Expiratory and inspiratory resistance and reactance from respiratory oscillometry defining expiratory flow limitation in obstructive lung diseases.

BACKGROUND: Expiratory flow limitation (EFL) during tidal breathing and lung hyperinflation have been identified as major decisive factors for disease status, prognosis and response to therapy in obstructive lung diseases. AIM: To investigate the delta values between expiratory and inspiratory resistance and reactance, measured using respiratory oscillometry and its correlation with air trapping and symptoms in subjects with obstructive lung diseases. METHODS: Four hundred and seventy-one subjects (96 with chronic obstructive pulmonary disease [COPD], 311 with asthma, 30 healthy smokers and 34 healthy subjects) were included. Spirometry, body plethysmography and respiratory oscillometry measurements were performed and the differences between the expiratory and inspiratory respiratory oscillometry values (as delta values) were calculated. Questionnaires regarding symptoms and quality of life were administered. RESULTS: Patients with COPD and healthy smokers had an increased delta resistance at 5 Hz (R5) compared with patients with asthma (p < 0.0001 and p = 0.037, respectively) and healthy subjects (p = 0.0004 and p = 0.012, respectively). Patients with COPD also had higher values of ΔR5-R19 than healthy subjects (p = 0.0001) and patients with asthma (p < 0.0001). Delta reactance at 5 Hz (X5) was significantly more impaired in COPD patients than in asthma and healthy subjects (p < 0.0001 for all). There was a correlation between the ratio of residual volume and total lung capacity and ΔR5 (p = 0.0047; r = 0.32), ΔR5-R19 (p = 0.0002; r = 0.41) and ΔX5 (p < 0.0001; r = -0.44), for all subjects. ΔX5 correlated with symptoms in COPD, healthy smokers and patients with asthma. In addition, ΔR5 correlated with asthma symptoms. CONCLUSION: EFL was most prominent in parameters measuring peripheral resistance and reactance and correlated with air trapping and airway symptoms.

Bronchodilator Responsiveness Measured by Spirometry and Impulse Oscillometry in Patients with Asthma After Short Acting Antimuscarinic and/or Beta-2-Agonists Inhalation.

Background: Bronchodilator responsiveness (BDR) in asthma involves both the central and peripheral airways but is primarily relieved with beta-2-agonists and evaluated by spirometry. To date, antimuscarinics can be added as a reliever medication in more severe asthma. We hypothesize that combining both short-acting beta-2 agonist (SABA) and short-acting muscarinic antagonist (SAMA) could also improve the responsiveness in mild-moderate asthma. Therefore, we aimed to compare the direct effects of inhaling SABA alone, SAMA alone or combining both SABA and SAMA on the central and peripheral airways in asthma. Methods: Twenty-three patients with mild-moderate BDR in asthma performed dynamic spirometry and impulse oscillometry before (baseline) and multiple timepoints within an hour after inhalation of SABA (salbutamol), SAMA (ipratropium bromide), or both SABA and SAMA at three different visits. Results: The use of SAMA alone did not show any improvement compared to the use of SABA alone. Inhalation of SABA+SAMA, however, averaged either similar or better BDR than SABA alone in FEV1, MMEF, FVC, R5, R20 and R5-R20. Inhaling SABA+SAMA reached a stable BDR in more patients within 0-10 minutes and also reached the FEV1 (Δ%)>12% faster (3.5 minutes) than inhaling SABA alone (5.1 minutes). Inhaling SABA+SAMA was significantly better than SAMA alone in FEV1 (p = 0.015), MMEF (p = 0.0059) and R20 (p = 0.0049). Using these three variables highlighted a subgroup (30%, including more males) of patients that were more responsive to inhaling SABA+SAMA than SABA alone. Conclusion: Overall, combining SAMA with SABA was faster and more consistent at increasing the lung function than SABA alone or SAMA alone, and the additive effect was best captured by incorporating peripheral-related variables. Therefore, SAMA should be considered as an add-on reliever for mild-moderate patients with BDR in asthma.

Neutrophil phenotypes in bronchial airways differentiate single from dual responding allergic asthmatics.

