Publications (34)137.58 Total impact
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Article: Effect of methacholine on peripheral lung mechanics and ventilation heterogeneity in asthma.
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ABSTRACT: Background: The forced oscillation technique (FOT) and multiple breath nitrogen washout (MBNW) are non-invasive tests that are potentially sensitive to peripheral airways, with MBNW indices being especially sensitive to heterogeneous changes in ventilation. Objective: To study methacholine-induced changes in the lung periphery of asthmatic patients and determine how changes in FOT variables respiratory system reactance (Xrs), resistance (Rrs) and frequency dependence of resistance (Rrs(5)-Rrs(19)) can be linked to changes in ventilation heterogeneity. The contributions of air trapping and airway closure, as extreme forms of heterogeneity, are also investigated. Methods: Xrs(5), Rrs(5), Rrs(19), Rrs(5)-Rrs(19) and inspiratory capacity (IC) were calculated from the FOT. Ventilation heterogeneity in acinar (S(acin)) and conducting (S(cond)) airways, and trapped gas (%VtrFRC/VC) were calculated from the MBNW. Measurements were repeated following methacholine. Methacholine-induced airway closure (percent change in forced vital capacity (FVC)) and hyperinflation (change in IC) were also recorded. Results: In 40 mild to moderate asthmatics, increase in Xrs(5) after methacholine was predicted by increases in S(acin) and FVC (r(2) = 0.37, p<0.001), but had no correlation with S(cond) increase, or IC decrease. Increases in Rrs(5) and Rrs(5)-Rrs(19) after methacholine were not correlated with increases in ventilation heterogeneity, trapped gas, hyperinflation or airway closure. Conclusion: Increased reactance in asthmatics after methacholine was indicative of heterogeneous changes in the lung periphery and airway closure. By contrast, increases in resistance and frequency dependence of resistance were not related to ventilation heterogeneity or airway closure, and were more indicative of changes in central airway calibre than of heterogeneity.Journal of Applied Physiology 01/2013; · 3.75 Impact Factor -
Article: The feasibility of home monitoring of impedance with the forced oscillation technique in chronic obstructive pulmonary disease subjects.
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ABSTRACT: Respiratory system resistance (Rrs) and reactance (Xrs) measured by forced oscillation technique (FOT) can be potentially used for home monitoring in COPD. Our aims were to determine the technical acceptability, adherence and variability of unsupervised, home FOT measurements over ten consecutive days. Supervised spirometry and FOT measurements were made on ten clinically stable COPD subjects at their homes at the study initiation. Subjects then self-recorded FOT twice daily for ten consecutive days with data transmitted to the laboratory server via a 3G mobile network. Subjects had a mean (SD) age of 68(8) years, smoking history 38.4(8.7) pack/years, post-bronchodilator FEV1 42.4(12.0)% predicted, FEV1/FVC ratio 0.45(0.10), mean Rrs 121.7(26.1)% predicted and mean Xrs 746.8(330.3)% predicted. The supervised measurements of mean Rrs and mean Xrs were similar to the unsupervised measurements (p = 0.34 and p = 0.92, respectively). 197 of 200 possible measurements were transmitted, all of which were deemed to be technically acceptable. The within-subject standard deviation, Sw, of Rrs-total and Xrs-total were 0.47 and 1.0 cmH(2)O L s(-1), respectively. Subjects who have COPD make reliable, unsupervised FOT measurements at home with a high degree of adherence. The day-to-day variability of FOT measurements was similar to that of supervised laboratory recordings. These results support the conduct of larger, longer-term studies of FOT monitoring in COPD.Physiological Measurement 12/2012; 34(1):67-81. · 1.68 Impact Factor -
Article: Day-to-day variability of oscillatory impedance and spirometry in asthma and COPD.
