Normal limits for oscillometric bronchodilator responses and relationships with clinical factors.

INTRODUCTION: We aimed to determine normal thresholds for positive bronchodilator responses for oscillometry in an Australian general population sample aged ≥40 years, to guide clinical interpretation. We also examined relationships between bronchodilator responses and respiratory symptoms, asthma diagnosis, smoking and baseline lung function. METHODS: Subjects recruited from Sydney, Melbourne and Busselton, Australia, underwent measurements of spirometry, resistance (R rs6 ) and reactance (X rs6 ) at 6 Hz, before and after inhalation of salbutamol 200 µg. Respiratory symptoms and/or medication use, asthma diagnosis, and smoking were recorded. Threshold bronchodilator responses were defined as the fifth percentile of decrease in R rs6 and 95th percentile increase in X rs6 in a healthy subgroup. RESULTS: Of 1318 participants, 1145 (570 female) were analysed. The lower threshold for ΔR rs6 was -1.38 cmH2O·s·L-1 (-30.0% or -1.42 Z-scores) and upper threshold for ΔX rs6 was 0.57 cmH2O·s·L-1 (1.36 Z-scores). Respiratory symptoms and/or medication use, asthma diagnosis, and smoking all predicted bronchodilator response, as did baseline oscillometry and spirometry. When categorised into clinically relevant groups according to those predictors, ΔX rs6 was more sensitive than spirometry in smokers without current asthma or chronic obstructive pulmonary disease (COPD), ∼20% having a positive response. Using absolute or Z-score change provided similar prevalences of responsiveness, except in COPD, in which responsiveness measured by absolute change was twice that for Z-score. DISCUSSION: This study describes normative thresholds for bronchodilator responses in oscillometry parameters, including intra-breath parameters, as determined by absolute, relative and Z-score changes. Positive bronchodilator response by oscillometry correlated with clinical factors and baseline function, which may inform the clinical interpretation of oscillometry.

Reduced lung elastic recoil and fixed airflow obstruction in asthma.

BACKGROUND AND OBJECTIVE: Fixed airflow obstruction (FAO) in asthma occurs despite optimal inhaled treatment and no smoking history, and remains a significant problem, particularly with increasing age and duration of asthma. Increased lung compliance and loss of lung elastic recoil has been observed in older people with asthma, but their link to FAO has not been established. We determined the relationship between abnormal lung elasticity and airflow obstruction in asthma. METHODS: Non-smoking asthmatic subjects aged >40 years, treated with 2 months of high-dose inhaled corticosteroid/long-acting beta-agonist (ICS/LABA), had FAO measured by spirometry, and respiratory system resistance at 5 Hz (Rrs5 ) and respiratory system reactance at 5 Hz (Xrs5 ) measured by forced oscillation technique. Lung compliance (K) and elastic recoil (B/A) were calculated from pressure-volume curves measured by an oesophageal balloon. Linear correlations between K and B/A, and forced expiratory volume in 1 s/forced vital capacity (FEV1 /FVC), Rrs5 and Xrs5 were assessed. RESULTS: Eighteen subjects (11 males; mean ± SD age: 64 ± 8 years, asthma duration: 39 ± 22 years) had moderate FAO measured by spirometry ((mean ± SD z-score) post-bronchodilator FEV1 : -2.2 ± 0.5, FVC: -0.7 ± 1.0, FEV1 /FVC: -2.6 ± 0.7) and by increased Rrs5 (median (IQR) z-score) 2.7 (1.9 to 3.2) and decreased Xrs5 : -4.1(-2.4 to -7.3). Lung compliance (K) was increased in 9 of 18 subjects and lung elastic recoil (B/A) reduced in 5 of 18 subjects. FEV1 /FVC correlated negatively with K (rs = -0.60, P = 0.008) and Rrs5 correlated negatively with B/A (rs = -0.52, P = 0.026), independent of age. Xrs5 did not correlate with lung elasticity indices. CONCLUSION: Increased lung compliance and loss of elastic recoil relate to airflow obstruction in older non-smoking asthmatic subjects, independent of ageing. Thus, structural lung tissue changes may contribute to persistent, steroid-resistant airflow obstruction. CLINICAL TRIAL REGISTRATION: ACTRN126150000985583 at anzctr.org.au (UTN: U1111-1156-2795).

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.

Contribution of air pollution to COPD and small airway dysfunction.

