[Guideline for the Diagnosis and Treatment of Asthma - Addendum 2020 - Guideline of the German Respiratory Society and the German Atemwegsliga in Cooperation with the Paediatric Respiratory Society and the Austrian Society of Pneumology]. / S2k-Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma ­ Addendum 2020.

The present addendum of the guideline for the diagnosis and treatment of asthma (2017) complements new insights into the diagnosis and management of asthma as well as for the newly approved drugs for the treatment of asthma. Current, evidence-based recommendations on diagnostic and therapeutic approaches are presented for children and adolescents as well as for adults with asthma.

[Guideline for the Diagnosis and Treatment of Asthma - Guideline of the German Respiratory Society and the German Atemwegsliga in Cooperation with the Paediatric Respiratory Society and the Austrian Society of Pneumology]. / S2k-Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma.

The present guideline is a new version and an update of the guideline for the diagnosis and treatment of asthma, which replaces the previous version for german speaking countries from the year 2006. The wealth of new data on the pathophysiology and the phenotypes of asthma, and the expanded spectrum of diagnostic and therapeutic options necessitated a new version and an update. This guideline presents the current, evidence-based recommendations for the diagnosis and treatment of asthma, for children and adolescents as well as for adults with asthma.

Angiopoietin-like protein 4 and cardiovascular function in COPD.

INTRODUCTION: The coexistence of chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) is frequent and might be inter-related through inflammation-related processes reflected by specific markers. Here, we studied angiopoietin-like protein 4 (ANGPTL4), an upcoming cardiovascular marker, in stable COPD, and its relationship to cardiovascular function with respect to well-known CVD risk factors. METHODS: In a prospective COPD cohort study, we investigated serum ANGPTL4 levels, vascular status (ankle-brachial index (ABI)) and cardiac function (N-terminal pro-B-type natriuretic peptide (NT-proBNP)) as well as airflow limitation, objectively measured physical activity, the metabolic syndrome, high-sensitive C reactive protein (hs-CRP) and other CVD risk factors at 2 time points. We initially studied 74 stable COPD patients and 18 controls. For internal validation, we additionally studied 160 COPD patients of a former visit. RESULTS: ANGPTL4 was significantly elevated in COPD patients compared with controls (p=0.026). After correction for traditional CVD risk factors, including hs-CRP, higher levels of ANGPTL4 were independently associated with lower ABI (p=0.023) and higher NT-proBNP (p<0.001). These findings were confirmed in the internal validation analysis, which included echocardiographic assessments. CONCLUSIONS: Serum ANGPTL4 is independently associated with cardiovascular function in COPD and might qualify as a biomarker reflecting a pathogenic link between COPD and CVD.

[Dyspnea. Profile of the most important diagnostic tests]. / Dyspnoe. Profile der wichtigsten diagnostischen Tests.

The diagnostic pathway for the evaluation of patients with dyspnea requires a thorough history taking and physical examination. Based on the results of these basic steps a broad variety of additional diagnostic tests are available. Each test can contribute valuable information when correctly indicated and performed. Among these are electrocardiography (ECG), laboratory parameters, X-ray examination, echocardiography, spirometry and whole body plethysmography and finally spiroergometry. This article presents a focused review of what each of these diagnostic modalities can contribute to the diagnostic process for dyspnea.

[Standardization of spirometry: 2015 update. Published by German Atemwegsliga, German Respiratory Society and German Society of Occupational and Environmental Medicine]. / Leitlinie zur Spirometrie. Leitlinie der Deutschen Atemwegsliga, der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin und der Deutschen Gesellschaft für Arbeitsmedizin und Umweltmedizin zur Spirometrie.

Spirometry is a simple test and considered the gold standard in lung function. An obstructive ventilatory defect is a disproportionate reduction of maximal airflow from the lung in relation to the maximal volume that can be displaced from the lung. It implies airway narrowing and is defined by a reduced FEV1/FVC ratio below the 5th percentile of the predicted value (lower limit of normal, LLN). A restrictive disorder may be suspected when vital capacity (FVC) is reduced and FEV1/FVC is normal. It is definitely proven, however, only by a decrease in TLC below the 5th percentile of predicted value (LLN). The measurement of TLC by body plethysmography is necessary to confirm or exclude a restrictive defect or hyperinflation of the lung when FVC is below the LLN. 2012 a task force of the ERS published new reference values based on 74,187 records from healthy non-smoking males and females from 26 countries. The new reference equations for the 3-95 age range are now available that include appropriate age-dependent mean values and lower limits of normal (LLN). This presentation aims at providing the reader with recommendations dealing with standardization and interpretation of spirometry.

