Norbert Berend

Physiology of obesity and effects on lung function

In obese people, the presence of adipose tissue around the rib cage and abdomen and in the visceral cavity loads the chest wall and reduces functional residual capacity (FRC). The reduction in FRC and in expiratory reserve volume is detectable, even at a modest increase in weight. However, obesity has little direct effect on airway caliber. Spirometric variables decrease in proportion to lung volumes, but are rarely below the normal range, even in the extremely obese, while reductions in expiratory flows and increases in airway resistance are largely normalized by adjusting for lung volumes. Nevertheless, the reduction in FRC has consequences for other aspects of lung function. A low FRC increases the risk of both expiratory flow limitation and airway closure. Marked reductions in expiratory reserve volume may lead to abnormalities in ventilation distribution, with closure of airways in the dependent zones of the lung and ventilation perfusion inequalities. Greater airway closure during tidal breathing is associated with lower arterial oxygen saturation in some subjects, even though lung CO-diffusing capacity is normal or increased in the obese. Bronchoconstriction has the potential to enhance the effects of obesity on airway closure and thus on ventilation distribution. Thus obesity has effects on lung function that can reduce respiratory well-being, even in the absence of specific respiratory disease, and may also exaggerate the effects of existing airway disease.

Ventilation heterogeneity is a major determinant of airway hyperresponsiveness in asthma, independent of airway inflammation

Background: Airway hyperresponsiveness is the ability of airways to narrow excessively in response to inhaled stimuli and is a key feature of asthma. Airway inflammation and ventilation heterogeneity have been separately shown to be associated with airway hyperresponsiveness. A study was undertaken to establish whether ventilation heterogeneity is associated with airway hyperresponsiveness independently of airway inflammation in subjects with asthma and to determine the effect of inhaled corticosteroids on this relationship. Methods: Airway inflammation was measured in 40 subjects with asthma by exhaled nitric oxide, ventilation heterogeneity by multiple breath nitrogen washout and airway hyperresponsiveness by methacholine challenge. In 18 of these subjects with uncontrolled symptoms, measurements were repeated after 3 months of treatment with inhaled beclomethasone dipropionate. Results: At baseline, airway hyperresponsiveness was independently predicted by airway inflammation (partial r2 = 0.20, p<0.001) and ventilation heterogeneity (partial r2 = 0.39, p<0.001). Inhaled corticosteroid treatment decreased airway inflammation (p = 0.002), ventilation heterogeneity (p = 0.009) and airway hyperresponsiveness (p<0.001). After treatment, ventilation heterogeneity was the sole predictor of airway hyperresponsiveness (r2 = 0.64, p<0.001). Conclusions: Baseline ventilation heterogeneity is a strong predictor of airway hyperresponsiveness, independent of airway inflammation in subjects with asthma. Its persistent relationship with airway hyperresponsiveness following anti-inflammatory treatment suggests that it is an important independent determinant of airway hyperresponsiveness. Normalisation of ventilation heterogeneity is therefore a potential goal of treatment that may lead to improved long-term outcomes.

The effects of body weight on airway calibre

Increased wheeze and asthma diagnosis in obesity may be due to reduced lung volume with subsequent airway narrowing. Asthma (wheeze and airway hyperresponsiveness), functional residual capacity (FRC) and airway conductance (Gaw) were measured in 276 randomly selected subjects aged 28–30 yrs. Data were initially adjusted for smoking and asthma before examining relationships between weight and FRC (after adjustment for height), and between body mass index (BMI = weight·height−2) and Gaw (after adjustment for FRC) by multiple linear regression, separately for females and males. For males and females, BMI (±95% confidence interval) was 27.0±4.6 kg·m−2 and 25.6±6.0 kg·m−2 respectively, Gaw was 0.64±0.04 L·s−1·cmH2O−1 and 0.57±0.03 L·s−1·cmH2O−1, and FRC was 85.3±3.4 and 84.0±2.9% of predicted. Weight correlated independently with FRC in males and females. BMI correlated independently and inversely with Gaw in males, but only weakly in females. In conclusion, obesity is associated with reduced lung volume, which is linked with airway narrowing. However, in males, airway narrowing is greater than that due to reduced lung volume alone. The mechanisms causing airway narrowing and sex differences in obesity are unknown.

Airway re-narrowing following deep inspiration in asthmatic and nonasthmatic subjects.

After bronchoconstriction, deep inspiration (DI) causes dilatation followed by airway re-narrowing. Re-narrowing may be faster in asthmatic than nonasthmatic subjects. This study investigated the relationship between re-narrowing and the magnitude of both DI-induced dilatation and the volume-dependence of respiratory system resistance (Rrs) during tidal breathing. In 25 asthmatic and 18 nonasthmatic subjects the forced oscillation technique was used to measure Rrs at baseline and after methacholine challenge, during 1 min of tidal breathing, followed by DI to total lung capacity (TLC) and passive return to functional residual capacity (FRC). Dilatation was measured as the decrease in Rrs between end tidal inspiration and TLC, re-narrowing as Rrs at FRC immediately after DI, as per cent Rrs at end-tidal expiration, and volume dependent tidal fluctuation as the difference between mean Rrs at end-expiration and end-inspiration. Asthmatic subjects had greater re-narrowing, less dilatation, and greater tidal fluctuations both at baseline and after challenge. Re-narrowing correlated with baseline tidal fluctuation and inversely with dilatation. Both baseline tidal fluctuation and dilatation were significant independent predictors of re-narrowing. Following deep inspiration-induced dilatation, faster airway re-narrowing in asthmatic than nonasthmatic subjects is associated not only with reduced deep inspiration-induced dilatation but also with some property of the airways that is detectable prior to challenge as an increased volume dependence of resistance.