INTRODUCTION: Allergic asthmatics with both an early (EAR) and a late allergic reaction (LAR) following allergen exposure are termed 'dual responders' (DR), while 'single responders' (SR) only have an EAR. Mechanisms that differentiate DR from SR are largely unknown, particularly regarding the role and phenotypes of neutrophils. Therefore, we aimed to study neutrophils in DR and SR asthmatics. METHODS: Thirty-four allergic asthmatics underwent an inhaled allergen challenge, samples were collected before and up to 24 h post-challenge. Cell differentials were counted from bronchial lavage, alveolar lavage and blood; and tissue neutrophils were quantified in immune-stained bronchial biopsies. Lavage neutrophil nuclei lobe segmentation was used to classify active (1-4 lobes) from suppressive neutrophils (≥5 lobes). Levels of transmigration markers: soluble (s)CD62L and interleukin-1Ra, and activity markers: neutrophil elastase (NE), DNA-histone complex and dsDNA were measured in lavage fluid and plasma. RESULTS: Compared with SR at baseline, DR had more neutrophils in their bronchial airways at baseline, both in the lavage (p = .0031) and biopsies (p = .026) and elevated bronchial neutrophils correlated with less antitransmigratory IL-1Ra levels (r = -0.64). DR airways had less suppressive neutrophils and more 3-lobed (active) neutrophils (p = .029) that correlated with more bronchial lavage histone (p = .020) and more plasma NE (p = .0016). Post-challenge, DR released neutrophil extracellular trap factors in the blood earlier and had less pro-transmigratory sCD62L during the late phase (p = .0076) than in SR. CONCLUSION: DR have a more active airway neutrophil phenotype at baseline and a distinct neutrophil response to allergen challenge that may contribute to the development of an LAR. Therefore, neutrophil activity should be considered during targeted diagnosis and bio-therapeutic development for DR.

Single-nucleotide polymorphisms in the sulfatase-modifying factor 1 gene are associated with lung function and COPD.

Single nucleotide polymorphisms (SNPs) in various genes have been shown to associate with COPD, suggesting a role in disease pathogenesis. Sulfatase modifying factor (SUMF1) is a key modifier in connective tissue remodelling, and we have shown previously that several SNPs in SUMF1 are associated with COPD. The aim of this study was to investigate the association between SUMF1 SNPs and advanced lung function characteristics. Never-, former and current smokers with (n=154) or without (n=405) COPD were genotyped for 21 SNPs in SUMF1 and underwent spirometry, body plethysmography, diffusing capacity of the lung for carbon monoxide (D LCO) measurement and impulse oscillometry. Four SNPs (rs793391, rs12634248, rs2819590 and rs304092) showed a significantly decreased odds ratio of having COPD when heterozygous for the variance allele, together with a lower forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) ratio and an impaired peripheral resistance and reactance. Moreover, individuals homozygous for the variance allele of rs3864051 exhibited a strong association to COPD, a lower FEV1/FVC, FEV1 and D LCO, and an impaired peripheral resistance and reactance. Other SNPs (rs4685744, rs2819562, rs2819561 and rs11915920) were instead associated with impaired lung volumes and exhibited a lower FVC, total lung capacity and alveolar volume, in individuals having the variance allele. Several SNPs in the SUMF1 gene are shown to be associated with COPD and impaired lung function. These genetic variants of SUMF1 may cause a deficient sulfation balance in the extracellular matrix of the lung tissue, thereby contributing to the development of COPD.

A new protocol for exercise testing in COPD; improved prediction algorithm for WMAX and validation of the endurance test in a placebo-controlled double bronchodilator study.

