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Abstract Background Peripheral neuropathy is a common comorbidity in COPD. We aimed to investigate associations between alterations commonly found in COPD and peripheral neuropathy, with particular emphasize on the distinction between direct and indirect effects. Methods We used visit 4 data of the COPD cohort COSYCONET, which included indicators of polyneuropathy (repeated tuning fork and monofilament testing), excluding patients with diabetes a/o increased HbA1c. These indicators were analysed for the association with COPD characteristics, including lung function, blood gases, 6-min walk distance (6-MWD), timed-up-and-go-test (TUG), exacerbation risk according to GOLD, C-reactive protein (CRP), and ankle-brachial index (ABI). Based on the results of conventional regression analyses adjusted for age, BMI, packyears and gender, we utilized structural equation modelling (SEM) to quantify the network of direct and indirect relationships between parameters. Results 606 patients were eligible for analysis. The indices of polyneuropathy were highly correlated with each other and related to base excess (BE), ABI and TUG. ABI was linked to neuropathy and 6-MWD, exacerbations depended on FEV1, 6-MWD and CRP. The associations could be summarized into a SEM comprising polyneuropathy as a latent variable (PNP) with three measured indicator variables. Importantly, PNP was directly dependent on ABI and particularly on BE. When also including patients with diabetes and/or elevated values of HbA1c (n = 742) the SEM remained virtually the same. Conclusion We identified BE and ABI as major determinants of peripheral neuropathy in patients with COPD. All other associations, particularly those with lung function and physical capacity, were indirect. These findings underline the importance of alterations of the micromilieu in COPD, in particular the degree of metabolic compensation and vascular status.

Background Air trapping and lung hyperinflation are major determinants of prognosis and response to therapy in chronic obstructive pulmonary disease (COPD). They are often determined by body plethysmography, which has limited availability, and so the question arises as to what extent they can be estimated via spirometry. Methods We used data from visits 1–5 of the COPD cohort COSYCONET. Predictive parameters were derived from visit 1 data, while visit 2–5 data was used to assess reproducibility. Pooled data then yielded prediction models including sex, age, height, and body mass index as covariates. Hyperinflation was defined as ratio of residual volume (RV) to total lung capacity (TLC) above the upper limit of normal. (ClinicalTrials.gov identifier: NCT01245933). Results Visit 1 data from 1988 patients (Global Initiative for Chronic Obstructive Lung Disease grades 1–4, n=187, 847, 766, 188, respectively) were available for analysis (n=1231 males, 757 females; mean±sd age 65.1±8.4 years; forced expiratory volume in 1 s (FEV1) 53.1±18.4 % predicted (% pred); forced vital capacity (FVC) 78.8±18.8 % pred; RV/TLC 0.547±0.107). In total, 7157 datasets were analysed. Among measures of hyperinflation, RV/TLC showed the closest relationship to FEV1 % pred and FVC % pred, which were sufficient for prediction. Their relationship to RV/TLC could be depicted in nomograms. Even when neglecting covariates, hyperinflation was predicted by FEV1 % pred, FVC % pred or their combination with an area under the curve of 0.870, 0.864 and 0.889, respectively. Conclusions The degree of air trapping/hyperinflation in terms of RV/TLC can be estimated in a simple manner from forced spirometry, with an accuracy sufficient for inferring the presence of hyperinflation. This may be useful for clinical settings, where body plethysmography is not available.

Background and Objective: Positive bronchodilator reversibility (BDR) is a diagnostic criterion for asthma. However, patients with asthma may exhibit a negative BDR response. Aim: To describe the frequency of positive and Negative BDR response in patients with severe asthma and study associations with phenotypic characteristics., Methods: A positive BDR response was defined as an increase in FEV1 >200 mL and >12% upon testing with a short-acting ß-agonist., Results: BDR data were available for 793 of the 2013 patients included in the German Asthma Net (GAN) severe asthma registry. Of these, 250 (31.5%) had a positive BDR response and 543 (68.5%) a egative BDR response. Comorbidities significantly associated with a negative response were gastroesophageal reflux disease (GERD) (28.0% vs 40.0%, P<.01) and eosinophilic granulomatosis with polyangiitis (0.4% vs 3.0%; P<.05), while smoking history (active: 2.8% vs 2.2%; ex: 40.0% vs 41.7%) and comorbid chronic obstructive pulmonary disease (COPD) (5.2% vs 7.2%) were similar in both groups. Patients with a positive BDR response had worse asthma control (median Asthma Control Questionnaire 5 score, 3.4 vs 3.0, P<.05), more frequently reported dyspnea at rest (26.8% vs 16.4%, P<.001) and chest tightness (36.4% vs 26.2%, P<.001), and had more severe airway obstruction at baseline (FEV1% predicted, 56 vs 64, P<.001) and higher fractional exhaled nitric oxide (FeNO) levels (41 vs 33 ppb, P<0.05). There were no differences in diffusion capacity of the lung for carbon monoxide, single breath (% pred, 70% vs 71%). Multivariate linear regression analysis identified an association between positive BDR response and lower baseline FEV1% (P<.001) and chest tightness (P<.05) and a negative association between BDR and GERD (P<.05)., Conclusion: In this real-life setting, most patients with severe asthma had a negative BDR response. Interestingly, this was not associated with smoking history or COPD, but with lower FeNO and presence of GERD.

