asthma therapy.

Methods: Retrospective survey on a database of 3565 patients with obstructive airway diseases who had sputum induced with hypertonic saline. The effect of baseline FEV, bronchitis and concomitant medication on saline-induced-bronchoconstriction (≥ 15% drop in FEV) were examined by logistic regression analysis. A subgroup had this re-examined 8-12 weeks after decreasing long-acting-beta-2-agonist dose or after adding Montelukast, which included an assessment of mast cell activity in sputum.

Results: 222 (6.2%) patients had saline-induced-bronchoconstriction despite pre-treatment with inhaled Salbutamol. Baseline airflow obstruction (FEV% predicted < 60% OR 3.29, p < 0.001) and long-acting-beta-agonist use (OR 2.02, p = 0.001), but not bronchitis, were predictors of saline-induced-bronchoconstriction, which decreased when long-acting-beta-agonist dose was decreased. Refractoriness to subsequent bronchodilation was associated with mast cell activity and was attenuated by Montelukast.

Conclusion: Sputum induction with saline provides information on bronchitis and additional physiological data on tolerance to beta-agonists and mast cell activity that may have implications for clinical therapy.
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http://dx.doi.org/10.1186/s13223-018-0256-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975466PMC
May 2018

Testing for Exercise-Induced Bronchoconstriction.

Immunol Allergy Clin North Am 2018 05;38(2):215-229

Respiratory Research Unit, Department of Respiratory Medicine, Bispebjerg Hospital, Bispebjerg Bakke 23, Copenhagen 2400, Denmark.

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 individual 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.
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http://dx.doi.org/10.1016/j.iac.2018.01.010DOI Listing
May 2018

Repurposing excipients as active inhalation agents: The mannitol story.

Adv Drug Deliv Rev 2018 08 5;133:45-56. Epub 2018 Apr 5.

Pharmaceutics, Pharmacology and Pharmaceutical Sciences, University of Sydney, Sydney, NSW 2006, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.addr.2018.04.003DOI Listing
August 2018

Cough sensitivity to mannitol inhalation challenge identifies subjects with chronic cough.

Eur Respir J 2018 05 17;51(5). Epub 2018 May 17.

Dept of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton, Australia.

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http://dx.doi.org/10.1183/13993003.00294-2018DOI Listing
May 2018

The efficacy and safety of mannitol challenge in a workplace setting for assessing asthma prevalence.

J Asthma 2018 12 4;55(12):1278-1285. Epub 2018 Jan 4.

a Department of Medicine , Medical School of Ribeirão Preto, University of São Paulo , Ribeirão Preto , São Paulo , Brazil.

Objective: There is no standard definition of asthma for epidemiological purposes; most surveys use symptoms and bronchial hyperresponsiveness. Few studies tested mannitol challenge test (MCT) in occupational settings. We sought to determine efficacy and safety of MCT in detecting subjects with asthma symptoms in the workplace.

Methods: In this cross-sectional study we recruited 908 workers in 2 universities; they underwent a respiratory questionnaire, spirometry, skin prick tests, and MCT.

Results: Eight hundred and eleven subjects completed the study; 11.1% had a positive MCT; 8.14% had asthma. MCT had low sensitivity (35.4-61.9%) but high specificity (90.2-94.9%) to detect symptomatic individuals. The most prevalent symptom was wheezing in the last 12 months. Twenty-four of those with a positive MCT (26.7%) had no positive replies to the questions on asthma symptoms. Among subjects with a positive MCT, 71.9% achieved 95% of baseline FEV after 15 minutes of salbutamol recovery treatment. Nine subjects (1.1%) had adverse events that prevented the test from being completed.

Conclusions: MCT has high specificity but low sensitivity to detect symptomatic subjects in the workplace. It may detect subjects with hyperresponsiveness but no symptoms, who could be at risk of developing airway diseases. The test is safe and well tolerated.
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http://dx.doi.org/10.1080/02770903.2017.1418887DOI Listing
December 2018

Exercise-induced Bronchoconstriction with Firefighting Contained Breathing Apparatus.

Med Sci Sports Exerc 2018 02;50(2):327-333

Thoracic Medicine, Concord Hospital, Sydney, AUSTRALIA.

Purpose: Protective self-contained breathing apparatus (SCBA) used for firefighting delivers decompressed (cold) dehumidified air that may enhance the severity of exercise-induced bronchoconstriction (EIB) in those susceptible. We investigated the effect of SCBA during exercise on airway caliber in people with asthma and healthy controls.