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ABSTRACT: Variability in airway function may be a marker of disease activity in COPD and asthma. The aim was to determine the effects of repeatability and airway obstruction on day-to-day variability in respiratory system resistance (Rrs) and reactance (Xrs) measured by forced oscillation technique (FOT). Three groups of 10 subjects; normals, stable asthmatic and stable COPD subjects underwent daily FOT recordings for 7 days. Mean total and inspiratory Rrs and Xrs, and expiratory flow limitation (EFL) Index (inspiratory - expiratory Xrs), were calculated. The ICC's were high for all parameters in all groups. Repeatability, in terms of absolute units, correlated with airway obstruction and was therefore lowest in COPD. Day-to-day variability was due mostly to repeatability, with a small contribution from the mean value for some parameters. FOT measures are highly repeatable in health, stable asthma and COPD in relation to the wide range of measures between subjects. For home monitoring in asthma and COPD, either the coefficient of variation or individualized SDs could be used to define day-to-day variability.Respiratory Physiology & Neurobiology 09/2012; · 2.24 Impact Factor -
Article: Airway closure on imaging relates to airway hyperresponsiveness and peripheral airway disease in asthma.
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ABSTRACT: The regional pattern and extent of airway closure measured by three-dimensional ventilation imaging may relate to airway hyperresponsiveness (AHR) and peripheral airways disease in asthmatic subjects. We hypothesized that asthmatic airways are predisposed to closure during bronchoconstriction in the presence of ventilation heterogeneity and AHR. Fourteen asthmatic subjects (6 women) underwent combined ventilation single photon emission computed tomography/computed tomography scans before and after methacholine challenge. Regional airway closure was determined by complete loss of ventilation following methacholine challenge. Peripheral airway disease was measured by multiple-breath nitrogen washout from which S(cond) (index of peripheral conductive airway abnormality) was derived. Relationships between airway closure and lung function were examined by multiple-linear regression. Forced expiratory volume in 1 s was 87.5 ± 15.8% predicted, and seven subjects had AHR. Methacholine challenge decreased forced expiratory volume in 1 s by 23 ± 5% and increased nonventilated volume from 16 ± 4 to 29 ± 13% of computed tomography lung volume. The increase in airway closure measured by nonventilated volume correlated independently with both S(cond) (partial R(2) = 0.22) and with AHR (partial R(2) = 0.38). The extent of airway closure induced by methacholine inhalation in asthmatic subjects is greater with increasing peripheral airways disease, as measured by ventilation heterogeneity, and with worse AHR.Journal of Applied Physiology 07/2012; 113(6):958-66. · 3.75 Impact Factor -
Article: Obesity, expiratory flow limitation and asthma symptoms.
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ABSTRACT: Obesity is associated with poor asthma control, but the reason for this is unclear. Reduction in operating lung volume, as occurs in obesity, and bronchoconstriction, as occurs in asthma, can increase expiratory flow limitation during tidal breathing (EFLt), which may in turn increase respiratory symptoms. The aim of this study was to determine the effect of obesity on EFLt at baseline and after bronchoconstriction in non-asthmatic and asthmatic subjects, and to determine the association between EFLt, and respiratory symptoms. Data from previously published studies in non-asthmatic and asthmatic subjects were reanalyzed using an index of EFLt derived from respiratory system reactance measured by the forced oscillation technique. The analysis showed that during bronchoconstriction both non-asthmatic and asthmatic obese individuals were more likely to develop EFLt than non-obese subjects, despite similar changes in FEV1. Furthermore the index of EFLt was a significant determinant of the severity of breathlessness during challenge in non-asthmatic subjects, and of asthma symptom control in asthmatic subjects following anti-inflammatory treatment. These studies suggest that the combination of bronchoconstriction and low resting lung volume increase the risk of EFLt, and that this altered response to bronchoconstriction may increase the severity of symptoms and lead to worse asthma control.Pulmonary Pharmacology & Therapeutics 05/2012; · 2.80 Impact Factor -
Article: Does increased baseline ventilation heterogeneity following chest wall strapping predispose to airway hyperresponsiveness?