BACKGROUND: Two new protocols have been developed for bicycle exercise testing in chronic obstructive pulmonary disease (COPD) with an individualized cardiopulmonary exercise test (ICPET) and subsequent customized endurance test (CET), which generate less interindividual spread in endurance time compared with the standard endurance test. Main objectives of this study were to improve the prediction algorithm for WMAX for the ICPET and validate the CET by examining treatment effects on exercise performance of indacaterol/glycopyrronium (IND/GLY) compared with placebo. METHODS: COPD patients, with forced expiratory volume in 1 s (FEV1) 40-80% predicted, were recruited. Pooled baseline data from two previous studies (n = 38) were used for the development of an improved WMAX prediction algorithm. Additional COPD patients (n = 14) were recruited and performed the ICPET, using the new prediction formula at visit 1. Prior to the CET at visits 2 and 3, they were randomized to a single dose of IND/GLY (110/50 µg) or placebo. RESULTS: The improved multiple regression algorithm for WMAX includes diffusing capacity for carbon monoxide (DLCO), FEV1, sex, age and height and correlated to measured WMAX (R2 = 0.89 and slope = 0.89). Treatment with IND/GLY showed improvement in endurance time versus placebo, mean 113 s [95% confidence interval (CI): 6-220], p = 0.037, with more prominent effect in patients with FEV1 < 70% predicted. CONCLUSION: The two new protocols for ICPET (including the new improved algorithm) and CET were retested with consistent results. In addition, the CET showed a significant and clinically relevant prolongation of endurance time for IND/GLY versus placebo in a small number of patients.

Reduced Variability of Endurance Time in New Protocols for Exercise Tests in COPD.

Purpose: For exercise testing of COPD patients, a standard endurance test (ET) with constant workload is recommended. The test suffers from large inter-individual variability and need for large sample sizes in order to evaluate treatment effects. Methods: A new protocol for ET in COPD was designed. In contrast to the standard ET, the new ET involved an increasing workload in order to reduce the standard deviation of endurance time. Two new ETs were compared with the standard ET. In Study A, the new ET started at 75% of the patient's maximum workload (WMAX) and increased stepwise with 3%/2 min until exhaustion. Study B started at 70% of WMAX and increased linearly with 1%/min. Results: In Study A, that included 15 patients, the standard deviation and range for endurance time and work capacity were narrower for the new versus the standard ET. However, the higher mean workload at end and the low mean work capacity relative to the standard ET indicated that the stepwise increase was too aggressive. In Study B, that included 18 patients, with a modified protocol, the averages for endurance time, workload at end and work capacity were similar for new and standard ET, while the standard deviations and ranges for endurance time and work capacity were kept more narrow in the new ET. The variances for endurance time were not equal between the standard ET and the two new ETs (p<0.05 for both according to Levene's test). Conclusion: The new ET reduced the number of patients with extreme endurance times (short and long) compared to the standard test. The new test showed a significant lower variance for endurance time, which potentially can lead to fewer patients needed in comparative studies. The overall best results were observed with a low linear increase during endurance.

Type 2 Inflammatory Biomarker Response After Exercise Challenge Testing.

INTRODUCTION: Exercise-induced bronchoconstriction is due to osmotic stimulus of the airway epithelium and leads to a cascade of biomarker release from several inflammatory cells. Several type 2 (T2) mediators have been linked to exercise-induced bronchoconstriction, but the T2 response per se has not been described during exercise. The aim of this study was therefore to investigate T2 biomarkers in plasma and urine from subjects with asthma and healthy controls before and after an exercise challenge. METHODS: Twenty-two subjects with mild asthma and 18 healthy controls performed an exercise challenge test on a treadmill, and fractional exhaled NO (FeNO) was measured at baseline. Blood and urine samples were collected repeatedly during 60 min after the test and Interleukin-13 (IL-13), thymus and activation-related chemokine (TARC), periostin and leukotrienes were measured. RESULTS: Asthmatics and controls showed similar levels of IL-13, TARC, periostin and Cys-LT in plasma at baseline, and there were no differences in baseline levels between subjects with a negative and positive exercise challenge. After exercise, there was an overall increase in interleukin-13 (IL-13) in plasma in all subjects (p<0.001), with a peak at 10 min after the exercise challenge in both the asthmatic and control group. An increase in TARC in plasma was also seen (p<0.001), but only in the control subjects. In contrast, Cys-LT in plasma showed an overall decrease in all subjects (p<0.001), while periostin in plasma did not change. In conjunction with plasma, the level of IL-13 was increased in urine 30 min after the exercise challenge (p=0.002) and decreased again at 60 min (p=0.004). Similarly, leukotriene E4 (LTE4) was increased in urine samples, with a peak at 60 min and most pronounced in asthmatic subjects (p<0.001) but was seen also in controls (p=0.008). DISCUSSION: In conclusion, circulating levels of IL-13 are increased after exercise to the same extent in asthmatics and healthy control subjects, which indicates a physiological rather than a pathophysiological response. Also, the levels of TARC and leukotrienes were affected after exercise.

