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We studied whether in patients with COPD the use of metformin for diabetes treatment was linked to a pattern of lung function decline consistent with the hypothesis of anti-aging effects of metformin. Patients of GOLD grades 1–4 of the COSYCONET cohort with follow-up data of up to 4.5 y were included. The annual decline in lung function (FEV1, FVC) and CO diffusing capacity (KCO, TLCO) in %predicted at baseline was evaluated for associations with age, sex, BMI, pack-years, smoking status, baseline lung function, exacerbation risk, respiratory symptoms, cardiac disease, as well as metformin-containing therapy compared to patients without diabetes and metformin. Among 2741 patients, 1541 (mean age 64.4 y, 601 female) fulfilled the inclusion criteria. In the group with metformin treatment vs. non-diabetes the mean annual decline in KCO and TLCO was significantly lower (0.2 vs 2.3, 0.8 vs. 2.8%predicted, respectively; p 1 and FVC. These results were confirmed using multiple regression and propensity score analyses. Our findings demonstrate an association between the annual decline of lung diffusing capacity and the intake of metformin in patients with COPD consistent with the hypothesis of anti-aging effects of metformin as reflected in a surrogate marker of emphysema.

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Alterations of cognitive functions have been described in COPD. Our study aimed to disentangle the relationship between the degree of cognitive function and COPD characteristics including quality of life (QoL).Data from 1969 COPD patients of the COSYCONET cohort (GOLD grades 1–4; 1216 male/ 753 female; mean (SD) age 64.9 ± 8.4 years) were analysed using regression and path analysis. The DemTect screening tool was used to measure cognitive function, and the St. George‘s respiratory questionnaire (SGRQ) to assess disease-specific QoL.DemTect scores were =60 years of age. For statistical reasons, we used the average of both algorithms independent of age in all subsequent analyses. The DemTect scores were associated with oxygen content, 6-min-walking distance (6-MWD), C-reactive protein (CRP), modified Medical Research Council dyspnoea scale (mMRC) and the SGRQ impact score. Conversely, the SGRQ impact score was independently associated with 6-MWD, FVC, mMRC and DemTect. These results were combined into a path analysis model to account for direct and indirect effects. The DemTect score had a small, but independent impact on QoL, irrespective of the inclusion of COPD-specific influencing factors or a diagnosis of cognitive impairment.We conclude that in patients with stable COPD lower oxygen content of blood as a measure of peripheral oxygen supply, lower exercise capacity in terms of 6-MWD, and higher CRP levels were associated with reduced cognitive capacity. Furthermore, a reduction in cognitive capacity was associated with reduced disease-specific quality of life. As a potential clinical implication of this work, we suggest to screen especially patients with low oxygen content and low 6-MWD for cognitive impairment.

We studied whether in patients with stable COPD blood gases (BG), especially oxygenated hemoglobin (OxyHem) as a novel biomarker confer information on disease burden and prognosis and how this adds to the information provided by the comorbidity pattern and systemic inflammation. Data from 2137 patients (GOLD grades 1–4) of the baseline dataset of the COSYCONET COPD cohort were used. The associations with dyspnea, exacerbation history, BODE-Index (cut-off ≤2) and all-cause mortality over 3 years of follow-up were determined by logistic and Cox regression analyses, with sex, age, BMI and pack years as covariates. Predictive values were evaluated by ROC curves. Capillary blood gases included SaO2, PaO2, PaCO2, pH, BE and the concentration of OxyHem [haemoglobin (Hb) x fractional SaO2, g/dL] as a simple-to-measure correlate of oxygen content. Inflammatory markers were WBC, CRP, IL-6 and -8, TNF-alpha and fibrinogen, and comorbidities comprised a broad panel including cardiac and metabolic disorders. Among BG, OxyHem was associated with dyspnoea, exacerbation history, BODE-Index and mortality. Among inflammatory markers and comorbidities, only WBC and heart failure were consistently related to all outcomes. ROC analyses indicated that OxyHem provided information of a magnitude comparable to that of WBC, with optimal cut-off values of 12.5 g/dL and 8000/µL, respectively. Regarding mortality, OxyHem also carried independent, additional information, showing a hazard ratio of 2.77 (95% CI: 1.85–4.15, p 8000/µL was 2.33 (95% CI: 1.60–3.39, p 2. It thus appears well suited for clinical use with minimal equipment, especially for GPs.