Methods: Two exercise challenges (EC) designed to elicit EIB were performed on separate days within 1 wk. The initial challenge was breathing room air (ECRA) with workload titrated to elicit >60% estimated maximum voluntary ventilation. The exercise intensity was repeated for the second challenge using SCBA (ECSCBA). Forced expiratory volume in 1 s (FEV1) was measured before and up to 20 min after exercise. Bronchial hyperresponsivenss (BHR) to the hyperosmolar mannitol test was measured in the subjects with asthma.

Results: Twenty subjects with current asthma (mean [SD]: age 27 [6] yr) and 10 healthy controls (31 [5] yr, P = 0.1) were studied. The percent fall in FEV1 after ECSCBA was greater in the mannitol-positive asthma subjects (14.4% [15.1%]) compared with mannitol-negative asthmatic subjects (1.6% [1.7%]; P = 0.02) and controls (2.3% [2.3%]; P = 0.04). The FEV1 response was not different between ECRA and ECSCBA (0.49% [5.57%]; P = 0.6). No BHR to mannitol (n = 7) was highly sensitive for identifying a negative response to ECSCBA (negative predictive value 100%).

Conclusions: The SCBA does not increase the propensity or severity for EIB in subjects with BHR. Those subjects with asthma but no BHR to inhaled mannitol did not exhibit EIB. The BHR to a hyperosmolar stimulus maybe considered a useful screening tool for potential recruits with a history of asthma.
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http://dx.doi.org/10.1249/MSS.0000000000001424DOI Listing
February 2018

Improving childcare staff management of acute asthma exacerbation - An Australian pilot study.

J Asthma 2017 Sep 11;54(7):732-740. Epub 2016 Nov 11.

b Department of Pharmacy, University of Sydney , Camperdown Campus , Sydney , Australia.

Objective: 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.

Methods: A pre/post-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 individual's skills and a brief lecture on asthma delivered via PowerPoint presentation.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1080/02770903.2016.1258076DOI Listing
September 2017

The effect of device resistance and inhalation flow rate on the lung deposition of orally inhaled mannitol dry powder.

Int J Pharm 2016 Nov 14;513(1-2):294-301. Epub 2016 Sep 14.

Advanced Drug Delivery Group, Faculty of Pharmacy (A15), Science Road, University of Sydney, NSW 2006, Australia. Electronic address:

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 Tc-DTPA was inhaled from an Osmohaler™ by healthy human volunteers at 50-70L/min peak inhalation flow rate (PIFR) using both a low and high resistance Osmohaler™, and 110-130L/min PIFR using the low resistance Osmohaler™ (n=9). At 50-70L/min PIFR, the resistance of the Osmohaler™ did not significantly affect the total and peripheral lung deposition of inhaled mannitol [for low resistance Osmohaler™, 20% total lung deposition (TLD), 0.3 penetration index (PI); for high resistance Osmohaler™, 17% TLD, 0.23 PI]. Increasing the PIFR 50-70L/min to 110-130L/min (low resistance Osmohaler™) significantly reduced the total lung deposition (10% TLD) and the peripheral lung deposition (PI 0.21). The total lung deposition showed dependency on the in vitro FPF (R=1.0). On the other hand, the PI had a stronger association with the MMAD (R=1.0) than the FPF (R=0.7). In conclusion the resistance of Osmohaler™ did not significantly affect the total and regional lung deposition at 50-70L/min PIFR. Instead, the total and regional lung depositions are dependent on the particle size of the aerosol and inhalation flow rate, the latter itself affecting the particle size distribution.
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http://dx.doi.org/10.1016/j.ijpharm.2016.09.047DOI Listing
November 2016

Exercise-induced bronchoconstriction update-2016.

J Allergy Clin Immunol 2016 11 21;138(5):1292-1295.e36. Epub 2016 Sep 21.

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.
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http://dx.doi.org/10.1016/j.jaci.2016.05.029DOI Listing
November 2016

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

J Aerosol Med Pulm Drug Deliv 2015 Dec 6;28(6):452-61. Epub 2015 Apr 6.

1 Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney , Sydney, New South Wales, Australia .

Background: Currently bronchial provocation testing (BPT) using mannitol powder cannot be performed in children under 6 years. A primary reason is it is challenging for children at this age to generate a consistent inspiratory effort to inhale mannitol efficiently from a dry powder inhaler. A prototype system, which does not require any inhalation training from the pediatric subject, is reported here. It uses an external source of compressed air to disperse mannitol powder into a commercial holding chamber. Then the subject uses tidal breathing to inhale the aerosol.