A new maximal bicycle test using a prediction algorithm developed from four large COPD studies.

Background: Maximum exercise workload (WMAX) is today assessed as the first part of Cardiopulmonary Exercise testing. The WMAX test exposes patients with COPD, often having cardiovascular comorbidity, to risks. Our research project was initiated with the final aim to eliminate the WMAX test and replace this test with a predicted value of WMAX, based on a prediction algorithm of WMAX derived from multicentre studies. Methods: Baseline data (WMAX, demography, lung function parameters) from 850 COPD patients from four multicentre studies were collected and standardized. A prediction algorithm was prepared using Random Forest modelling. Predicted values of WMAX were used in a new WMAX test, which used a linear increase in order to reach the predicted WMAX within 8 min. The new WMAX test was compared with the standard stepwise WMAX test in a pilot study including 15 patients with mild/moderate COPD. Results: The best prediction algorithm of WMAX included age, sex, height, weight, and six lung function parameters. FEV1 and DLCO were the most important predictors. The new WMAX test had a better correlation (R2 = 0.84) between predicted and measured WMAX than the standard WMAX test (R2 = 0.66), with slopes of 0.50 and 0.46, respectively. The results from the new WMAX test and the standard WMAX test correlated well. Conclusion: A prediction algorithm based on data from four large multicentre studies was used in a new WMAX test. The prediction algorithm provided reliable values of predicted WMAX. In comparison with the standard WMAX test, the new WMAX test provided similar overall results.

Expression, activity and localization of lysosomal sulfatases in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death world-wide. Recently, we showed that COPD is associated with gene polymorphisms in SUMF1, a master regulator of sulfatases. Sulfatases are involved in extracellular matrix remodeling and activated by SUMF1, but their role in the lung is poorly described. We aimed to examine how sulfatases are affected in the airways of patients with COPD compared to ever smokers and never smokers. We observed that mRNA expression of the sulfatases GALNS, GNS and IDS was increased, while protein expression of many sulfatases was decreased in COPD fibroblasts. Several sulfatases, including GALNS, IDS, and SGSH, showed increased activity in COPD fibroblasts. Examination of different sulfatases by immunofluorescence showed that IDS, ARSB, GNS and SGSH in fibroblasts were localized to sites other than their reported destination. Using a master panel from different organs, RNA expression of all sulfatases could be observed in lung tissue. Additionally, immunohistochemistry on lung biopsies indicated differing expression of sulfatases in COPD patients. In conclusion, mRNA, protein expression, sulfatase activity levels, and localization of sulfatases are altered in lung fibroblasts and lung tissue from COPD patients and may be mechanistically important in COPD pathogenesis. This could contribute to the understanding of the disease mechanism in COPD and in the long run, to lead to more individualized therapies.

The Efficiency Index (EFFi), based on volumetric capnography, may allow for simple diagnosis and grading of COPD.

Background: Spirometry, the main tool for diagnosis and follow-up of COPD, incompletely describes the disease. Based on volumetric capnography (VCap), an index was developed for the diagnosis and grading of COPD, aimed as a complement or alternative to spirometry. Methods: Nine non-smokers, 10 smokers/former smokers without COPD and 54 smokers/former smokers with COPD were included in the study. Multiple breath washout of N2 and VCap were studied with Exhalyzer D during tidal breathing. VCap was based on signals for flow rate and CO2 and was recorded during one breath preceding N2 washout. Efficiency Index (EFFi) is the quotient between exhaled CO2 volume and the hypothetical CO2 volume exhaled from a completely homogeneous lung over a volume interval equal to 15% of predicted total lung capacity. Results: EFFi increased with increased Global initiative for chronic Obstructive Lung Disease (GOLD) stage and the majority of subjects in GOLD 2 and all subjects in GOLD 3 and 4 could be diagnosed as having COPD using the lower 95% confidence interval of the healthy group. EFFi also correlated with N2 washout (r=-0.73; p<0.001), forced expiratory volume in 1 second (r=0.70; p<0.001) and diffusion capacity for carbon oxide (r=0.69; p<0.001). Conclusion: EFFi measures efficiency of tidal CO2 elimination that is limited by inhomogeneity of peripheral lung function. EFFi allows diagnosis and grading of COPD and, together with FEV1, may explain limitation of physical performance. EFFi offers a simple, effortless and cost-effective complement to spirometry and might serve as an alternative in certain situations.