Although in many Western countries levels of ambient air pollution have been improving with the setting of upper limits and better urban planning, air pollution in developing countries and particularly those with rapid industrialization has become a major global problem. Together with increased motor vehicle ownership and traffic congestion, there is a growing issue with airborne particles of respirable size. These particles are thought responsible for respiratory and cardiovascular effects and have also been implicated in cancer pathogenesis. The pathologic effects in the lung are mediated via inflammatory pathways and involve oxidative stress similar to cigarette smoking. These effects are seen in the peripheral airways where the smaller particle fractions are deposited and lead to airway remodelling. However, emphysema and loss of bronchioles seen with cigarette smoking have not been described with ambient air pollution, and there are few studies specifically looking at peripheral airway function. Definitive evidence of air pollution causing COPD is lacking and a different study design is required to link air pollution and COPD.

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. Subjects then self-recorded FOT twice daily for ten consecutive days with data transmitted to the laboratory server via a 3G mobile network. Subjects had a mean (SD) age of 68(8) years, smoking history 38.4(8.7) pack/years, post-bronchodilator FEV1 42.4(12.0)% predicted, FEV1/FVC ratio 0.45(0.10), mean Rrs 121.7(26.1)% predicted and mean Xrs 746.8(330.3)% predicted. The supervised measurements of mean Rrs and mean Xrs were similar to the unsupervised measurements (p = 0.34 and p = 0.92, respectively). 197 of 200 possible measurements were transmitted, all of which were deemed to be technically acceptable. The within-subject standard deviation, Sw, of Rrs-total and Xrs-total were 0.47 and 1.0 cmH(2)O L s(-1), respectively. Subjects who have COPD make reliable, unsupervised FOT measurements at home with a high degree of adherence. The day-to-day variability of FOT measurements was similar to that of supervised laboratory recordings. These results support the conduct of larger, longer-term studies of FOT monitoring in COPD.

Cut-points for response to mannitol challenges using the forced oscillation technique.

The forced oscillation technique (FOT) can be used to determine airway hyperresponsiveness, but the cut-points for changes in respiratory system conductance (Grs) and reactance (Xrs) that define a positive mannitol challenge are not known. Furthermore, the effects of changes in lung volume on these cut-points or on the repeatability of the test are unknown. In 15 non-asthmatic and 52 asthmatic subjects, response to mannitol challenge was measured by Grs and Xrs, using FOT, and by FEV(1). The FOT variables were adjusted for inspiratory capacity (IC) at each dose. Dose response slope (DRS) was used in receiver operator characteristic (ROC) analysis to compare the ability of adjusted and unadjusted DRSGrs and DRSXrs to detect a positive challenge, defined as PD(15)FEV(1) ≤635 mg mannitol. Mannitol challenges were positive in 32 asthmatic and 2 non-asthmatic subjects. Both DRSGrs and DRSXrs detected positive challenges (p < 0.0001 for both), and this was not altered by adjustment for IC for either DRSGrs (p = 0.21) or DRSXrs (p = 0.90). FOT cut-points for a positive challenge were 27% fall in Grs or 0.93 cm H(2)O/L/s decrease in Xrs at 635 mg. Repeatability of DRSGrs (±2.01 doubling doses) and DRSXrs (±1.95dd) was comparable with DRSFEV(1) (±1.67dd) and was not improved by adjustment for IC. Grs and Xrs, measured by FOT, provide a sensitive, repeatable measure of response to mannitol challenge. Adjusting for lung volume does not alter the ability of these variables to detect a positive response or the repeatability of the measurement.

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-alpha) 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.

Cigarette smoking increases neutrophil formyl methionyl leucyl phenylalanine receptor numbers.

STUDY OBJECTIVES: The purpose of this study was to explore the relationship between cigarette smoking and COPD on the number of formyl methionyl leucyl phenylalanine (FMLP) receptors on peripheral neutrophils. DESIGN AND PARTICIPANTS: Three groups of subjects were studied: subjects with COPD (n = 13), healthy smokers (n = 6), and healthy nonsmokers (n = 6). INTERVENTIONS: Fifty milliliters of venous blood were collected from each subject, and neutrophils were isolated. Neutrophil FMLP receptor numbers were determined by incubating with tritiated FMLP at six doubling concentrations from 1.4 to 45 pmol. Three of the subjects from group 1 (the COPD group) were current smokers, and we elected to analyze these subjects as a separate group. MEASUREMENTS AND RESULTS: The analysis of variance looking at the three factors-FMLP, COPD and smoking-showed significant differences among levels of FMLP (p = 0.0001), as would be expected, and also overall smoking vs nonsmoking (p = 0001) and COPD vs non-COPD (p = 0.02). Within each level of FMLP, there was only one instance of a significant difference between COPD nonsmokers and normal nonsmokers, and no instance of a significant difference between COPD smokers and normal smokers. At five of the six concentrations of tritiated FMLP, smoking was a significant factor. CONCLUSIONS: This study suggests that the overriding influence on peripheral neutrophil FMLP receptor numbers is current smoking rather than the presence of COPD.