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ABSTRACT: Baseline ventilation heterogeneity is associated with airway hyperresponsiveness (AHR) in asthma; however, it is unknown whether increased baseline ventilation heterogeneity leads to AHR or both are independent effects of similar disease pathophysiology. Reducing functional residual capacity (FRC) in healthy subjects increases baseline ventilation heterogeneity and airway responsiveness, but the relationship between the two is unclear. The aim was to determine whether an increase in baseline ventilation heterogeneity due to a reduction in FRC correlated with the increase in response to methacholine. In 13 healthy male subjects, ventilation heterogeneity was measured by multiple-breath N(2) washout before a cumulative high-dose (0.79-200 μmol) methacholine challenge. On a separate day, the protocol was performed with chest wall strapping (CWS) to reduce FRC. Indexes of ventilation heterogeneity in the convection-dependent (Scond) and diffusion-convection-dependent (Sacin) airways were calculated from the multiple-breath N(2) washout. CWS decreased FRC by 15.6 ± 2.7% (P < 0.0001). CWS increased the percent fall in forced expiratory volume in 1 s during bronchial challenge (P = 0.006), and the magnitude of this effect was independently determined by the effect of CWS on Sacin and FRC (r(adj)(2) = 0.55, P = 0.02). This suggests that changes in baseline ventilation heterogeneity in healthy subjects are sufficient to increase airway responsiveness, independent of the presence of disease pathology.Journal of Applied Physiology 05/2012; 113(1):25-30. · 3.75 Impact Factor -
Article: Ventilation heterogeneity predicts asthma control in adults following inhaled corticosteroid dose titration.
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ABSTRACT: Asthma guidelines recommend inhaled corticosteroid (ICS) dose titration for patients on the basis of an assessment of current asthma control. However, the physiological determinants of asthma symptom control are poorly understood and spirometry is a poor predictor of symptomatic response. To determine the role of small airway measurements in predicting the symptom response following ICS dose titration. Adult asthmatic patients had the Asthma Control Questionnaire (ACQ) scores and lung function measured at baseline and after 8 weeks. Tests included spirometry, plethysmography, sputum cell count, exhaled nitric oxide, airway hyperresponsiveness to mannitol, respiratory system mechanics using the forced oscillation technique, and ventilation heterogeneity using the multiple breath nitrogen washout. The parameters ventilation heterogeneity in convection-dependent airways and ventilation heterogeneity in diffusion-dependent airways were derived as measures of ventilation heterogeneity in the small airways. The dose of ICS was doubled if the ACQ score was greater than or equal to 1.5 (uptitration) and quartered if the ACQ score was less than 1.5 (downtitration). The relationships between baseline physiological parameters and the change in the symptom-only 5-item ACQ (deltaACQ-5) were examined by using Spearman correlations, forward stepwise linear regressions, and receiver operator curve analyses. ICS dose uptitration (n= 20) improved ACQ-5 scores (1.76 to 1.16; P= .04). Baseline fraction of exhaled nitric oxide (r= -0.55; P= .01) and ventilation heterogeneity in convection-dependent airways (r= -0.64; P= .002) correlated with deltaACQ-5, but ventilation heterogeneity in convection-dependent airways was the only independent predictor (r(2) = 0.34; P = 0.007). ICS dose downtitration (n= 41) worsened ACQ-5 scores (0.46 to 0.80; P< .001), with 29% of the patients having a deltaACQ-5 of greater than 0.5. Only baseline ventilation heterogeneity in diffusion-dependent airways correlated with deltaACQ-5 (r= 0.40; P= .009) and identified subjects with deltaACQ-5 of greater than 0.5 (receiver operator curve area under the curve= 0.78; P= .0003). Ventilation heterogeneity predicts symptomatic responses to ICS dose titration. Worse small airways function predicts symptomatic improvement to ICS dose uptitration and loss of symptom control during downtitration.The Journal of allergy and clinical immunology 03/2012; 130(1):61-8. · 9.17 Impact Factor -
Article: The relationship between airflow obstruction, emphysema extent, and small airways function in COPD.