Endoplasmic reticulum, Golgi, and lysosomes are disorganized in lung fibroblasts from chronic obstructive pulmonary disease patients.

Chronic Obstructive Pulmonary Disease (COPD) is often caused by smoking and other stressors. This causes oxidative stress, which induces numerous changes on both the transcriptome and proteome of the cell. We aimed to examine if the endomembrane pathway, including the endoplasmic reticulum (ER), Golgi, and lysosomes, was disrupted in fibroblasts from COPD patients as opposed to healthy ever-smokers or never-smokers, and if the response to stress differed. Different cellular compartments involved in the endomembrane pathway, as well as mRNA expression and apoptosis, were examined before and after the addition of stress in lung fibroblasts from never-smokers, ever-smokers, and patients with COPD. We found that the ER, Golgi, and lysosomes were disorganized in fibroblasts from COPD patients under baseline conditions. After a time course with ER stress inducing chemicals, changes to the phenotypes of cellular compartments in COPD patient fibroblasts were observed, and the expression of the ER stress-induced gene ERP72 was upregulated more in the COPD patient's cells compared to ever-smokers or never-smokers. Lastly, a tendency of increased active Caspase-3 was observed in COPD fibroblasts. Our results show that COPD patients have phenotypic changes in the lung fibroblasts endomembrane pathway, and respond differently to stress. Furthermore, these fibroblasts were cultured for several weeks outside the body, but they were not able to regain proper ER structure, indicating that the internal changes to the endomembrane system are permanent in smokers. This vulnerability to cellular stress might be a cause as to why some smokers develop COPD.

Club cell protein (CC16) in plasma, bronchial brushes, BAL and urine following an inhaled allergen challenge in allergic asthmatics.

BACKGROUND: Club cell protein (CC16) is a pneumoprotein secreted by epithelial club cells. CC16 possesses anti-inflammatory properties and is a potential biomarker for airway epithelial damage. We studied the effect of inhaled allergen on pulmonary and systemic CC16 levels. METHODS: Thirty-four subjects with allergic asthma underwent an inhaled allergen challenge. Bronchoscopy with bronchoalveolar lavage (BAL) and brushings was performed before and 24 h after the challenge. CC16 was quantified in BAL and CC16 positive cells and CC16 mRNA in bronchial brushings. CC16 was measured in plasma and urine before and repeatedly after the challenge. Thirty subjects performed a mannitol inhalation challenge prior to the allergen challenge. RESULTS: Compared to baseline, CC16 in plasma was significantly increased in all subjects 0-1 h after the allergen challenge, while CC16 in BAL was only increased in subjects without a late allergic response. Levels of CC16 in plasma and in the alveolar fraction of BAL correlated significantly after the challenge. There was no increase in urinary levels of CC16 post-challenge. Mannitol responsiveness was greater in subjects with lower baseline levels of CC16 in plasma. CONCLUSIONS: The increase in plasma CC16 following inhaled allergen supports the notion of CC16 as a biomarker of epithelial dysfunction.

Sulfatase modifying factor 1 (SUMF1) is associated with Chronic Obstructive Pulmonary Disease.