[Expert meeting chronic obstructive airway disease--cardiovascular aspects of COPD]. / Expertentreffen obstruktive Atemwegserkrankungen: Kardiovaskuläre Aspekte der COPD.

This overview presents data that take advantage of a new step of insight into COPD. Large population-based retrospective studies and intensively investigated prospective cohorts are two important sources of knowledge that have been recently developed. One of the contributions introduces the German COSYCONET which is on its way shortly after the American ECLIPSE cohort. The vast amount of new data has also contributed to some corrections of the recommendations of the international GOLD committee. Clinically important are the waiver of the reversibility test for the diagnosis of COPD, the inclusion of sympotom scores to evaluate quality of life and the estimation of exacerbations. The COPD types I through IV were originally the result of expert opinion, but their impact on prognosis has recently been evaluated empirically.The top issues of the expert meeting were cardiovascular aspects of COPD. Besides the comorbidity of two significant chronic diseases, it became clear that cardiovascular events have an outstanding significance for COPD patients. Inversely, advanced COPD is an important risk factor in cardiac and vascular diseases. The mutual influence of both disease entities does not only affect the long term progression but also the outcome of acute events like myocardial infarction and COPD exacerbation. The following contributions investigate the topic with regard to epidemiology, the biology of vessels, and especially with regard to acute COPD exacerbations and pharmakotherapy. Recent evidence enables a fresh view on the cardiovascular toxicity of COPD medication and on possible protective effects of cardiovascular drugs (i.e. statins and ß-receptor antagonists) for patients with COPD.

[Roflumilast in combination with long-acting bronchodilators in the management of patients with severe and very severe COPD. A cost-effectiveness analysis for Germany]. / Roflumilast in Kombination mit langwirksamen Bronchodilatatoren in der Versorgung von Patienten mit schwerer und sehr schwerer COPD. Eine Kosten-Effektivitäts-Analyse für Deutschland.

OBJECTIVE: To calculate the cost-effectiveness of roflumilast in combination with a long-acting beta agonist (LABA) versus LABA as a monotherapy in patients with severe and very severe COPD in Germany. METHODS: The cost-effectiveness of Roflumilast plus LABA vs. LABA as monotherapy was calculated by a long-term model (Markov). The effectiveness data are based on the clinical trials AURA and HERMES (M2-124 and M2-125). Roflumilast plus LABA compared to LABA monotherapy reduced the exacerbation rate by 20.7 % (95 % CI, -31,-9) and improved post-bronchodilator FEV1 by 46 ml (2). These data were used to calculate the mean life expectancy of the COPD cohort (start age: 64 years). Costs for the treatment of exacerbations in the inpatient setting and the outpatient setting were included in the model. Endpoints were incremental costs per avoided exacerbation and per quality adjusted life year (QALY). The input variables were addressed in sensitivity analyses. German data on epidemiology and management of COPD were to populate the model and the cost-effectiveness was analyzed from the perspective of German statutory health insurance (SHI). RESULTS: The model predicts a mean life expectancy of 8.1 years for patients with roflumilast plus LABA and 7.8 years for patients with LABA alone. This corresponds with a gain of 0.26 life years or 0.23 QALYs. Within this time span patients receiving roflumilast plus LABA experienced 2.43 exacerbations less than the comparator group. The incremental cost for roflumilast plus LABA is €1,852 per exacerbation avoided and €19,457 per QALY gained. CONCLUSION: The model calculation indicates that the cost-effectiveness of roflumilast as an add-on to LABA in patients with severe and very severe COPD is comparable to the cost-effectiveness of established and reimbursed treatment options in Germany. Analogue consideration of the cost-effectiveness of the treatment options LAMA, LABA and ICS are advisable.

A randomised, placebo- and active-controlled dose-finding study of aclidinium bromide administered twice a day in COPD patients.