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ABSTRACT: The severities of COPD (FEV(1) % predicted) and airflow obstruction (FEV(1)/FVC) are considered to be due to both emphysema and small airways disease. To our knowledge, this has not been previously confirmed by combined measurements of emphysema and of small airway function. We hypothesized that small airways disease and emphysema extent contribute independently to the severity of both COPD and airflow obstruction. Twenty-six subjects with COPD underwent measurements with forced oscillation technique (FOT) at 6 Hz and single-breath nitrogen washout. Respiratory system resistance, respiratory system reactance (Xrs), and expiratory flow limitation (EFL) index (measured as mean inspiratory Xrs − expiratory Xrs) were derived from FOT. Closing volume/vital capacity (CV/VC) was derived from the washout. Emphysema extent was measured as low attenuation areas < -910 Hounsfield units, expressed as a percentage of CT scan lung volume from multislice CT scans taken at total lung capacity. Subjects were aged (mean ± SD) 69.6 ± 8.0 years. Postbronchodilator FEV(1) was 64.8 ± 19.8% predicted, and diffusing capacity of lung for carbon monoxide was 50.7 ± 15.8% predicted. Emphysema extent was 22.6% ± 15.0% CT scan volume. CV/VC was 16.9% ± 7.9%; Xrs, -3.72 ± 3.03 cm H(2)O/L/s; and EFL index, 3.88 ± 3.93 cm H(2)O/L/s. In multiple regression analyses, FEV(1)/FVC was predicted by both emphysema and CV/VC (model r(2) = 0.54, P < .0001) whereas FEV(1) % predicted was predicted by emphysema and EFL index (model r(2) = 0.38, P = .0014). The severities of COPD and airflow obstruction are independently predicted by both small airways disease and emphysema extent.Chest 02/2012; 142(2):312-9. · 5.25 Impact Factor -
Article: The role of the small airways in the clinical expression of asthma in adults.
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ABSTRACT: The clinical relevance of increased ventilation heterogeneity, a marker of small-airways disease, in asthmatic patients is unclear. Ventilation heterogeneity is an independent determinant of airway hyperresponsiveness (AHR), improves with bronchodilators and inhaled corticosteroids (ICSs), and worsens during exacerbations, but its relationship to asthma control is unknown. We sought to determine the association between ventilation heterogeneity and current asthma control before and after ICS treatment. Adult subjects with asthma had lung function and asthma control (5-item Asthma Control Questionnaire [ACQ-5 score] ≥1.5 = poorly controlled, ACQ-5 score ≤0.75 = well controlled) measured at baseline. A subgroup with AHR had repeat measurements after 3 months of high-dose ICS treatment. The indices of ventilation heterogeneity in the regions of the lung where gas transport occurs predominantly through convection (ventilation heterogeneity in convection-dependent airways [Scond]) and through diffusion (ventilation heterogeneity in diffusion-dependent airways [Sacin]) were derived by using the multiple-breath nitrogen washout technique. At baseline (n = 105), subjects with poorly controlled asthma had worse FEV(1), fraction of exhaled nitric oxide measured at 200 mL/s (Feno), Scond, and Sacin values. In the treatment group (n = 50) spirometric, Feno, residual volume (RV)/total lung capacity (TLC), AHR, and Scond values significantly improved. Asthma control also improved (mean ACQ-5 score, 1.3-0.7; P < .0001). The change in ACQ-5 score correlated with changes in Feno (r(s) = 0.31, P = .03), Sacin (r(s) = 0.32, P = .02), and Scond (r(s) = 0.41, P = .003) values. The independent predictors of a change in asthma control were changes in Scond and Sacin values (model r(2) = 0.20, P = .005). Current asthma control is associated with markers of small-airways disease. Improvements in ventilation heterogeneity with anti-inflammatory therapy are associated with improvements in symptoms. Sensitive measures of small-airway function might be useful in monitoring the response to therapy in asthmatic subjects.The Journal of allergy and clinical immunology 12/2011; 129(2):381-7, 387.e1. · 9.17 Impact Factor -
Article: Asthma and obesity: a known association but unknown mechanism.
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ABSTRACT: The obese asthma phenotype is an increasingly common encounter in our clinical practice. Epidemiological data indicate that obesity increases the prevalence and incidence of asthma, and evidence that obesity precedes the development of asthma raises the possibility of a causal association. Obese patients with asthma experience more symptoms and increased morbidity compared with non-obese asthma patients. Despite more than a decade of research into this association, the exact mechanisms that underlie the interaction of obesity with asthma remain unclear. It is unlikely that the asthma-obesity association is simply due to comorbidities such as obstructive sleep apnoea or gastroesophageal reflux disease. Although inflammatory pathways are purported to play a role, there is scant direct evidence in humans that systemic inflammation modulates the behaviour of the asthmatic airway or the expression of symptoms in the obese. The role of non-eosinophilic airway inflammation also requires further study. Obesity results in important changes to the mechanical properties of the respiratory system, and these obesity-related factors appear to exert an additive effect to the asthma-related changes seen in the airways. An understanding of the various physiological perturbations that might be contributing to symptoms in obese patients with asthma will allow for a more targeted and rational treatment approach for these patients.Respirology 10/2011; 17(3):412-21. · 2.42 Impact Factor -
Article: A 'Good' muscle in a 'Bad' environment: the importance of airway smooth muscle force adaptation to airway hyperresponsiveness.
