Linnea Jarenbäck

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.

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.

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

BackgroundIt 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.MethodsSUMF1 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.ResultsCertain 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.ConclusionsWe 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.

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 patients 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.

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.