Method: The setup consists of a commercially available powder disperser and Volumatic™ holding chamber. Taguchi experimental design was used to identify the effect of dispersion parameters (flow rate of compressed air, time compressed air is applied, mass of powder, and the time between dispersion and inhalation) on the fine particle dose (FPD). The prototype was tested in vitro using a USP throat connected to a next generation impactor. The aerosols from the holding chamber were drawn at 10 L/min. A scaling factor for estimating the provoking dose to induce a 15% reduction in forced expiratory volume in 1 second (FEV1) (PD15) was calculated using anatomical dimensions of the human respiratory tract at various ages combined with known dosing values from the adult BPT.

Results: Consistent and doubling FPDs were successfully generated based on the Taguchi experimental design. The FPD was reliable over a range of 0.8 (±0.09) mg to 14 (±0.94) mg. The calculated PD15 for children aged 1-6 years ranged from 7.1-30 mg. The FPDs generated from the proposed set up are lower than the calculated PD15 and therefore are not expected to cause sudden bronchoconstriction.

Conclusion: A prototype aerosol delivery system has been developed that is consistently able to deliver doubling doses suitable for bronchial provocation testing in young children.
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http://dx.doi.org/10.1089/jamp.2015.1208DOI Listing
December 2015

The effect of omega-3 fatty acids on bronchial hyperresponsiveness, sputum eosinophilia, and mast cell mediators in asthma.

Chest 2015 Feb;147(2):397-405

Firestone Institute for Respiratory Health, St. Joseph's Healthcare and McMaster University, Hamilton, ON, Canada.

Background: Omega-3 fatty acid supplements have been reported to inhibit exercise-induced bronchoconstriction (EIB). It has not been determined whether omega-3 supplements inhibit airway sensitivity to inhaled mannitol, a test for bronchial hyperresponsiveness (BHR) and model for EIB in people with mild to moderate asthma.

Methods: In a double-blind, crossover trial, subjects with asthma who had BHR to inhaled mannitol (n = 23; 14 men; mean age, 28 years; one-half taking regular inhaled corticosteroids) were randomized to omega-3 supplements (4.0 g/d eicosapentaenoic acid and 2.0 g/d docosahexaenoic acid) or matching placebo for 3 weeks separated by a 3-week washout. The primary outcome was the provoking dose of mannitol (mg) to cause a 15% fall in FEV1 (PD15). Secondary outcomes were sputum eosinophil count, spirometry, Asthma Control Questionnaire (ACQ) score, serum triacylglyceride level, and lipid mediator profile in urine and serum.

Results: PD15 (geometric mean, 95% CI) to mannitol following supplementation with omega-3s (78 mg, 51-119 mg) was not different from placebo (88 mg, 56-139 mg, P = .5). There were no changes in sputum eosinophils (mean ± SD) in a subgroup of 11 subjects (omega-3, 8.4% ± 8.2%; placebo, 7.8% ± 11.8%; P = .9). At the end of each treatment period, there were no differences in FEV1 % predicted (omega-3, 85% ± 13%; placebo, 84% ± 11%; P = .9) or ACQ score (omega-3, 1.1% ± 0.5%; placebo, 1.1% ± 0.5%; P = .9) (n = 23). Omega-3s caused significant lowering of blood triglyceride levels and expected shifts in serum fatty acids and eicosanoid metabolites, confirming adherence to the supplements; however, no changes were observed in urinary mast cell mediators.

Conclusions: Three weeks of omega-3 supplements does not improve BHR to mannitol, decrease sputum eosinophil counts, or inhibit urinary excretion of mast cell mediators in people with mild to moderate asthma, indicating that dietary omega-3 supplementation is not useful in the short-term treatment of asthma.

Trial Registry: ClinicalTrials.gov; No.: NCT00526357; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1378/chest.14-1214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314816PMC
February 2015

Where to from here for exercise-induced bronchoconstriction: the unanswered questions.

Immunol Allergy Clin North Am 2013 Aug 29;33(3):423-42, ix. Epub 2013 Mar 29.

Division of Pulmonary and Critical Care, University of Washington, Department of Medicine, 1959 NE Pacific Street, Box 356166, Seattle, WA 98195-6522, USA.

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.
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http://dx.doi.org/10.1016/j.iac.2013.02.010DOI Listing
August 2013

Lipid mediator serum profiles in asthmatics significantly shift following dietary supplementation with omega-3 fatty acids.

Mol Nutr Food Res 2013 Aug 4;57(8):1378-89. Epub 2013 Jul 4.

Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden.

