Kate M. Hardaker

Obesity is a determinant of asthma control independent of inflammation and lung mechanics

BACKGROUND 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. METHODS 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. 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). CONCLUSIONS 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.

Predictors of airway hyperresponsiveness differ between old and young patients with asthma

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.

A Systematic Approach to Multiple Breath Nitrogen Washout Test Quality

Background Accurate estimates of multiple breath washout (MBW) outcomes require correct operation of the device, appropriate distraction of the subject to ensure they breathe in a manner representative of their relaxed tidal breathing pattern, and appropriate interpretation of the acquired data. Based on available recommendations for an acceptable MBW test, we aimed to develop a protocol to systematically evaluate MBW measurements based on these criteria. Methods 50 MBW test occasions were systematically reviewed for technical elements and whether the breathing pattern was representative of relaxed tidal breathing by an experienced MBW operator. The impact of qualitative and quantitative criteria on inter-observer agreement was assessed across eight MBW operators (n = 20 test occasions, compared using a Kappa statistic). Results Using qualitative criteria, 46/168 trials were rejected: 16.6% were technically unacceptable and 10.7% were excluded due to inappropriate breathing pattern. Reviewer agreement was good using qualitative criteria and further improved with quantitative criteria from (κ = 0.53–0.83%) to (κ 0.73–0.97%), but at the cost of exclusion of further test occasions in this retrospective data analysis. Conclusions The application of the systematic review improved inter-observer agreement but did not affect reported MBW outcomes.

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. OBJECTIVES 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.

Association between peripheral airway function and neutrophilic inflammation in asthma

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.

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. Indices of acinar (Sacin) and conducting (Scond) airway ventilation heterogeneity were calculated from the multiple breath nitrogen washout. Predictors of AHR were then determined. In COPD, AHR was predicted by lower Sacin and lower FVC (model r(2)=0.35, p=0.001). In asthma, AHR was predicted by higher Sacin and higher residual volume (model r(2)=0.62, p<0.001). These findings suggest that airway responsiveness in COPD and asthma is determined by underlying disease-specific processes, rather than a common pattern of physiological abnormality.

Multiple breath washout: From renaissance to enlightenment?

Much has been made of the “renaissance” of the multiple breath washout (MBW) technique, a test dating as far back as the 1940s for the measurement of lung volumes and ventilation heterogeneity. This rebirth has been made possible with the emergence of new technologies capable of measuring or deducing inert gas concentration with high precision and accuracy as it changes throughout the breathing cycle. The increasing acceptance of the test can also be attributed to its relative ease (i.e., high feasibility) in those age groups where conventional lung function is challenging, such as in infants and young children, and its ability to detect structural lung involvement in important respiratory conditions, such as cystic fibrosis (CF). More recently, similar clinical comparisons between MBW outcomes and lung structure have emerged in younger infants as well as initial reports suggesting beneficial effect of interventions and prognostic information about later lung function achieved with MBW outcomes. A variety of MBW techniques have been developed, which measure inert gas concentration either directly or indirectly. While most MBW research to date has been performed on custom-built, highly specialized equipment (e.g., using a respiratory mass-spectrometer), this is now changing with the availability of commercial devices, which may utilize one of several different gas concentration measurement technique options (e.g., using molar mass analysis). In recognition of this, recent efforts have focused on improving standardization of MBW equipment and procedures for testing and data analysis across laboratories, culminating in the publication of a consensus statement in 2013 for MBW testing in school-aged children and above. A current ATS task force is addressing the issues specific to the preschool age group because of the unique challenges of MBW testing in this age group and the exciting initial data suggesting potential clinical utility as an assessment tool. Thework presented in this journal, byAnagnostopoulou et al., is based on specific commercial infant MBW equipment (Exhalyzer D, Eco Medics AG, Switzerland) and analysis software (WBreath Version 3.28.0.0, ndd Medizintechnik AG, Switzerland). This equipment and analysis approach calculates inert gas concentration indirectly by examining changes in mainstream molar mass. The work focuses on identification of the start point of the washout, conventionally the starting inert gas concentration, or in this case starting molar mass value. This is important because the end point of the MBW is set at 1/40th of this value, and contributes to the calculation of all MBW variables. The authors demonstrated how variation in start point identification, and therefore the step change in molar mass used (between the start and end

Comparison of facemask and mouthpiece interfaces for multiple breath washout measurements

BACKGROUND Different interfaces (mouthpiece/nose clip vs. facemask) are used during multiple breath washout (MBW) tests in young children. METHODS We investigated the effect of interface choice and breathing modalities on MBW outcomes in healthy adults and preschool children. RESULTS In adults (n = 26) facemask breathing significantly increased LCI, compared to mouthpiece use (mean difference (95% CI) 0.4 (0.2; 0.6)), with results generalizable across sites and different equipment. Exclusively nasal breathing within the facemask increased LCI, as compared to oral breathing. In preschoolers (2-6 years, n = 46), no significant inter-test difference was observed across interfaces for LCI or FRC. Feasibility and breathing stability were significantly greater with facemask (incorporating dead space volume minimization), vs. mouthpiece. This was more pronounced in subjects <4 years of age. CONCLUSION Both nasal vs. oral breathing and mouthpiece vs. facemask affect LCI measurements in adults. This effect was minimal in preschool children, where switching between interfaces is most likely to occur.

Is twice the duration of washout sufficient time between multiple breath nitrogen washout tests

Multiple breath washout (MBW) assesses both lung volume (functional residual capacity (FRC)) and ventilation inhomogeneity (lung clearance index (LCI)). The latters insight into underlying lung pathology and response to intervention has triggered a recent MBW resurgence [1–4]. Validated commercial equipment has become available [5], increasing suitability for widespread use, and a European Respiratory Society/American Thoracic Society endorsed MBW consensus statement has been published to guide manufacturers and operators [6]. This document highlights the need for further evidence across several recommendation areas. In the May 2015 issue of this journal Salamon et al. [7] tackled one such important issue: what duration should be employed between two MBW tests within a testing session? Previous recommendations of gaps of ≥15 min in healthy and ≤60 min in obstructed patients [8] were shown to be too conservative. Using a gap of the previous washout duration led to 10% lower FRC values (p<0.001) but no effect was observed if this was doubled, in line with the recent consensus-based recommendation. [9]. The results presented here address two important limitations to the data presented by Salamon et al. [7], as acknowledged by the authors themselves, to further strengthen the recommendations evidence base. First, in their paediatric cohort, an alternate, fixed-gap duration protocol was used (5 and 15 min), which translated to an excessive duration between tests (mean 2.6×). Secondly, LCI data was not reported, which may have compromised the ability to detect any detrimental effects. A wait time between MBNW tests of twice the washout duration has no detrimental effect on LCI and FRC outcomes http://ow.ly/RF8y304V3PB

Predictors of Airway HyperresponsivenessDiffer Between Old and Young PatientsWith Asthma

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.