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ABSTRACT: Asthma is characterized by airway inflammation, with a consequent increase in spasmogens, and exaggerated airway narrowing in response to stimuli, termed airway hyperresponsiveness (AHR). The nature of any relationship between inflammation and AHR is less clear. Recent ex vivo data has suggested a novel mechanism by which inflammation may lead to AHR, in which increased basal ASM-tone, due to the presence of spasmogens in the airways, may "strengthen" the ASM and ultimately lead to exaggerated airway narrowing. This phenomenon was termed "force adaptation" [Bossé, Y., Chin, L.Y., Paré, P.D., Seow, C.Y., 2009. Adaptation of airway smooth muscle to basal tone: relevance to airway hyperresponsiveness. Am. J. Respir. Cell Mol. Biol. 40, 13-18]. However, it is unknown whether the magnitude of the effect of force adaptation ex vivo could contribute to exaggerated airway narrowing in vivo. Our aim was to utilize a computational model of ASM shortening in order to quantify the potential effect of force adaptation on airway narrowing when all other mechanical factors were kept constant. The shortening in the model is dictated by a balance between physiological loads and ASM force-generating capacity at different lengths. The results suggest that the magnitude of the effect of force adaptation on ASM shortening would lead to substantially more airway narrowing during bronchial challenge at any given airway generation. We speculate that the increased basal ASM-tone in asthma, due to the presence of inflammation-derived spasmogens, produces an increase in the force-generating capacity of ASM, predisposing to AHR during subsequent challenge.Respiratory Physiology & Neurobiology 09/2011; 179(2-3):269-75. · 2.24 Impact Factor -
Article: The effect of airway remodelling on airway hyper-responsiveness in asthma.
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ABSTRACT: The mechanisms of airway hyper-responsiveness are only partially understood and the contribution of airway remodelling is unknown. Airway remodelling can be assessed by measuring airway distensibility, which is reduced in asthma, even when lung function is normal. We hypothesised that airway remodelling contributes to airway hyper-responsiveness in asthma, independent of steroid-responsive airway inflammation. To determine the relationship between airway distensibility and airway responsiveness at baseline and after 12 weeks of inhaled corticosteroid therapy in a group of asthmatics with airway hyper-responsiveness. Nineteen doctor-diagnosed asthmatics had airway distensibility measured as the slope of the relationship between conductance and lung volume by the forced oscillation technique. Lung function, exhaled nitric oxide and methacholine challenge were also measured. Subjects had inhaled corticosteroid therapy for 12 weeks after which all measurements were repeated. At baseline, airway distensibility (mean, 95%CI) was 0.19(0.14-0.23) cm H(2)O(-1)s(-1), exhaled nitric oxide was 13.1(10.3-16.6)ppb and airway distensibility correlated with eNO (p=0.04) and disease duration (p=0.02) but not with airway responsiveness (p=0.46), FEV(1) (p=0.09) or age (p=0.23). After treatment, exhaled nitric oxide decreased (p=0.0002), FEV(1) improved (p=0.0001), airway responsiveness improved (p=0.0002), and there was a small improvement in airway distensibility but it did not normalise (p=0.05). Airway distensibility was not correlated with either exhaled nitric oxide (p=0.49) or airway responsiveness (p=0.20). Uncontrolled airway inflammation causes a small decrease in the distensibility of the airways of asthmatics with airway hyper-responsiveness. The lack of association between airway responsiveness and airway distensibility, both before and after 12 weeks ICS treatment, suggests that airway remodelling does not contribute to airway hyper-responsiveness in asthma.Respiratory medicine 08/2011; 105(12):1798-804. · 2.33 Impact Factor -
Article: Improved respiratory system conductance following bronchodilator predicts reduced exertional dyspnoea.