Scope: In contrast to well-characterized PUFA levels in serum, little is known regarding their downstream metabolic products. However, many of these compounds are lipid mediators with prominent roles during pro- and antiinflammatory processes.

Methods And Results: In this double blind crossover study on asthmatics, shifts in serum levels of ω-3 and ω-6 PUFA-derived oxidized fatty acids (e.g. eicosanoids, oxylipins) were quantified following dietary fish oil supplementation. Serum was obtained from subjects following fasting at three occasions; (i) prior to supplementation, (ii) following a 3-week supplement intake of either placebo or fish oil, and (iii) following a 3-week washout period with a subsequent 3-week period of either fish oil or placebo supplement. A total of 87 oxylipins representing cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) metabolic pathways were screened via LC-MS/MS. The primary alterations observed were in CYP- and 15-LOX-derived EPA- and CYP-derived DHA oxylipins.

Conclusion: The results indicate that intake of an ω-3 rich diet alters not only the PUFA ratio, but also the ratio of downstream oxylipins. These data further support that dietary manipulation with ω-3 PUFAs affects not only PUFA levels, but importantly also the downstream metabolic profile.
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http://dx.doi.org/10.1002/mnfr.201200827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943463PMC
August 2013

Airway hyperresponsiveness in asthma: mechanisms, clinical significance, and treatment.

Front Physiol 2012 10;3:460. Epub 2012 Dec 10.

Respiratory Function Laboratory, Department of Respiratory and Sleep Medicine, Westmead Hospital Sydney, NSW, Australia.

Airway hyperresponsiveness (AHR) and airway inflammation are key pathophysiological features of asthma. Bronchial provocation tests (BPTs) are objective tests for AHR that are clinically useful to aid in the diagnosis of asthma in both adults and children. BPTs can be either "direct" or "indirect," referring to the mechanism by which a stimulus mediates bronchoconstriction. Direct BPTs refer to the administration of pharmacological agonist (e.g., methacholine or histamine) that act on specific receptors on the airway smooth muscle. Airway inflammation and/or airway remodeling may be key determinants of the response to direct stimuli. Indirect BPTs are those in which the stimulus causes the release of mediators of bronchoconstriction from inflammatory cells (e.g., exercise, allergen, mannitol). Airway sensitivity to indirect stimuli is dependent upon the presence of inflammation (e.g., mast cells, eosinophils), which responds to treatment with inhaled corticosteroids (ICS). Thus, there is a stronger relationship between indices of steroid-sensitive inflammation (e.g., sputum eosinophils, fraction of exhaled nitric oxide) and airway sensitivity to indirect compared to direct stimuli. Regular treatment with ICS does not result in the complete inhibition of responsiveness to direct stimuli. AHR to indirect stimuli identifies individuals that are highly likely to have a clinical improvement with ICS therapy in association with an inhibition of airway sensitivity following weeks to months of treatment with ICS. To comprehend the clinical utility of direct or indirect stimuli in either diagnosis of asthma or monitoring of therapeutic intervention requires an understanding of the underlying pathophysiology of AHR and mechanisms of action of both stimuli.
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http://dx.doi.org/10.3389/fphys.2012.00460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517969PMC
December 2012

Warm-up exercise can reduce exercise-induced bronchoconstriction.

Br J Sports Med 2013 Jul 4;47(10):657-8. Epub 2012 Oct 4.

Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1136/bjsports-2012-091725DOI Listing
July 2013

Cough response to isocapnic hyperpnoea of dry air and hypertonic saline are interrelated.

Cough 2011 Oct 14;7(1). Epub 2011 Oct 14.

Department of Respiratory Medicine, Kuopio University Hospital, P,O, Box 1777, 70211 Kuopio, Finland.

Background: Mechanisms behind asthmatic cough are largely unknown. It is known that hyperosmolar challenges provoke cough in asthmatic but not in the healthy subjects. It has been postulated that isocapnic hyperpnea of dry air (IHDA) and hypertonic aerosols act via similar mechanisms in asthma to cause bronchoconstriction. We investigated whether there is an association between cough response induced by IHDA and hypertonic saline (HS) challenges.

Methods: Thirty-six asthmatic and 14 healthy subjects inhaled HS solutions with increasing osmolalities administered via ultrasonic nebuliser until 15 cumulative coughs were recorded. The IHDA consisted of three three-minute ventilation steps: 30%, 60% and 100% of maximal voluntary ventilation with an end-point of 30 cumulative coughs. The challenges were performed on separate days at least 48 hours between them and within one week. Inhaled salbutamol (400 mcg) was administered before the challenges to prevent bronchoconstriction. The cough response was expressed as the cough-to-dose ratio (CDR) which is the total number of coughs divided by the maximal osmolality inhaled or the maximal ventilation achieved.

