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. METHODS: Eighty smokers with normal spirometry completed a symptom questionnaire, had ventilation heterogeneity in diffusion (Sacin) and convection-dependent (Scond) airways and trapped gas volume at functional residual capacity as a percentage of vital capacity (%VtrFRC/VC) measured by MBNW. Respiratory resistance and reactance at 5 and 20 Hz were measured using IOS. RESULTS: Respiratory symptoms were reported in 55 (68%) subjects. Forty (50%) subjects had at least one abnormal MBNW parameter, predominantly in Sacin. Forty-one (51%) subjects had at least one abnormal IOS parameter, predominantly in resistance. Sixty-one (76%) subjects had an abnormality in either MBNW or IOS. Chronic bronchitis symptoms were associated with an increased Scond, while wheeze was associated with lower spirometry and an increased resistance. Abnormalities in MBNW and IOS parameters were unrelated to each other. CONCLUSIONS: Respiratory symptoms and peripheral airway dysfunction are common in smokers with normal spirometry. Symptoms of chronic bronchitis related to conductive airway abnormalities, while wheeze was related to spirometry and IOS. The clinical significance of abnormalities in peripheral airway function in smokers remains undetermined.

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). METHODS: Ventilation heterogeneity in peripheral conductive (Scond) and acinar (Sacin) airways were measured in 50 asymptomatic smokers and 20 never-smokers using multiple breath nitrogen washout, before and 20 min after inhalation of 200 µg salbutamol and 80 µg ipratropium bromide. Z-scores were calculated to define abnormality in Sacin and Scond. RESULTS: Nineteen smokers had abnormal Sacin, and 12 had abnormal Scond; 7 had abnormalities in both. After BD, Sacin improved in smokers with normal Sacin (6.5 ± 15.9%, P = 0.02), smokers with abnormal Sacin (9.2 ± 16.9%, P = 0.03) and in control subjects (11.7 ± 18.2%, P = 0.01), with no differences in improvements between groups. Sacin remained abnormal in 15/19 smokers and their post-BD values correlated with smoking exposure (r = 0.53, P = 0.02). After BD, Scond improved in smokers with abnormal Scond (28.3 ± 15.9%, P = 0.002) and normalized in 9/12 subjects, but not in those with normal Scond (0.25 ± 32.7%, P = 0.44) or control subjects (-1.7 ± 21.2%, P = 0.64). CONCLUSION: In smokers with normal spirometry, abnormal conductive airway function could be attributed to increased bronchomotor tone. In contrast, bronchomotor tone in acinar airways is unaffected by smoking and functional abnormality. There may be different causal mechanisms underlying acinar and conductive airway abnormalities in smokers with normal spirometry.

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. %Predicted values for Scond and Sacin were calculated from published reference equations to adjust for the effects of age. Univariate correlations were assessed using the Spearman test. Multivariate linear regressions were performed to account for potential confounders, including age, gender, disease duration, body mass index and ICS dose. RESULTS: Sacin (%predicted) correlated significantly with neutrophil% (rs = 0.33, P = 0.02), ICS dose (rs = -0.28, P = 0.04) and age (rs = 0.27, P = 0.05). In multivariate analysis, Sacin related only to neutrophil% (adjusted R(2) = 0.18, P = 0.001). Scond (%predicted) correlated significantly only with eosinophil% (rs = 0.39, P = 0.004). There was a trend for a negative relationship with ICS dose (rs = -0.26, P = 0.06). In multivariate analysis, Scond related to eosinophil% and ICS dose independently (adjusted R(2) = 0.12, P = 0.02). CONCLUSIONS: Acinar and conductive airway dysfunction is associated with different inflammatory profiles in asthmatic airways, independently of the effects of age and disease duration. The association between acinar airway dysfunction and neutrophilic airway inflammation may have implications for asthma treatment.

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 1.5 cm H2O/L/s. Subjects took a DI either immediately after or 30 minutes after the last dose. The extent of renarrowing following the bronchodilator effect of DI was used to assess the continued action of MCh (calculated as percent change in Rrs from the pre-DI Rrs). We then used human bronchial rings to determine whether ASM can maintain shortening during a progressive decrease of carbachol concentration. MEASUREMENTS AND MAIN RESULTS: The increased Rrs induced by MCh was maintained for 30 minutes despite waning of MCh concentration over that period, measured as attenuated renarrowing when the DI was taken 30 minutes after compared with immediately after the last dose (7 min post-DI, -36.2 ± 11.8 vs. 14.4 ± 13.2%; 12 min post-DI, -39.5 ± 9.8 vs. 15.2 ± 17.8%). Ex vivo, ASM shortening was largely maintained during a progressive decrease of carbachol concentration, even down to concentrations that would not be expected to induce shortening. CONCLUSIONS: The maintenance of airway narrowing despite MCh clearance in humans is attributed to an intrinsic ability of ASM to maintain shortening during a progressive decrease of contractile stimulation.