This Phase IIb, double-blind, double-dummy, placebo- and active-comparator-controlled crossover study (ClinicalTrials.gov identifier: NCT01120093) assessed efficacy and safety of three doses of aclidinium bromide in patients with moderate to severe chronic obstructive pulmonary disease. Patients were randomised to one of five treatment sequences each consisting of twice-daily (BID) aclidinium 100 µg, 200 µg, 400 µg (via Genuair®*), formoterol 12 µg (via Aerolizer®) and matched placebo for 7 days, with a 5- to 9-day washout period. Primary endpoint was mean change from baseline in forced expiratory volume in 1 s (FEV1) normalised area under the curve (AUC)0-12 on Day 7. Secondary endpoints were: change from baseline in FEV1 normalised AUC12-24, FEV1 normalised AUC0-24 and morning pre-dose FEV1 on Day 7. Adverse events were monitored throughout the study. Of 79 randomised patients, 68 (86.1%) completed the study. After 7 days of treatment, aclidinium and formoterol produced statistically significantly greater changes from baseline in FEV1 normalised AUC0-12 vs placebo (p<0.0001). FEV1 normalised AUC12-24, FEV1 normalised AUC0-24, and morning pre-dose FEV1 were also statistically significantly greater with all aclidinium doses vs placebo (p<0.0001). Improvements in primary and secondary endpoints were statistically significantly greater with aclidinium 400 µg vs 100 µg. The safety profile of aclidinium was comparable to placebo. These results demonstrated that twice-daily aclidinium produced dose-dependent clinically meaningful improvements in FEV1 compared with placebo. This study also confirmed the use of an aclidinium BID dosing regimen and established aclidinium 200 µg and 400 µg as suitable doses for further investigation in Phase III trials.

[COPD and Clinical Trials. Results of an expert meeting "Castles in the Air" 2010]. / COPD und Studien. Ergebnisse des Expertentreffens Luftschlösser 2010, Mainz, 3.­4. Dezember 2010 (Sponsor: Boehringer Ingelheim Pharma GmbH & Co KG).

Clinical trials in COPD patients aim at achieving progress in diagnosis and treatment. Study results should be applicable to a large number of patients. However, an analysis of the methods and design of current and previous trials reveals considerable room for improvement. COPD is a complex disease with different clinical phenotypes. Genetic factors need to be evaluated systematically to allow appropriate stratification of patients. Frequently used endpoints such as the FEV1 that had previously been considered reliable have shown limitations in recent trials. Thus, researchers now aim to identify new surrogate parameters that are related to the prognosis of the disease, e. g., composite endpoints and biomarkers. Physical activity and capacity are becoming increasingly important for the evaluation of disease progression. The focus of pharmaceutical development is long acting bronchodilators and new anti-inflammatory drugs. The value of non-drug interventions will also be evaluated.

Body plethysmography--its principles and clinical use.

Body plethysmography allows to assess functional residual capacity (FRC(pleth)) and specific airway resistance (sRaw) as primary measures. In combination with deep expirations and inspirations, total lung capacity (TLC) and residual volume (RV) can be determined. Airway resistance (Raw) is calculated as the ratio of sRaw to FRC(pleth). Raw is a measure of airway obstruction and indicates the alveolar pressure needed to establish a flow rate of 1 L s(-1). In contrast, sRaw can be interpreted as the work to be performed by volume displacement to establish this flow rate. These measures represent different functional aspects and should both be considered. The measurement relies on the fact that generation of airflow needs generation of pressure. Pressure generation means that a mass of air is compressed or decompressed relative to its equilibrium volume. This difference is called "shift volume". As the body box is sealed and has rigid walls, its free volume experiences the same, mirror image-like shift volume as the lung. This shift volume can be measured via the variation of box pressure. The relationship between shift volume and alveolar pressure is assessed in a shutter maneuver, by identifying mouth and alveolar pressure under zero-flow conditions. These variables are combined to obtain FRC(pleth), sRaw and Raw. This presentation aims at providing the reader with a thorough and precise but non-technical understanding of the working principle of body plethysmography. It also aims at showing that this method yields significant additional information compared to spirometry and even bears a potential for further development.

Treatment of advanced emphysema with emphysematous lung sealant (AeriSeal®).