Results: Cough response to IHDA correlated with the HS challenge (Rs = 0.59, p < 0.001). Cough response to IHDA was at its strongest during the first minute after the challenge. IHDA induced more cough among asthmatic than healthy subjects CDR being (mean ± SD) 0.464 ± 0.514 and 0.011 ± 0.024 coughs/MVV%, p < 0.001, respectively. Salbutamol effectively prevented bronchoconstriction to both challenges.

Conclusions: Asthmatic patients are hypersensitive to the cough-provoking effect of hyperpnoea, as they are to hypertonicity. Cough response induced by IHDA and HS correlated well suggesting similar mechanisms behind the responses.
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http://dx.doi.org/10.1186/1745-9974-7-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205007PMC
October 2011

Feasibility and acceptability of using bronchial hyperresponsiveness to manage asthma in primary care: a pilot study.

Prim Care Respir J 2012 Mar;21(1):28-34

Medical School, Australian National University, Canberra, ACT 2606, Australia.

Aims: To determine if indirect testing for bronchial hyperresponsiveness (BHR) to monitor inhaled corticosteroid (ICS) treatment in asthma is feasible and acceptable in primary care.

Methods: Fourteen adult patients with asthma aged 22-70 years (4M:10F, forced expiratory volume in 1 s >70% predicted) taking ICS performed a test for BHR using mannitol on three visits 6 weeks apart. ICS dose adjustments were made based on the presence of BHR. The Asthma Quality of Life Questionnaire (AQLQ) and the Asthma Control Questionnaire were used at each visit. A semi structured interview at study exit assessed subject acceptability.

Results: BHR did not return in those with no BHR at study entry (n=9) with decreasing ICS dose. Improvements in BHR with increasing ICS dose (n=5) were observed with clinically significant improvements in AQLQ (mean score increase >0.5, p=0.02). Feasibility and acceptability of BHR testing was demonstrated.

Conclusions: It is feasible and acceptable to perform BHR testing using mannitol to help identify patients with asthma who would benefit from ICS dose increases and those with no BHR who could have a dose reduction.

Trial Registration: Australia New Zealand Clinical Trial Registry ACTRN12610000807055.
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http://dx.doi.org/10.4104/pcrj.2011.00079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547886PMC
March 2012

The occurrence of refractoriness and mast cell mediator release following mannitol-induced bronchoconstriction.

J Appl Physiol (1985) 2011 Apr 20;110(4):1029-35. Epub 2011 Jan 20.

The Unit for Experimental Asthma and Allergy Research, Division of Physiology, The National Institute of EnvironmentalMedicine, Sweden.

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.
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http://dx.doi.org/10.1152/japplphysiol.00978.2010DOI Listing
April 2011

Bronchial provocation testing: the future.

Curr Opin Allergy Clin Immunol 2011 Feb;11(1):46-52

Department of Respiratory & Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.

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.
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http://dx.doi.org/10.1097/ACI.0b013e3283423183DOI Listing
February 2011

The inflammatory basis of exercise-induced bronchoconstriction.

Phys Sportsmed 2010 Dec;38(4):67-73

Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, New South Wales, Australia.

Exercise-induced bronchoconstriction (EIB) is common in individuals 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 individuals 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.
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http://dx.doi.org/10.3810/psm.2010.12.1827DOI Listing
December 2010

Bronchial hyperresponsiveness in the assessment of asthma control: Airway hyperresponsiveness in asthma: its measurement and clinical significance.

Authors:
John D Brannan

Chest 2010 Aug;138(2 Suppl):11S-17S

Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.

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.
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http://dx.doi.org/10.1378/chest.10-0231DOI Listing
August 2010

Sodium cromoglycate alone and in combination with montelukast on the airway response to mannitol in asthmatic subjects.

J Asthma 2010 May;47(4):429-33

Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.

Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: The addition of montelukast to sodium cromoglycate provided only a small additional benefit against the airway response to mannitol.
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http://dx.doi.org/10.3109/02770900903584043DOI Listing
May 2010

Inhaled mannitol as a test for bronchial hyper-responsiveness.

Expert Rev Respir Med 2009 Oct;3(5):457-68

Department of Respiratory and Sleep Medicine, 11 West, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia.

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.
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http://dx.doi.org/10.1586/ers.09.38DOI Listing
October 2009