Bronchiectasis (BE) might be frequently present in COPD but masked by COPD symptoms. We studied the relationship of clinical signs of bronchiectasis to the presence and extent of its radiological signs in patients of different COPD severity. Visit 4 data (GOLD grades 1-4) of the COSYCONET cohort was used. Chest CT scans were evaluated for bronchiectasis in 6 lobes using a 3-point scale (0: absence, 1: ≤50%, 2: >50% BE-involvement for each lobe). 1176 patients were included (61%male, age 67.3y), among them 38 (3.2%) with reported physicians' diagnosis of bronchiectasis and 76 (6.5%) with alpha1-antitrypsin deficiency (AA1D). CT scans were obtained in 429 patients. Within this group, any signs of bronchiectasis were found in 46.6% of patients, whereby ≤50% BE occurred in 18.6% in ≤2 lobes, in 10.0% in 3-4 lobes, in 15.9% in 5-6 lobes; >50% bronchiectasis in at least 1 lobe was observed in 2.1%. Scores ≥4 correlated with an elevated ratio FRC/RV. The clinical diagnosis of bronchiectasis correlated with phlegm and cough and with radiological scores of at least 3, optimally ≥5. In COPD patients, clinical diagnosis and radiological signs of BE showed only weak correlations. Correlations became significant with increasing BE-severity implying radiological alterations in several lobes. This indicates the importance of reporting both presence and extent of bronchiectasis on CT. Further research is warranted to refine the criteria for CT scoring of bronchiectasis and to determine the relevance of radiologically but not clinically detectible bronchiectasis and their possible implications for therapy in COPD patients.

The COPD Assessment Test (CAT) is in widespread use for the evaluation of patients with chronic obstructive pulmonary disease (COPD). We assessed whether the CAT items carry additional information beyond the sum score regarding COPD characteristics including emphysema. Patients of GOLD grades 1 to 4 from the COPD cohort COSYCONET (German COPD and Systemic Consequences - Comorbidities Network) with complete CAT data were included (n = 2270), of whom 493 had chest CT evaluated for the presence of emphysema. Comorbidities and lung function were assessed following standardised procedures. Cross-sectional data analysis was based on multiple regression analysis of the single CAT items against a panel of comorbidities, lung function, or CT characteristics (qualitative score, 15th percentile of mean lung density), with age, BMI and gender as covariates. This was supported by exploratory factor analysis. Regarding the relationship to comorbidities and emphysema, there were marked differences between CAT items, especially items 1 and 2 versus 3 to 8. This grouping was basically confirmed by factor analysis. Items 4 and 5, and to a lower degree 1, 2 and 6, appeared to be informative regarding the presence of emphysema, whereas the total score was not or less informative. Regarding comorbidities, similar findings as for the total CAT score were obtained for the modified Medical Research Council scale (mMRC) which was also informative regarding emphysema. Our findings suggest that the usefulness of the CAT can be increased if evaluated on the basis of single items which may be indicating the presence of comorbidities and emphysema.

Rationale Alterations of acid-base metabolism are an important outcome predictor in acute exacerbations of COPD, whereas sufficient metabolic compensation and adequate renal function are associated with decreased mortality. In stable COPD there is, however, only limited information on the combined role of acid-base balance, blood gases, renal and respiratory function on exacerbation risk grading. Methods We used baseline data of the COPD cohort COSYCONET, applying linear and logistic regression analyses, the results of which were implemented into a comprehensive structural equation model. As most informative parameters it comprised the estimated glomerular filtration rate (eGFR), lung function defined via forced expiratory volume in 1 s (FEV1), intrathoracic gas volume (ITGV) and (diffusing capacity for carbon monoxide (DLCO), moreover arterial oxygen content (CaO2), partial pressure of oxygen (PaCO2), base exess (BE) and exacerbation risk according to GOLD criteria. All measures were adjusted for age, gender, body-mass index, the current smoking status and pack years. Results 1506 patients with stable COPD (GOLD grade 1–4; mean age 64.5 ± 8.1 y; mean FEV1 54 ± 18 %predicted, mean eGFR 82.3 ± 16.9 mL/min/1.73 m2) were included. BE was linked to eGFR, lung function and PaCO2 and played a role as indirect predictor of exacerbation risk via these measures; moreover, eGFR was directly linked to exacerbation risk. These associations remained significant after taking into account medication (diuretics, oral and inhaled corticosteroids), whereby corticosteroids had effects on exacerbation risk and lung function, diuretics on eGFR, BE and lung function. Conclusion Even in stable COPD acid-base metabolism plays a key integrative role in COPD risk assessment despite rather small deviations from normality. It partially mediates the effects of impairments in kidney function, which are also directly linked to exacerbation risk.

