Peripheral airway dysfunction and relationship with symptoms in smokers with preserved spirometry.

Background And Objective: Smokers develop respiratory symptoms and peripheral airway dysfunction even when spirometry is preserved. Multiple breath nitrogen washout (MBNW) and impulse oscillometry system (IOS) are potentially useful measures of peripheral airway function but they have not been compared in such subjects. We hypothesized that MBNW and IOS are jointly abnormal in smokers with normal spirometry and that these abnormalities relate to respiratory symptoms.

Peripheral ventilation heterogeneity determines the extent of bronchoconstriction in asthma.

In asthma, bronchoconstriction causes topographically heterogeneous airway narrowing, as measured by three-dimensional ventilation imaging. Computation modeling suggests that peripheral airway dysfunction is a potential determinant of acute airway narrowing measured by imaging. We hypothesized that the development of low-ventilation regions measured topographically by three-dimensional imaging after bronchoconstriction is predicted by peripheral airway function.

Bronchodilator responsiveness of peripheral airways in smokers with normal spirometry.

Background And Objective: Cigarette smoke exposure increases airway smooth muscle (ASM) contractility. Abnormalities in peripheral airway function in smokers with normal spirometry could be due to the effects of ASM tone. We aimed to determine the contribution of ASM tone to peripheral airway function in smokers with normal spirometry from the response to bronchodilator (BD).

Expiratory flow limitation relates to symptoms during COPD exacerbations requiring hospital admission.

Background: Expiratory flow limitation (EFL) is seen in some patients presenting with a COPD exacerbation; however, it is unclear how EFL relates to the clinical features of the exacerbation. We hypothesized that EFL when present contributes to symptoms and duration of recovery during a COPD exacerbation. Our aim was to compare changes in EFL with symptoms in subjects with and without flow-limited breathing admitted for a COPD exacerbation.

Association between peripheral airway function and neutrophilic inflammation in asthma.

Background And Objective: Small airway dysfunction is associated with asthma severity and control, but its association with airway inflammation is unknown. The aim was to determine the association between sputum inflammatory cells and the site of small airway dysfunction, measured by multiple breath nitrogen washout in convection-dependent (Scond) and more peripheral diffusion-dependent (Sacin) airways.

Methods: Fifty-three (20-67 years) subjects with asthma on inhaled corticosteroid (ICS) treatment were characterized by spirometry, Scond, Sacin and induced sputum differential counts.

Smooth muscle in the maintenance of increased airway resistance elicited by methacholine in humans.

Rationale: Airway narrowing is maintained for a prolonged period after acute bronchoconstriction in humans in the absence of deep inspirations (DIs).

Objectives: To determine whether maintenance of airway smooth muscle (ASM) shortening is responsible for the persistence of airway narrowing in healthy subjects following transient methacholine (MCh)-induced bronchoconstriction.

Methods: On two separate visits, five healthy subjects underwent MCh challenges until respiratory system resistance (Rrs) had increased by approximately 1.

Changes in oscillatory impedance and nitrogen washout with combination fluticasone/salmeterol therapy in COPD.

Introduction: Combination inhaled corticosteroid/long-acting bronchodilator (ICS/LABA) therapy reduces the exacerbation rate and improves spirometry and quality of life in COPD. We hypothesized that ICS/LABA therapy also improves small airway function measured by FOT.

Methods: 14 subjects with COPD were commenced on combination fluticasone propionate/salmeterol therapy for 3 months.

Deep inspiration volume and the impaired reversal of bronchoconstriction in asthma.

It is unclear whether the failure to reverse bronchoconstriction with deep inspiration (DI) in asthma is due to reduced maximal dilatation of the DI. We compared the effect of different DI volumes on maximal dilatation and reversal of bronchoconstriction in nine asthmatics and ten non-asthmatics. During bronchoconstriction, subjects took DI to 40%, 70% and 100% inspiratory capacity, on separate days.