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. Treatment outcomes were conversion of sputum culture results at 2 months and time to conversion of sputum microscopy results. RESULTS: Among 200 patients with pulmonary tuberculosis and 88 controls, FENO was lower for patients with pulmonary tuberculosis at diagnosis (geometric mean FENO, 12.7 parts per billion [ppb]; 95% confidence interval [CI], 11.6-13.8) than for controls (geometric mean FENO, 16.6 ppb; 95% CI, 14.2-19.5; P = .002), fell further after treatment initiation (nadir at 1 week), and then recovered by 6 months (P = .03). Lower FENO was associated with more-severe tuberculosis disease, with FENO directly proportional to weight (P < .001) and forced vital-capacity (P = .001) and inversely proportional to radiological score (P = .03). People whose FENO increased or remained unchanged by 2 months were 2.7-fold more likely to achieve conversion of sputum culture than those whose FENO decreased (odds ratio, 2.72; 95% CI, 1.05-7.12; P = .04). CONCLUSIONS: Among patients with pulmonary tuberculosis, impaired pulmonary NO bioavailability is associated with more-severe disease and delayed mycobacterial clearance. Measures to increase pulmonary NO warrant investigation as adjunctive tuberculosis treatments.

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.

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). METHODS: Asthmatic subjects (n = 26), aged ≥55 years (68% female), were studied, and AHR to 4.5% saline challenge was measured by the response-dose ratio (%fall in forced expiratory volume in 1 s (FEV1 )/mg saline). Airway closure was assessed during bronchoconstriction percent change in forced vital capacity (FVC)/percent change in FEV1 (i.e. Closing Index). Airway inflammation was assessed by induced sputum and exhaled nitric oxide (eNO). RESULTS: Mean patient age was 67 years (confidence interval: 63-71) with a mean FEV1 of 78 % predicted (confidence interval: 70-85%). AHR correlated with sputum eosinophils (r = 0.68, P = 0.005) and eNO (r = 0.71, P < 0.001), but not with neutrophils or neutrophil mediators. The Closing Index correlated with total sputum neutrophils (r = 0.66, P = 0.005), neutrophil elastase, matrix metalloproteinase-9 and interleukin-8 (all P < 0.05). Further, FEV1 /FVC and residual volume/total lung capacity at rest correlated with neutrophil elastase (r = -0.46 and 0.66 respectively, P < 0.05) but not with eosinophils or eNO. CONCLUSIONS: In older patients with asthma, airway inflammatory cells are linked to abnormal airway physiology. Eosinophilic airway inflammation is associated with AHR while neutrophilic inflammation may be an important determinant of airflow limitation at rest and airway closure during bronchoconstriction. The clinical implications of these findings remain to be determined.

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.

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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

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.

The dynamic face of respiratory research: understanding the effect of airway disease on a lung in constant motion.

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.

Deep inspirations protect against airway closure in nonasthmatic subjects.

The mechanism by which deep inspirations protect against increased airway responsiveness in nonasthmatic subjects is not known. The aim was to investigate the role of airway closure and airway narrowing in deep inspiration bronchoprotection. Twelve nonasthmatic and nine asthmatic subjects avoided deep inspirations (DI) for 20 min, then took five DI expired to functional residual capaciy (DI-FRC) or, on a separate day, no DI (no DI) before inhaling a single dose of methacholine. On another day, eight nonasthmatic subjects took five DI expired to residual volume (DI-RV). Peripheral airway function was measured by respiratory system reactance (Xrs), using the forced oscillation technique, and by forced vital capacity (FVC) as an index of airway closure. Respiratory system resistance (Rrs) and forced expiratory volume in 1 s (FEV1)/FVC were measured as indexes of airway narrowing. In nonasthmatic subjects, DI-FRC reduced the response measured by FEV1 (P=0.019), Xrs (P=0.02), and FVC (P=0.0005) but not by Rrs (P=0.15) or FEV1/FVC (P=0.52) compared with no DI. DI-RV had a less protective effect than DI-FRC on response measured by FEV1 (P=0.04) and FVC (P=0.016). There was no difference between all protocols when the response was measured by Xrs (P=0.20), Rrs (P=0.88), or FEV1/FVC (P=0.88). DI had no effect on methacholine response in asthmatic subjects. DI protect against airway responsiveness through an effect on peripheral airways involving reduced airway closure. The protective effect of DI on FEV1 and FVC was abolished by expiration to residual volume. We speculate that the reduced airway closure is due to reduced baseline ventilation heterogeneity and/or reduced airway surface tension.