Das Obstruktive Schlafapnoesyndrom (OSAS) ist ein in der Gesamtbevölkerung weit verbreitetes Krankheitsbild, welches in der Regel mit exzessiver Tagesschläfrigkeit und hoher Beeinträchtigung von Lebensqualität und Leistungsfähigkeit der betroffenen Patienten einhergeht. Um das Krankheitsbild OSAS zweifelsfrei diagnostizieren zu können, ist eine stationäre Diagnostik mittels Polysomnographie vonnöten, welche zeit-, arbeits- und kostenintensiv ist. Die nicht-invasive Analyse flüchtiger organischer Substanzen (engl.: Volatile Organic Compounds = VOCs) stellt eine innovative Alternative in der Diagnostik des Obstruktiven Schlafapnoesyndroms dar. Im Rahmen einer am Universitätsklinikum Marburg durchgeführten klinischen Studie wurden in der vorliegenden Arbeit in einem Studienkollektiv von 15 Patienten mit Obstruktivem Schlafapnoesyndrom und 15 gesunden Kontrollprobanden flüchtige organische Substanzen von vier verschiedenen biologischen Materialien (Atemwegsexhalat (EB), Atemwegskondensat (EBC), Rachenspülwasser (PW) und Serum) mittels Ionenmobilitätsspektrometrie in Kopplung an eine Multikapillarsäule (MCC-IMS) und mittels chemischer Mustererkennung durch die elektronische Nase Cyranose 320 untersucht und analysiert. Die statistische Auswertung der bei der VOC-Analyse aufgezeichneten Daten erfolgte mittels Leave-One-Out-Kreuzvalidierung (LOO-CV). Ferner wurde im vorliegenden Studienkollektiv eine laborchemische Analyse der Serumparameter CRP, IL-6, IL-8 und TNF-α durchgeführt. Anhand der VOC-Analyse von Atemwegsexhalat mittels Cyranose 320 und MCC-IMS konnte gezeigt werden, dass sich die Atemwegsprofile von OSAS-Patienten und Kontrollprobanden im vorliegenden Studienkollektiv signifikant unterscheiden. Darüber hinaus ist es gelungen, sowohl mittels Cyranose 320 als auch via MCC-IMS einen signifikanten Gruppenunterschied in den Headspace-VOC-Profilen von Atemwegskondensat, Rachenspülwasser und Serum zu demonstrieren. In Bezug auf die mittels MCC-IMS erhobenen Daten war es weiterhin möglich, den im Gruppenvergleich relevant unterschiedlichen Analyten mit Hilfe von Referenzdatenbanken flüchtige organische Substanzen zuzuordnen. Hierbei kann die höchste diagnostische Genauigkeit und Trennschärfe der Substanz 2-Methylfuran in den Messreihen Serum und Atemwegsexhalat zugeordnet werden, bei der Analyse von Atemwegskondensat den Substanzen 2-Undecanon und n-Decan sowie bei der Analyse von Rachenspülwasser der Substanz Toluol. Ferner konnte eine Substanzzuordnung für diejenigen Analyten erfolgen, anhand derer ein relevanter Gruppenunterschied in mehreren biologischen Materialen festgestellt werden konnte: 2-Methylfuran in den Materialien Atemwegsexhalat, Serum und Rachenspülwasser, Toluol in Rachenspülwasser und Serum, Hexanal und 3-Methylbutanal bzw. 3-Methylbutyraldehyd in Atemwegsexhalat und Rachenspülwasser sowie Aceton in Atemwegsexhalat und Atemwegskondensat. Bezüglich der laborchemischen Analyse der Serumparameter CRP, IL-6, IL-8 und TNF-α war im vorliegenden Studienkollektiv für keinen der Parameter ein signifikanter Unterschied zwischen Patienten mit OSAS und gesunden Kontrollprobanden festgestellt worden. Die Ergebnisse der durchgeführten Labordiagnostik können somit keinen krankheitsrelevanten Unterschied im Rahmen des OSAS demonstrieren. Zusammenfassend zeigen die Ergebnisse der vorliegenden Arbeit, dass es mittels Cyranose 320 und MCC-Ionenmobilitätsspektrometrie möglich ist, signifikante