Ventilation heterogeneity is associated with airway responsiveness in asthma but not COPD.

Airway hyperresponsiveness (AHR) occurs in both asthma and COPD. In older people with asthma, AHR is associated with increased acinar ventilation heterogeneity, but it is unknown if this association exists in COPD. Thirty one COPD and 19 age-matched asthmatic subjects had measures of spirometry, lung volumes, exhaled nitric oxide, ventilation heterogeneity, and methacholine challenge.

The effect of low lung volume on airway function in obesity.

Introduction: Obesity is associated with reduced operating lung volume. We hypothesized that obesity induces airway dysfunction independent of reduced FRC.

Methods: 18 obese (BMI: 41.

Impaired pulmonary nitric oxide bioavailability in pulmonary tuberculosis: association with disease severity and delayed mycobacterial clearance with treatment.

Background: Nitric oxide (NO), a key macrophage antimycobacterial mediator that ameliorates immunopathology, is measurable in exhaled breath in individuals with pulmonary tuberculosis. We investigated relationships between fractional exhale NO (FENO) and initial pulmonary tuberculosis severity, change during treatment, and relationship with conversion of sputum culture to negative at 2 months.

Methods: In Papua, we measured FENO in patients with pulmonary tuberculosis at baseline and serially over 6 months and once in healthy controls.

Relationship between airway pathophysiology and airway inflammation in older asthmatics.

Background And Objective: Asthma-related morbidity is greater in older compared with younger asthmatics. Airway closure is also greater in older asthmatics, an observation that may be explained by differences in airway inflammation. We hypothesized that in older adult patients with asthma, neutrophil airway inflammation increases airway closure during bronchoconstriction, while eosinophil airway inflammation increases airway hyperresponsiveness (AHR).

Effect of methacholine on peripheral lung mechanics and ventilation heterogeneity in asthma.

The forced oscillation technique (FOT) and multiple-breath nitrogen washout (MBNW) are noninvasive tests that are potentially sensitive to peripheral airways, with MBNW indexes being especially sensitive to heterogeneous changes in ventilation. The objective was to study methacholine-induced changes in the lung periphery of asthmatic patients and determine how changes in FOT variables of respiratory system reactance (Xrs) and resistance (Rrs) and frequency dependence of resistance (Rrs5-Rrs19) can be linked to changes in ventilation heterogeneity. The contributions of air trapping and airway closure, as extreme forms of heterogeneity, were also investigated.

The feasibility of home monitoring of impedance with the forced oscillation technique in chronic obstructive pulmonary disease subjects.

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.

Day-to-day variability of oscillatory impedance and spirometry in asthma and COPD.

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.

Airway closure on imaging relates to airway hyperresponsiveness and peripheral airway disease in asthma.

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.

Obesity, expiratory flow limitation and asthma symptoms.

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.

Does increased baseline ventilation heterogeneity following chest wall strapping predispose to airway hyperresponsiveness?

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.

Ventilation heterogeneity predicts asthma control in adults following inhaled corticosteroid dose titration.

Background: 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.

Objective: To determine the role of small airway measurements in predicting the symptom response following ICS dose titration.

The relationship between airflow obstruction, emphysema extent, and small airways function in COPD.

Background: 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.

The role of the small airways in the clinical expression of asthma in adults.

Background: 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.

Objective: We sought to determine the association between ventilation heterogeneity and current asthma control before and after ICS treatment.

Asthma and obesity: a known association but unknown mechanism.

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.

A 'Good' muscle in a 'Bad' environment: the importance of airway smooth muscle force adaptation to airway hyperresponsiveness.

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.

The effect of airway remodelling on airway hyper-responsiveness in asthma.

Rationale: 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.

Improved respiratory system conductance following bronchodilator predicts reduced exertional dyspnoea.

Background: 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.

Methods: 17 COPD subjects were recruited into a double blind placebo controlled randomised cross over study.