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ABSTRACT: In COPD, improvements in lung mechanics following bronchodilator, measured using the forced oscillation technique (FOT), are more sensitive than spirometry at detecting improvement in lung function following bronchodilator. The relationship between these improvements in lung mechanics and improvements in functional outcomes, such as exertional dyspnoea, following bronchodilator, in COPD is unknown. 17 COPD subjects were recruited into a double blind placebo controlled randomised cross over study. Dyspnoea was induced using a standardised six-minute walk test (6 MWT), and measured by borg score throughout the test. Measurement of respiratory system conductance (Grs), respiratory system reactance (Xrs), inspiratory capacity (IC) and spirometry were made at baseline and 1 h after a single dose of either 18 μg of tiotropium bromide plus 200 μg salbutamol, or placebo. Subjects had a mean baseline FEV(1) of 45.5 ± 11.0% predicted. The bronchodilator induced reduction in exertional dyspnoea correlated significantly with the increase in Grs (r(s) = 0.59, p = 0.01) and approached significance with FEV(1) (r(s) = 0.45, p = 0.07) but not with FVC (r(s) = 0.30, p = 0.24), Xrs (r(s) = 0.19, p = 0.47) or IC (r(s) = -0.08, p = 0.78). Increase in Grs was the best and sole predictor of reduction in exertional dyspnoea, explaining 41% of the variance. There was no additional contribution to the model from the increase in FEV(1) or IC. Bronchodilator induced improvements in exertional dyspnoea in moderate to severe COPD are predicted by improvements in Grs, measured by FOT, independent of improvements in spirometry or hyperinflation. The findings suggest that FOT may be useful for measuring response to bronchodilator in COPD.Respiratory medicine 04/2011; 105(9):1345-51. · 2.33 Impact Factor -
Article: The dynamic face of respiratory research: understanding the effect of airway disease on a lung in constant motion.
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ABSTRACT: The lungs are in a constant state of motion. The dynamic nature of tidal breathing, whereby cycles of pressure changes across the lungs cause the chest wall, lung tissue and airways to repeatedly expand and contract, ventilates the lung tissue and allows respiration to occur. However, these regular cycles of tidal inspirations and expirations are punctuated by breaths of differing volumes, most particularly periodic deep inspirations. In normal, healthy subjects, these deep inspirations have a dual effect in reducing airway responsiveness. Firstly, deep inspirations taken under baseline conditions protect the airways against subsequent bronchoconstriction, termed DI bronchoprotection. Secondly, deep inspirations are able to dramatically reverse bronchoconstriction. The ability for deep inspirations to reverse bronchoconstriction appears to be due to both the ability to dilate the airways with a full inspiration to total lung capacity (TLC) and the rate at which the airways re-narrow once tidal breathing is resumed. Deep inspiration reversal is reduced in subjects with asthma and is due both to a reduced ability to dilate the airways as well as an increase in the rate of re-narrowing. On the other hand, DI bronchoprotection is completely absent in asthma. Although the mechanisms behind these abnormalities remain unclear, the inability for deep inspirations to both protect against and fully reverse bronchoconstriction in patients with asthma appears critical in the development of airway hyperresponsiveness. As such, determining the pathophysiology responsible for the malfunction of deep inspirations in asthma remains critical to understanding the disease and is likely to pave the way for novel therapeutic targets.Pulmonary Pharmacology & Therapeutics 04/2011; 24(5):505-12. · 2.80 Impact Factor -
Article: Obesity is a determinant of asthma control independent of inflammation and lung mechanics.