Unterschiede im Vergleich der VOC-Profile von Patienten mit OSAS und gesunden Kontrollen anhand der Analyse der biologischen Materialien Atemwegsexhalat, Atemwegskondensat, Rachenspülwasser und Serum zu detektieren. Diesbezüglich deuten die Ergebnisse darauf hin, dass die Zusammensetzung flüchtiger organischer Substanzen der alveolären Exspirationsluft, des Atemwegsepithels, des oberen Respirationstrakts sowie systemisch zirkulierender VOCs im Rahmen eines OSAS verändert sein könnte. Die vorliegende Arbeit kann durch die Ergebnisse der durchgeführten VOC-Analyse einen relevanten Beitrag zum Thema der nicht-invasiven VOC-Diagnostik des OSAS liefern., The Obstructive Sleep Apnea Syndrome (OSAS) is a widely spread disease among the total population. Its clinical presentation usually comes along with excessive daytime sleepiness and impacts negatively on health and quality of life. Gold standard in the diagnosis of OSAS is a polysomnographic examination, which is work-intensive, time-consuming and expensive. Non-invasive analysis of Volatile Organic Compounds (VOCs) represents an innovative alternative to facilitate diagnosis of OSAS. In this study we used ion mobility spectrometry coupled to a multicapillary column (MCC-IMS) as well as the electronic nose system Cyranose 320 to analyze and compare VOC profiles of 15 patients with OSAS and 15 healthy controls (HC). All the VOCs have been emitted by four different biological materials (Exhaled breath (EB), Exhaled breath condensate (EBC), Pharyngeal washings (PW) und serum). Data analysis was performed by Leave-One-Out-Cross-Validation (LOO-CV). Furthermore, we performed laboratory analysis of the serum parameters CRP, IL-6, IL-8 and TNF-α to compare both study groups. Within the recruited sample, we could demonstrate that MCC-IMS and Cyranose 320 were able to distinguish breathprints of OSAS-patients and healthy controls. In addition it was possible to significantly separate both of the groups by means of headspace VOC profiles coming from EBC, PW and serum. Regarding cross-validated MCC-IMS data, we were able to assign volatile organic substances to recorded analytes via database matching. Best separation between OSAS and HC could be achieved by 2-Methylfuran referring to the measurement series of EB and serum. In reference to EBC, the chemical compounds 2-Undecanon and n-Decan have featured the most significant distinction between both groups. With regard to PW, we could identify Toluene to have the strongest power to separate between OSAS and HC. Furthermore, we were able to detect same chemical compounds in various of the analyzed biological materials: 2-Methylfuran (EB, PW and serum), Toluene (PW and serum), Hexanal and 3-Methylbutanal/3-Methylbutyraldehyd (EB and PW) as well as Acetone (EB and EBC). Analysis of the serum parameters CRP, IL-6, IL-8 and TNF-α could not demonstrate significant distinction among healthy controls and patients with OSAS. In conclusion, it can be said that MCC-IMS and Cyranose 320 are able to detect significant distinctions in the VOC profiles of patients with OSAS and healthy controls. These findings could be ascertained among four different biological materials (EB, EBC, PW and serum) what can be seen as an indication for a changing overall VOC profile within the scope of OSAS. The results of this study can support further exploration of OSAS VOC profiles and contribute non-invasive diagnosis of the disease.