Mechanisms of airway hyperresponsiveness in asthma.

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.

Short-term variability of airway caliber-a marker of asthma?

Variability in airway caliber is a characteristic feature of asthma. Previous studies reported that the variability in respiratory system impedance (Zrs), measured by the forced oscillation technique during several minutes of tidal breathing, is increased in asthma and may be a marker of inherent instability of the airways. The aims of this study were to determine if short-term variability in impedance correlates with peak expiratory flow (PEF) variability or airway hyperresponsiveness (AHR). The SD of log-transformed impedance (lnZrsSD) was measured as a marker of short-term variability and compared with the diurnal variability of PEF over 2 wk in 28 asthmatic and 7 nonasthmatic subjects and with AHR to histamine in a cohort of 17 asthmatic and 82 nonasthmatic subjects. In addition, lnZrsSD was measured in eight nonasthmatic subjects before and after methacholine challenge in the upright and supine positions. There were no significant differences in lnZrsSD between asthmatic and nonasthmatic subjects (P = 0.68). Furthermore, in asthmatic subjects, lnZrsSD did not correlate with diurnal variability of PEF (rs = -0.12 P = 0.54) or with AHR to histamine (r = 0.10, P = 0.71). Neither methacholine challenge nor supine posture caused any significant change in lnZrsSD. We conclude that our findings do not support previous reports about the utility of short-term variability of impedance. Our findings suggest that, using standard methods for forced oscillometry, impedance variability does not provide clinically useful information about the severity of asthma.

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. Fourteen asthmatic subjects underwent ventilation single-photon-emission computed tomography/computed tomography scan imaging before and after methacholine challenge. One-liter breaths of Technegas were inhaled from functional residual capacity in upright posture before supine scanning. The lung regions with the lowest ventilation (Ventlow) were calculated using a thresholding method and expressed as a percentage of total ventilation (Venttotal). Multiple-breath nitrogen washout was used to measure diffusion-dependent and convection-dependent ventilation heterogeneity (Sacin and Scond, respectively) and lung clearance index (LCI), before and after challenge. Forced expiratory volume in 1 s (FEV1) was 87.6 ± 15.8% predicted, and seven subjects had airway hyperresponsiveness. Ventlow at baseline was unrelated to spirometry or multiple-breath nitrogen washout indices. Methacholine challenge decreased FEV1 by 23 ± 5% of baseline while Ventlow increased from 21.5 ± 2.3%Venttotal to 26.3 ± 6.7%Venttotal (P = 0.03). The change in Ventlow was predicted by baseline Sacin (rs = 0.60, P = 0.03) and by LCI (rs = 0.70, P = 0.006) but not by Scond (rs = 0.30, P = 0.30). The development of low-ventilation lung units in three-dimensional ventilation imaging is predicted by ventilation heterogeneity in diffusion-dependent airways. This relationship suggests that acinar ventilation heterogeneity in asthma may be of mechanistic importance in terms of bronchoconstriction and airway narrowing.NEW & NOTEWORTHY Using ventilation SPECT/CT imaging in asthmatics, we show induced bronchoconstriction leads to the development of areas of low ventilation. Furthermore, the relative volume of the low-ventilation regions was predicted by ventilation heterogeneity in diffusion-dependent acinar airways. This suggests that the pattern of regional airway narrowing in asthma is determined by acinar airway function.

Effects of methacholine on small airway function measured by forced oscillation technique and multiple breath nitrogen washout in normal subjects.

The multiple breath nitrogen washout (MBNW) can be analysed to produce the parameters Scond and Sacin as measures of ventilation heterogeneity in conductive and acinar airways, respectively. The derivation of these parameters is based on a model of pulmonary ventilation and results of similar modelling suggest that respiratory system conductance (Grs) measured by forced oscillation technique (FOT) is also sensitive to heterogeneity and to airway closure. Therefore, Scond, the volume of gas trapping at FRC (VtrappedFRC) and Grs may be inter-related parameters. These relationships were examined in 12 normals under baseline and bronchoconstricted states. Specific Grs was measured at 5Hz (sGrs5=Grs5/FRC) and Scond, Sacin and VtrappedFRC by MBNW, before and after methacholine challenge. Scond was independently predicted by VtrappedFRC and FRC in a multivariate model (R2=0.68, p=0.002). Post methacholine challenge, Scond related only to VtrappedFRC (R2=0.79, p<0.0001). The absolute change in Scond induced by methacholine challenge were predicted by the changes in VtrappedFRC and sGrs5 in a multivariate model (R2=0.82, p=0.0002). Sacin was unrelated to VtrappedFRC and sGrs5 before and after methacholine challenge. In conclusion, Scond and sGrs5 are measurements that are sensitive to changes occurring to the function of peripheral conducting airways, in particular heterogeneity and airway closure, while Sacin and presumably heterogeneity in terminal airways, are independent of these. Scond is also related to lung size. We review the current state of knowledge of FOT and MBNW in obstructive lung diseases and discuss future research directions.