BACKGROUND: It has been observed that mice lacking the sulfatase modifying factor (Sumf1) developed an emphysema-like phenotype. However, it is unknown if SUMF1 may play a role in Chronic Obstructive Pulmonary Disease (COPD) in humans. The aim was to investigate if the expression and genetic regulation of SUMF1 differs between smokers with and without COPD. METHODS: SUMF1 mRNA was investigated in sputum cells and whole blood from controls and COPD patients (all current or former smokers). Expression quantitative trait loci (eQTL) analysis was used to investigate if single nucleotide polymorphisms (SNPs) in SUMF1 were significantly associated with SUMF1 expression. The association of SUMF1 SNPs with COPD was examined in a population based cohort, Lifelines. SUMF1 mRNA from sputum cells, lung tissue, and lung fibroblasts, as well as lung function parameters, were investigated in relation to genotype. RESULTS: Certain splice variants of SUMF1 showed a relatively high expression in lung tissue compared to many other tissues. SUMF1 Splice variant 2 and 3 showed lower levels in sputum cells from COPD patients as compared to controls. Twelve SNPs were found significant by eQTL analysis and overlapped with the array used for genotyping of Lifelines. We found alterations in mRNA expression in sputum cells and lung fibroblasts associated with SNP rs11915920 (top hit in eQTL), which validated the results of the lung tissue eQTL analysis. Of the twelve SNPs, two SNPs, rs793391 and rs308739, were found to be associated with COPD in Lifelines. The SNP rs793391 was also confirmed to be associated with lung function changes. CONCLUSIONS: We show that SUMF1 expression is affected in COPD patients compared to controls, and that SNPs in SUMF1 are associated with an increased risk of COPD. Certain COPD-associated SNPs have effects on either SUMF1 gene expression or on lung function. Collectively, this study shows that SUMF1 is associated with an increased risk of developing COPD.

Bronchodilator response of advanced lung function parameters depending on COPD severity.

BACKGROUND: COPD is defined as partly irreversible airflow obstruction. The response pattern of bronchodilators has not been followed in advanced lung function parameters. PURPOSE: The aim of this study was to investigate bronchodilator response pattern in advanced lung function parameters in a continuous fashion along forced expiratory volume in 1 second (FEV1) percent predicted (%p) in COPD patients and controls. PATIENTS AND METHODS: Eighty-one smokers/ex-smokers (41 controls and 40 COPD) performed spirometry, body plethysmography, impulse oscillometry and single-breath helium dilution carbon monoxide diffusion at baseline, after salbutamol inhalation and then after an additional inhalation of ipratropium. RESULTS: Most pulmonary function parameters showed a linear increase in response to decreased FEV1%p. The subjects were divided into groups of FEV1%p <65 and >65, and the findings from continuous analysis were verified. The exceptions to this linear response were inspiratory capacity (IC), forced vital capacity (FVC), FEV1/FVC and expiratory resistance (Rex), which showed a segmented response relationship to FEV1%p. IC and FVC, with break points (BP) of 57 and 58 FEV1%p respectively, showed no response above, but an incresed slope below the BP. In addition, in patients with FEV1%p <65 and >65, response of FEV1%p did not correlate to response of volume parameters. CONCLUSION: Response of several advanced lung function parameters differs depending on patients' baseline FEV1%p, and specifically response of volume parameters is most pronounced in COPD patients with FEV1%p <65. Volume and resistance responses do not follow the flow response measured with FEV1 and may thus be used as a complement to FEV1 reversibility to identify flow, volume and resistance responders.

Acinar ventilation heterogeneity in COPD relates to diffusion capacity, resistance and reactance.

The aim of this study was to investigate heterogenic ventilation in the acinar (Sacin) and conductive (Scond) airways of patients with varying chronic obstructive pulmonary disease (COPD) severity and how these relates to advanced lung function parameters, primarily measured by impulse oscillometry (IOS). A secondary aim was to investigate the effects of a short acting beta2-agonist and a muscarinic antagonist on the heterogenic ventilation. Eleven never smoking controls, 12 smoking controls, and 57 COPD patients (7 GOLD 1, 25 GOLD 2, 14 GOLD 3 and 11 GOLD 4) performed flow-volume spirometry, IOS, body plethysmography, single breath carbon monoxide diffusion, and N2-multiple breath washout. Six smoking controls and 13 of the COPD patients also performed double reversibility test by using salbutamol and its combination with ipratropium. Sacin was significantly higher in GOLD 2-4 compared to never smoking controls and smoking controls, but showed similar levels in GOLD 3 and 4. A factor analysis identified 4 components consisting of; 1) IOS parameters, 2) volume parameters, 3) diffusion parameters, Sacin and some IOS parameters and 4) Scond with central obstruction/air trapping. Salbutamol and its combination with ipratropium had no effect on Sacin and Scond. Increased Sacin in COPD was strongly related to diffusion capacity and lung volumes, but also weakly to resistance and reactance, showing a link between ventilation heterogeneity in the acinar airways and parameters measured by IOS.

