Claude S. Farah

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. 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.

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.

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. METHODS 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. RESULTS 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). CONCLUSIONS 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.

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.

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. 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.

Thoracic Society of Australia and New Zealand oxygen guidelines for acute oxygen use in adults: 'Swimming between the flags'.

The purpose of the Thoracic Society of Australia and New Zealand guidelines is to provide simple, practical evidence‐based recommendations for the acute use of oxygen in adults in clinical practice. The intended users are all health professionals responsible for the administration and/or monitoring of oxygen therapy in the management of acute medical patients in the community and hospital settings (excluding perioperative and intensive care patients), those responsible for the training of such health professionals, and both public and private health care organizations that deliver oxygen therapy.

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.

The contractile lability of smooth muscle in asthmatic airway hyperresponsiveness.

The contractile capacity of airway smooth muscle is not fixed but modulated by an impressive number of extracellular inflammatory mediators. Targeting the transient component of airway hyperresponsiveness ascribed to this contractile lability of ASM is a quest of great promises in order to alleviate asthma symptoms during inflammatory flares. However, owing to the plethora of mediators putatively involved and the molecular heterogeneity of asthma, it is more likely that many mediators conspire to increase the contractile capacity of ASM, each of which contributing to a various extent and in a time-varying fashion in individuals suffering from asthma. The task of identifying a common mend for a tissue rendered hypercontractile by imponderable assortments of inflammatory mediators is puzzling.

Obesity and asthma control in an urban population

minimum of 4 to 6 weeks lag to a disease response as reported by Dr Summers et al, all subjects received 2 to 5 doses at least 4 weeks before June 9 (90%, >_6 weeks). This compliance was identical by treatment group despite that subjects on T suis had an unexpected 3 to 19-fold higher rate of episodes with moderate to severe diarrhoea, abdominal pain, and flatulence (median duration, 2 days) compared with placebo. Hepworth et al also write that a dose of 2,500 T suis ova every 21 days might be insufficient to effectively alter systemic responses considering the lack of colonization and rapid clearance of T suis. However, we observed an altered systemic T suis IgG response in more than 92% of subjects. In addition, Table I demonstrates that subjects who did not clear T suis by means of diarrhea or subjects who responded in the upper quartile of T suis IgG titers (>29.9 milligram antibody per liter serum) showed no reduction in their skin reactions to allergens or grass IgE titers after 6 months. A few insignificant changes in the size of skin reactions were likely an after effect of higher pollen and more variable indoor allergen exposure during the summer months. Finally, our demonstration of an absence of an effect of T suis on measures of allergic reactivity in skin, blood, and airways even after 6 months is not compatible with the insignificant effect on self-reported medication usage noted by Dr Summers et al. In conclusion, an even closer look at our data suggests that T suis will not show sufficient efficacy in treatment of subjects who have already had an allergic disease. Peter Bager, PhD Jan Wohlfahrt, PhD Bjarne Kristensen, MSc Lars K. Poulsen, PhD Mads Melbye, DMSc From Statens Serum Institut, Department of Epidemiology Research, Copenhagen, Denmark; Phadia ApS, Allerød, Denmark; and the Allergy Clinic, National University Hospital, Copenhagen, Denmark. E-mail: pbg@ssi.dk. Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.