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. SUBJECTS AND METHODS: A total of 29 subjects with COPD were recruited within 48 hours of admission to West China Hospital for an acute exacerbation. Daily measurements of post-bronchodilator spirometry, resistance, and reactance using the forced oscillation technique and symptom (Borg) scores until discharge were made. Flow-limited breathing was defined as the difference between inspiratory and expiratory respiratory system reactance (EFL index) greater than 2.8 cmH2O·s·L(-1). The physiological predictors of symptoms during recovery were determined by mixed-effect analysis. RESULTS: Nine subjects (31%) had flow-limited breathing on admission despite similar spirometry compared to subjects without flow-limited breathing. Spirometry and resistance measures did not change between enrolment and discharge. EFL index values improved in subjects with flow-limited breathing on admission, with resolution in four patients. In subjects with flow-limited breathing on admission, symptoms were related to inspiratory resistance and EFL index values. In subjects without flow-limited breathing, symptoms related to forced expiratory volume in 1 second/forced vital capacity. In the whole cohort, EFL index values at admission was related to duration of stay (Rs=0.4, P=0.03). CONCLUSION: The presence of flow-limited breathing as well as abnormal respiratory system mechanics contribute independently to symptoms during COPD exacerbations.

Modeling airway resistance dynamics after tidal and deep inspirations.

Using the forced oscillation technique, we tracked airway resistance continuously during quiet breathing (QB) and deep inspiration (DI), thus observing fluctuations in resistance that may reflect mechanisms of airway stretch and renarrowing. After DI, however, the resistance may be depressed for a period not related to volume changes. We hypothesized that this gradual increase in resistance after DI-induced dilation was determined by a simple time constant. Furthermore, to the extent that this effect reflects dynamic characteristics of airway renarrowing, the resistance change after each tidal inspiration should also be constrained by this temporal limit. A model relating resistance fluctuations to the breathing pattern, including both instantaneous and delayed effects, was developed and applied to data from 14 nonasthmatic and 17 asthmatic subjects (forced expiratory volume in 1 s = 103 +/- 13 and 83 +/- 12%, respectively, means +/- SD) after methacholine challenge (dose 145 +/- 80 and 3.0 +/- 3.4 micromol, respectively) that resulted in respective forced expiratory volume in 1 s reductions of 16 +/- 7 and 24 +/- 6% from baseline. Resistance was measured continuously for 1 min of QB, a DI, followed by a further minute of QB. Resistance values at end expiration (Ree) and end inspiration were calculated. We found that the sequence of Ree after DI was best modeled by a power-law function of time rather than an exponential decay (r2 = 0.82 +/- 0.18 compared with 0.63 +/- 0.16; P < 0.01). Furthermore, the coefficient characterizing this "renarrowing function" was close to equal to the coefficient characterizing the equivalent function of resistance change between each resistance value at end inpiration and subsequent Ree during QB, particularly in the nonasthmatic subjects for whom the intraclass correlation was 0.66. This suggests that the same time-dependent factors determine renarrowing after both large and small breaths.

A single high dose of inhaled corticosteroids: a possible treatment of asthma exacerbations.

UNLABELLED: Recovery from an asthma exacerbation may take days or weeks even after the introduction of appropriate exacerbation therapy. However airway responsiveness and sputum eosinophils can be reduced within 6 hours by a single dose of inhaled corticosteroids. AIM: To determine if a single dose of 3200 microg of budesonide increases the rate of recovery from an asthma exacerbation. METHODS: Nineteen asthmatic subjects with an asthma exacerbation following withdrawal of inhaled corticosteroids were randomised to receive either usual care (doubling their dose of inhaled corticosteroids) plus placebo or usual care plus a single dose of 3200 microg of budesonide in a double-blind manner. Subjects monitored peak flow (PEF), symptoms, and beta agonist use daily for four weeks. The lowest PEF reading for each week was calculated as a percentage of the best peak flow value achieved in the recent past (PEF lowest % best). RESULTS: In the first week following exacerbation, PEF (lowest % best) was significantly greater in the budesonide group than in the placebo group (87.4 +/- 4.7 vs. 76.7 +/- 5.3; p = 0.029). However in the fourth week following exacerbation PEF was not significantly different (p = 0.728). The proportion of subjects who had a symptom free day during the first week was significantly higher in the budesonide group (p = 0.0012). CONCLUSION: A single high dose of inhaled corticosteroids added to usual exacerbation treatment might increase the rate of recovery from a mild exacerbation of asthma.