A new approach to assess COPD by identifying lung function break-points.

PURPOSE: COPD is a progressive disease, which can take different routes, leading to great heterogeneity. The aim of the post-hoc analysis reported here was to perform continuous analyses of advanced lung function measurements, using linear and nonlinear regressions. PATIENTS AND METHODS: Fifty-one COPD patients with mild to very severe disease (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stages I-IV) and 41 healthy smokers were investigated post-bronchodilation by flow-volume spirometry, body plethysmography, diffusion capacity testing, and impulse oscillometry. The relationship between COPD severity, based on forced expiratory volume in 1 second (FEV1), and different lung function parameters was analyzed by flexible nonparametric method, linear regression, and segmented linear regression with break-points. RESULTS: Most lung function parameters were nonlinear in relation to spirometric severity. Parameters related to volume (residual volume, functional residual capacity, total lung capacity, diffusion capacity [diffusion capacity of the lung for carbon monoxide], diffusion capacity of the lung for carbon monoxide/alveolar volume) and reactance (reactance area and reactance at 5Hz) were segmented with break-points at 60%-70% of FEV1. FEV1/forced vital capacity (FVC) and resonance frequency had break-points around 80% of FEV1, while many resistance parameters had break-points below 40%. The slopes in percent predicted differed; resistance at 5 Hz minus resistance at 20 Hz had a linear slope change of -5.3 per unit FEV1, while residual volume had no slope change above and -3.3 change per unit FEV1 below its break-point of 61%. CONCLUSION: Continuous analyses of different lung function parameters over the spirometric COPD severity range gave valuable information additional to categorical analyses. Parameters related to volume, diffusion capacity, and reactance showed break-points around 65% of FEV1, indicating that air trapping starts to dominate in moderate COPD (FEV1 =50%-80%). This may have an impact on the patient's management plan and selection of patients and/or outcomes in clinical research.

Oral iodinated activated charcoal improves lung function in patients with COPD.

The effect of 8 weeks treatment with oral iodinated activated charcoal (IAC) on lung function of patients with moderate chronic obstructive pulmonary disease (COPD) was examined in a double blind randomized placebo controlled parallel group study with 40 patients. In the IAC group, patients showed a statistically significant improvement of FEV1 baseline by 130 ml compared to placebo, corresponding to 8.2% improvement (p = 0.031*). Correlation statistics revealed that the improvement of FEV1 baseline was significantly correlated both to FEV1 post-bronchodilator (p = 0.0020**) and FEV1 post-exercise (0.033*) values. This demonstrates that the improved baseline lung function by IAC did not inhibit a further beta2-adrenoceptor relaxation, and thus that patients did not reach a limit for maximal improvement of the lung function after IAC treatment. Eight patients in the IAC group developed abnormal thyroid hormone levels transiently during the treatment. This side effect was not correlated to improvement of lung function (p = 0.82). No serious adverse effects directly related to the treatment were recorded. In summary, this study demonstrates that iodinated activated charcoal surprisingly and significantly improved lung function of patients with moderate COPD. The underlying mechanism of action is unclear, but is likely to be different from the drugs used today. The immediate conclusion is that further studies are now justified in order to determine clinical efficacy of IAC in COPD and explore possible mechanisms of action.

Increase of club cell (Clara) protein (CC16) in plasma and urine after exercise challenge in asthmatics and healthy controls, and correlations to exhaled breath temperature and exhaled nitric oxide.