BACKGROUND: This report summarizes initial tests of an emphysematous lung synthetic polymer sealant (ELS) designed to reduce lung volume in patients with advanced emphysema. OBJECTIVES: The primary study objective was to define a therapeutic strategy to optimize treatment safety and effectiveness. METHODS: ELS therapy was administered bronchoscopically to 25 patients with heterogeneous emphysema in an open-label, noncontrolled study at 6 centers in Germany. Treatment was performed initially at 2-4 subsegments. After 12 weeks, patients were eligible for repeat therapy to a total of 6 sites. Safety and efficacy were assessed after 6 months. Responses were evaluated in terms of changes from baseline in lung physiology, functional capacity, and health-related quality of life. Follow-up is available for 21 of 25 patients. RESULTS: Treatment was well tolerated. There were no treatment-related deaths (i.e., within 90 days of treatment), and an acceptable short- and long-term safety profile. Physiological and clinical benefits were observed at 24 weeks. Efficacy responses were better among Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage III patients [n = 14; change in residual volume/total lung capacity (ΔRV/TLC) = -7.4 ± 10.3%; Δ forced expiratory volume in 1 s (ΔFEV(1)) = +15.9 ± 22.6%; change in forced vital capacity (ΔFVC) = +24.1 ± 22.7%; change in carbon monoxide lung diffusion capacity (ΔDLCO) = +19.3 ± 34.8%; change in 6-min walk test (Δ6MWD) = +28.7 ± 59.6 m; change in Medical Research Council Dyspnea (ΔMRCD) score = -1.0 ± 1.04 units; change in St. George's Respiratory Questionnaire (ΔSGRQ) score = -9.9 ± 15.3 units] than for GOLD stage IV patients (n = 7; ΔRV/TLC = -0.5 ± 6.4%; ΔFEV(1) = +2.3 ± 12.3%; ΔFVC = +2.6 ± 21.1%; ΔDLCO = -2.8 ± 17.2%; Δ6MWD = +28.3 ± 58.4 m; ΔMRCD = 0.3 ± 0.81 units; ΔSGRQ = -6.7 ± 7.0 units). CONCLUSIONS: ELS therapy shows promise for treating patients with advanced heterogeneous emphysema. Additional studies to assess responses in a larger cohort with a longer follow-up are warranted.

Indacaterol once-daily is equally effective dosed in the evening or morning in COPD.

UNLABELLED: Indacaterol is a novel, inhaled, long-acting ß(2)-agonist providing 24-h bronchodilation with once-daily (o.d.) dosing in patients with COPD. In this double-blind, incomplete block crossover study, patients with moderate-to-severe COPD were randomised to receive three treatment cycles from: indacaterol 300 µg o.d. dosed PM or AM, salmeterol 50 µg twice daily or placebo, each for 14 days. Trough FEV(1) was measured 24 h after indacaterol, and 12 h after salmeterol. Ninety-six patients (mean age: 64 years; post-bronchodilator FEV(1) 57% predicted, FEV(1)/FVC 55%) were randomised; 83 completed. After 14 days, the difference vs. placebo in trough FEV(1) for PM indacaterol was 200 mL (p < 0.001 [primary analysis]) and for AM indacaterol was 200 mL (p < 0.001). Compared with salmeterol, trough FEV(1) for PM indacaterol was 110 mL higher (p < 0.001), and for AM indacaterol was 50 mL higher (p = NS). Over 14 days, vs. placebo, both PM and AM indacaterol improved the % of nights with no awakenings (by 11.9 and 8.1 points; p < 0.01); the % of days with no daytime symptoms (by 6.7 and 5.5 points; p < 0.05); and the % of days able to perform usual activities (by 6.7 and 7.8 points; p < 0.05). Indacaterol provided 24-h bronchodilation and improvement in symptoms regardless of whether taken regularly in the morning or evening. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00615030.

Deposition and metabolism of inhaled ciclesonide in the human lung.

Ciclesonide is an inhaled corticosteroid, administered as a prodrug via a metered-dose inhaler. Following deposition in the lung, ciclesonide is hydrolysed by esterases to form the pharmacologically active metabolite desisobutyryl-ciclesonide (des-CIC). Formation of des-CIC, as well as reversible esterification of des-CIC with fatty acids, has been demonstrated in vitro. The aim of this study was to investigate the in vivo metabolism of ciclesonide in the human lung. This single-dose, open-label, nonrandomised study was performed in 20 patients undergoing planned lung surgery for treatment of malignant pulmonary lesions. Patients inhaled a single dose of 1,280 µg ciclesonide at various time-points between 2 and 24 h prior to lung tissue resection. The concentration of ciclesonide, des-CIC and fatty acid conjugates of des-CIC in tissue samples was determined. Serum samples for pharmacokinetic analysis were taken at several time-points after inhalation. The pharmacokinetics in serum indicated that the inhalation by the patients was adequate. Metabolites (des-CIC, des-CIC oleate and des-CIC palmitate) were detected in the resected central and peripheral lung tissues. A substantial portion of ciclesonide was already activated to des-CIC at the first time-point of tissue analysis. Activation of ciclesonide and formation of des-CIC fatty acid conjugates was confirmed in vivo in the human lung.