Effect of obesity on breathlessness and airway responsiveness to methacholine in non-asthmatic subjects.

Background:Obesity is associated with increased prevalence and incidence of asthma, but the mechanism is unknown. Obesity reduces lung volumes, which can increase airway responsiveness, and increases resistive and elastic work of breathing, which can increase dyspnea.Objective:To determine if the intensity of dyspnea due to airway narrowing or if airway responsiveness is increased in obese, non-asthmatic subjects.Subjects:Twenty-three obese (BMI (body mass index) ⩾30 kg m−2) and 26 non-obese (BMI <30 kg m−2) non-asthmatic subjects, aged between 18 and 70 years.Methods:High-dose methacholine challenge was used to determine the sensitivity and the maximal response to methacholine. Respiratory system resistance (Rrs) and reactance were measured, using the forced oscillation technique, as indicators of resistive and elastic loads during challenge. Perception of dyspnea was measured by the Borg score during challenge. Static lung volumes were measured by body plethysmography.Results:Static lung volumes were reduced in the obese subjects. There were no significant differences in the sensitivity or maximal response to methacholine between obese and non-obese subjects. The magnitude of change in Rrs was similar in both groups, but obese subjects had more negative reactance after challenge (P=0.002) indicating a greater elastic load. The intensity of dyspnea was greater in obese subjects (P=0.03).Conclusions:Obesity reduces lung volumes, but does not alter the sensitivity or maximal response to methacholine. However, obese subjects have enhanced perception of dyspnea, associated with greater apparent stiffness of the respiratory system, and may therefore be at greater risk of symptoms.

The effect of short-term withdrawal from continuous positive airway pressure therapy on sympathetic activity and markers of vascular inflammation in subjects with obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is commonly associated with cardiovascular disease and sympathetic activation. However, it is unclear whether this association is independent of obesity and to what extent treatment with nasal continuous positive airway pressure (CPAP) alleviates the vascular inflammation that underpins cardiovascular disease. We therefore evaluated whether short‐term withdrawal from CPAP therapy in subjects with moderate–severe OSA would result in increased levels of sympathetic activity and circulating inflammatory cytokines independent of weight. Vascular inflammatory markers (hsCRP, hsIL‐6 and hsTNF‐α) were assessed in 20 subjects after one and seven nights of withdrawal from CPAP together with the hypoxia‐responsive angiogenic marker VEGF and urinary catecholamines. Compared with baseline on CPAP, withdrawal from therapy resulted in an immediate return of OSA with an increase in RDI to 26.7 ± 5.2 and 39.0 ± 5.9 events per hour after one and seven nights without CPAP, respectively (both P < 0.0001). This was accompanied by a concomitant rise in daytime urinary noradrenaline (P < 0.0001) after seven nights CPAP withdrawal that was positively associated with the severity of hypoxaemia. In contrast, withdrawal from CPAP therapy was not accompanied by any change in measured cytokines or VEGF (all P > 0.1). In conclusion, 1 week of CPAP withdrawal was associated with a return of OSA and a marked increase in sympathetic activity without a concomitant elevation of vascular inflammatory markers.

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.

Increased airway closure is a determinant of airway hyperresponsiveness

In order to investigate whether increased airway closure is a component of airway hyperresponsiveness (AHR), airway closure was compared during induced bronchoconstriction in 62 asthmatic, 41 nonasthmatic nonobese (control) and 20 nonasthmatic obese (obese) subjects. Airway closure and airway narrowing were measured by spirometry as percentage change in forced vital capacity (%ΔFVC) and change in forced expiratory ratio (ΔFER), respectively. Multiple regression analyses were used to assess the determinants of AHR, assessed by the dose response slope (DRS). The DRS was significantly increased in asthmatics compared with controls but did not differ between obese and controls. The spirometric predictors of logDRS were baseline FER, ΔFER, body mass index (BMI) and %ΔFVC. There was a negative relationship between BMI and logDRS in the regression, suggesting a protective effect. The present findings suggest that the extent of airway closure during induced bronchoconstriction is a determinant of airway hyperresponsiveness, independent of the level of airway narrowing. However, after adjusting for airway closure, obesity appears to protect against airway hyperresponsiveness.

Mechanisms of airway hyperresponsiveness in asthma.

Abstract:  Airway hyperresponsiveness (AHR) is a fundamental abnormality in asthma. There are many potential factors contributing to the excessive airway response demonstrable on airway challenge. These range from abnormalities of airway smooth muscle, airway remodelling and airway inflammation to abnormalities in the neural control of airway calibre. None of these by themselves fully explains the abnormalities seen on the dose response curves of the asthmatic. In this review, the main mechanisms are described, together with recent evidence providing a pathway by which a number of these mechanisms may interact to cause AHR through abnormality in ventilation distribution and airway closure. There is now evidence for a close relationship between ventilation heterogeneity and AHR which could be exploited clinically.

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.