Exercise is known to affect the airway epithelium through dehydration, followed by a release of mediators, such as club cell (Clara) protein (CC16). The aim of this study was to follow the CC16 levels at repeated time points in plasma and urine after exercise in asthmatic subjects and controls, and to relate the findings to exhaled breath temperature (EBT) and exhaled nitric oxide (NO). Twenty-two asthmatics and 18 healthy subjects performed an exercise challenge test on a treadmill. Lung function, CC16 in plasma and urine, EBT and fractional exhaled NO were investigated before and repeatedly for 60 min after the exercise. The increase in CC16 concentration in plasma was seen already one minute after exercise (p < 0.001) and increased further after 20 (p = 0.009) until 60 min (p = 0.001). An increase in urinary levels of CC16 peaked after 30 min (p < 0.001), and declined after 60 min but were still higher than baseline (p = 0.002). There were no differences in plasma or urine CC16 levels between asthmatics and controls, but males had higher plasma levels compared to females (p < 0.001) at all time points. EBT peaked at 15 min (p < 0.001) and thereafter declined, and FENO50 (p < 0.0001), alveolar NO concentration (p = 0.049) and bronchial flux of NO (p = 0.0055) decreased after exercise. In conclusion, this study shows that CC16 in plasma increased during 60 min after exercise, not synchronized with CC16 levels in urine. CC16 levels in plasma correlated to EBT and exhaled NO, reflecting an overall epithelial involvement. There was no difference between asthmatics and healthy controls, showing a physiological rather than pathophysiological response.

Flow-Volume Parameters in COPD Related to Extended Measurements of Lung Volume, Diffusion, and Resistance.

Classification of COPD into different GOLD stages is based on forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) but has shown to be of limited value. The aim of the study was to relate spirometry values to more advanced measures of lung function in COPD patients compared to healthy smokers. The lung function of 65 COPD patients and 34 healthy smokers was investigated using flow-volume spirometry, body plethysmography, single breath helium dilution with CO-diffusion, and impulse oscillometry. All lung function parameters, measured by body plethysmography, CO-diffusion, and impulse oscillometry, were increasingly affected through increasing GOLD stage but did not correlate with FEV1 within any GOLD stage. In contrast, they correlated fairly well with FVC%p, FEV1/FVC, and inspiratory capacity. Residual volume (RV) measured by body plethysmography increased through GOLD stages, while RV measured by helium dilution decreased. The difference between these RV provided valuable additional information and correlated with most other lung function parameters measured by body plethysmography and CO-diffusion. Airway resistance measured by body plethysmography and impulse oscillometry correlated within COPD stages. Different lung function parameters are of importance in COPD, and a thorough patient characterization is important to understand the disease.

Pharmacokinetics of budesonide and formoterol administered via 1 pressurized metered-dose inhaler in patients with asthma and COPD.

In 3 open-label studies, the systemic bioavailability of budesonide and formoterol administered via pressurized metered-dose inhaler (pMDI) or dry powder inhaler (DPI) formulations was evaluated in asthma (24 children, 55 adults) or chronic obstructive pulmonary disease (COPD; n = 26) patients. Treatments were administered at doses high enough to estimate pharmacokinetic parameters reliably. Two of the studies included an experimental budesonide pMDI formulation. In study 1 (asthma, adults), budesonide area under the curve (AUC) was 32% and 31% lower and maximal budesonide concentration (C(max)) 45% and 56% lower after budesonide/formoterol pMDI and budesonide pMDI versus budesonide DPI. Formoterol AUC and C(max) were 13% and 39% lower after budesonide/formoterol pMDI versus formoterol DPI. In study 2 (asthma, children), budesonide AUC and C(max) were 27% and 41% lower after budesonide/formoterol pMDI versus budesonide DPI + formoterol DPI. In study 3 (COPD/asthma, adults), budesonide AUC and C(max) were similar and formoterol AUC and C(max) 18% and 22% greater after budesonide/formoterol pMDI versus budesonide pMDI + formoterol DPI (COPD). Budesonide and formoterol AUC were 12% and 15% higher in COPD versus asthma patients. In conclusion, systemic exposure generally is similar or lower with budesonide/formoterol pMDI versus combination therapy via separate DPIs or monotherapy and comparable between asthma and COPD patients.