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ABSTRACT: It is unclear why obesity is associated with worse asthma control. We hypothesized that (1) obesity affects asthma control independent of spirometry, airway inflammation, and airway hyperresponsiveness (AHR) and (2) residual symptoms after resolution of inflammation are due to obesity-related changes in lung mechanics. Forty-nine subjects with asthma underwent the following tests, before and after 3 months of high-dose inhaled corticosteroid (ICS) treatment: five-item asthma control questionnaire (ACQ-5), spirometry, fraction of exhaled nitric oxide (Feno), methacholine challenge, and the forced oscillation technique, which allows for the calculation of respiratory system resistance (Rrs) and respiratory system reactance (Xrs) as indicators of airway caliber and elastic load, respectively. The effects of treatment were assessed by BMI group (18.5-24.9, 25-29.9, and ≥ 30 kg/m²) using analysis of variance. Multiple regression analyses determined the independent predictors of ACQ-5 results. At baseline, the independent predictors of ACQ-5 results were FEV(1), Feno, and BMI (model r² = 0.38, P < .001). After treatment, asthma control, spirometry, airway inflammation, and AHR improved similarly across BMI groups. The independent predictors of ACQ-5 results after treatment were Rrs and BMI (model r² = 0.42, P < .001). BMI is a determinant of asthma control independent of airway inflammation, lung function, and AHR. After ICS treatment, BMI again predicts ACQ-5 results, but independent of obesity-related changes in lung mechanics.Chest 03/2011; 140(3):659-66. · 5.25 Impact Factor -
Article: Predictors of airway hyperresponsiveness differ between old and young patients with asthma.
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ABSTRACT: Age-related increases in morbidity and mortality due to asthma may be due to changes in pathophysiology as patients with asthma get older. There is limited knowledge about the effects of age on the predictors of airway hyperresponsiveness (AHR), a key feature of asthma. The aim of this study was to determine if the pathophysiologic predictors of AHR, including inflammation, ventilation heterogeneity, and airway closure, differed between young and old patients with asthma. Sixty-one young (18-46 years) and 43 old (50-80 years) patients with asthma had lung function, lung volumes, fraction of exhaled nitric oxide, ventilation heterogeneity, and airway responsiveness to methacholine measured. Airway response to methacholine was measured by the dose-response slope, as the percent fall in FEV(1) per micromole of methacholine. Indices of ventilation heterogeneity were calculated for convection-dependent and diffusion-dependent airways. In young patients with asthma, the independent predictors of AHR were convection-dependent ventilation heterogeneity, exhaled nitric oxide, and % predicted FEV(1)/FVC (model r(2) = 0.51, P < .0001). In old patients with asthma, the independent predictors of airway responsiveness were % predicted residual volume, diffusion-dependent ventilation heterogeneity, and % predicted FEV(1) (model r(2) = 0.57, P < .0001). In old patients with asthma, AHR is predicted by gas trapping and ventilation heterogeneity in peripheral, diffusion-dependent airways. In the young, it is predicted by ventilation heterogeneity in less peripheral conducting airways and by inflammation. These findings suggest that there are differences in the pathophysiologic determinants of AHR between young and old patients with asthma.Chest 03/2011; 139(6):1395-401. · 5.25 Impact Factor -
Article: Effect of deep inspiration avoidance on ventilation heterogeneity and airway responsiveness in healthy adults.
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ABSTRACT: The mechanisms by which deep inspiration (DI) avoidance increases airway responsiveness in healthy subjects are not known. DI avoidance does not alter respiratory mechanics directly; however, computational modeling has predicted that DI avoidance would increase baseline ventilation heterogeneity. The aim was to determine if DI avoidance increased baseline ventilation heterogeneity and whether this correlated with the increase in airway responsiveness. Twelve healthy subjects had ventilation heterogeneity measured by multiple-breath nitrogen washout (MBNW) before and after 20 min of DI avoidance. This was followed by another 20-min period of DI avoidance before the inhalation of a single methacholine dose. The protocol was repeated on a separate day with the addition of five DIs at the end of each of the two periods of DI avoidance. Baseline ventilation heterogeneity in convection-dependent and diffusion-convection-dependent airways was calculated from MBNW. The response to methacholine was measured by the percent fall in forced expiratory volume in 1 s/forced vital capacity (FVC) (airway narrowing) and percent fall in FVC (airway closure). DI avoidance increased baseline diffusion-convection-dependent airways (P = 0.02) but did not affect convection-dependent airways (P = 0.9). DI avoidance increased both airway closure (P = 0.002) and airway narrowing (P = 0.02) during bronchial challenge. The increase in diffusion-convection-dependent airways due to DI avoidance did not correlate with the increase in either airway narrowing (r(s) = 0.14) or airway closure (r(s) = 0.12). These findings suggest that DI avoidance increases diffusion-convection-dependent ventilation heterogeneity that is not associated with the increase in airway responsiveness. We speculate that DI avoidance reduces surfactant release, which increases peripheral ventilation heterogeneity and also predisposes to peripheral airway closure.Journal of Applied Physiology 02/2011; 110(5):1400-5. · 3.75 Impact Factor -
Article: Cut-points for response to mannitol challenges using the forced oscillation technique.
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ABSTRACT: The forced oscillation technique (FOT) can be used to determine airway hyperresponsiveness, but the cut-points for changes in respiratory system conductance (Grs) and reactance (Xrs) that define a positive mannitol challenge are not known. Furthermore, the effects of changes in lung volume on these cut-points or on the repeatability of the test are unknown. In 15 non-asthmatic and 52 asthmatic subjects, response to mannitol challenge was measured by Grs and Xrs, using FOT, and by FEV(1). The FOT variables were adjusted for inspiratory capacity (IC) at each dose. Dose response slope (DRS) was used in receiver operator characteristic (ROC) analysis to compare the ability of adjusted and unadjusted DRSGrs and DRSXrs to detect a positive challenge, defined as PD(15)FEV(1) ≤635 mg mannitol. Mannitol challenges were positive in 32 asthmatic and 2 non-asthmatic subjects. Both DRSGrs and DRSXrs detected positive challenges (p < 0.0001 for both), and this was not altered by adjustment for IC for either DRSGrs (p = 0.21) or DRSXrs (p = 0.90). FOT cut-points for a positive challenge were 27% fall in Grs or 0.93 cm H(2)O/L/s decrease in Xrs at 635 mg. Repeatability of DRSGrs (±2.01 doubling doses) and DRSXrs (±1.95dd) was comparable with DRSFEV(1) (±1.67dd) and was not improved by adjustment for IC. Grs and Xrs, measured by FOT, provide a sensitive, repeatable measure of response to mannitol challenge. Adjusting for lung volume does not alter the ability of these variables to detect a positive response or the repeatability of the measurement.Respiratory medicine 11/2010; 105(4):533-40. · 2.33 Impact Factor -
Article: Indices of bronchial reactivity and sensitivity.
Thorax 10/2010; 66(3):265-6; author reply 266. · 6.84 Impact Factor -
Article: Avoiding deep inspirations increases the maximal response to methacholine without altering sensitivity in non-asthmatics.
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ABSTRACT: Airway hyperresponsiveness is characterised by a leftward shift of the dose-response curve (DRC) and an increase in the maximal response. Deep inspiration (DI) avoidance increases responsiveness in non-asthmatic, but not asthmatic, subjects. The aim was to determine the effect of DI avoidance on the sensitivity and maximal response of the FEV(1) DRC to methacholine. Thirteen non-asthmatic and ten asthmatic subjects underwent a standard cumulative high-dose methacholine challenge (0.1-200μmol). Subsequently, on separate days, increasing single doses of methacholine were administered after 10min of DI avoidance. A sigmoidal equation was fitted to the data to obtain values for α, the position constant, as a measure of sensitivity. The fall in FEV(1) at the highest common dose was used as a measure of the maximal response. The change in flow at 40% control vital capacity on the maximal (V˙40m) and partial (V˙40p) curves were calculated from the first manoeuvre after methacholine and the ratio of the values for V˙40m and V˙40p was calculated as a measure of the bronchodilator effect of DI (BD(DI)). In non-asthmatic subjects, avoiding DI increased the maximum fall in FEV(1) at the highest common dose (p=0.0001) but did not alter α (p=0.75). Avoiding DI before challenge did not alter BD(DI) (p=0.13). DI avoidance had no effect on airway responsiveness in asthmatic subjects. In non-asthmatic subjects, DI avoidance increases airway responsiveness by increasing the maximal response, but does not alter the sensitivity, suggesting that the loss of the effect of DI in asthma contributes to excessive bronchoconstriction.Respiratory Physiology & Neurobiology 09/2010; 173(2):157-63. · 2.24 Impact Factor
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2007–2012
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Woolcock Institute of Medical Research
Sydney, New South Wales, Australia
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2011
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Providence Health Care
Vancouver, British Columbia, Canada
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