Purpose: It has been estimated that, in 2019, 54,000 patients in Germany had uncontrolled GINA step 4/5 asthma. In the current study we analyzed which health care providers were involved in the management of these patients and their role in disease phenotyping., Patients and Methods: The year 2019 was retrospectively analyzed using the IQVIA TM LRx, a longitudinal anonymized prescription database, and the electronic, anonymized medical records database, the IQVIA Disease Analyzer., Results: Of 54,000 uncontrolled GINA step 4/5 asthma patients in Germany, 52% had consulted both general practitioners (GPs) and pulmonologists, and 48% were seen exclusively by a GP. Of these 54,000 patients, 45% were being prescribed and were thus overusing short-acting β2-agonists (SABAs) and oral corticosteroids (OCS) for ≥2 years, 26% for ≥3 years, and 16% for ≥4 years. In most regions, pulmonologists saw one of their uncontrolled GINA step 4/5 asthma patients per week. Laboratory tests from consultations with a GP were available for only 10% of patients referred to a pulmonologist. In 50% of uncontrolled asthma patients treated according to GINA step 4/5, these were initiated by the pulmonologist, and 34% received laboratory testing within the first year (in GINA step 4/5 asthma, the numbers are 20% and 18%, respectively)., Conclusion: Fifty percent of uncontrolled asthma patients treated according to GINA step 4/5 were regularly seen by pulmonologists, who performed most of the phenotyping confirming their importance in the management of severe, uncontrolled asthma in Germany. To understand treatment pathways for these patients, further studies are needed., Competing Interests: C.N. received honoraria and advisory board fees from GSK, Sanofi, AstraZeneca and Novartis. D.K. reports speaker and/or advisory fees from AstraZeneca, Boehringer, Chiesi, Berlin-Chemie, GSK, Novartis, and Sanofi. K.C.B. and O.S. have no relevant competing interests to disclose. S.H. is a GSK employee and shareholder. K.M. reports speaker and/or advisory fees from Astrazeneca, GSK, Novartis, Sanofi. D.S. received honoraria for lectures and/or consultancy from AstraZeneca, Bayer, Berlin-Chemie, BMBF, Boehringer, Chiesi, DFG, GSK, Janssen, MSD, Novartis, Sanofi, Pfizer. F.S. is affiliated with IQVIA Commercial GmbH & Co and reports grants from GSK. J.C.V. has lectured for and received honoraria from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Altana, Pfizer, Revotar, Sandoz-Hexal, Stallergens, TEVA, UCB/Schwarz-Pharma, and Zydus/Cadila, and has participated in advisory boards for Avontec, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Regeneron, Revotar, Roche, Sanofi-Aventis, Sandoz-Hexal, TEVA, and UCB/Schwarz-Pharma, and has received research grants from Deutsche Forschungsgesellschaft, Land Mecklenburg-Vorpommern, GSK, and MSD, and is a full-time employee of the Universitätsmedizin Rostock. The authors report no other conflicts of interest in this work., (© 2023 Timmermann et al.)

Purpose: Asthma is one of the most prevalent chronic diseases in Germany affecting 4-5% of all adults and 10% of children. Despite the availability of biologicals in recent years, studies show patients with inadequately controlled severe asthma in real life. The aim of the current study was to characterize and estimate the number of patients with NVL/GINA level 4 or 5 asthma and signs of poor control in Germany., Patients and Methods: In 2021, we retrospectively analyzed data collected during 2019 using the IQVIA™ LRx and IQVIA™ Disease Analyzer databases which contain anonymized longitudinal data covering approximately 80% of statutory health insurance (GKV) prescriptions in Germany with most relevant information about prescriptions, basic patient demographics or location of the prescriber; the IQVIA™ Disease Analyzer anonymized electronic medical records from a representative sample of office-based GPs and specialists. An expert committee of pulmonologists from different hospitals and expert practices supported the study. Asthma patients treated according to NVL/GINA 4/5 who used SABAs frequently (≥3 on days with no ICS-containing prescriptions/year) and/or received prescriptions for oral corticosteroids (OCS) (score of ≥2/year, a pulmonologist prescription scored 1.0, GP 0.75) were classified as severe, uncontrolled asthma., Results: In 2019, 3.4 million patients received at least two prescriptions of respiratory medications and 2.4 million patients on maintenance respiratory treatment have asthma. A total of 625,000 asthma patients were treated according to NVL/GINA step 4 or 5. Among these, 54,000 were uncontrolled according to the pre-defined OCS and/or SABA use, which corresponds to approximately 15% of patients in certain regions., Conclusion: In 2019, approximately 54,000 patients in Germany treated according to NVL/GINA step 4/5 had evidence suggestive for poor asthma control, up to 15% of patients in certain regions. Yet, only 12,000 patients overall were being treated with biologicals suggesting a possible treatment gap that requires further investigation., Competing Interests: KCB and OS have no relevant competing interests to disclose. SH is a GSK employee and shareholder. KM reports speaker and/ or advisory fees from AstraZeneca, GSK, Novartis, Sanofi. CN received honoraria and advisory board fees from GSK, Sanofi, AstraZeneca and Novartis. DS received honoraria for lectures and/or consultancy from AstraZeneca, Bayer, Berlin-Chemie, Boehringer, Chiesi, GSK, Janssen, Novartis, Pfizer. RL is an employee of IQVIA. IQVIA is a technology service provider that carried out the database studies within the scope of a commercial engagement with GSK. DK reports personal fees from GSK. JCV has lectured for and received honoraria from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Altana, Pfizer, Revotar, Sandoz-Hexal, Stallergens, TEVA, UCB/Schwarz-Pharma, Zydus/Cadila and has participated in advisory boards for Avontec, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Regeneron, Revotar, Roche, Sanofi-Aventis, Sandoz-Hexal, TEVA, UCB/Schwarz-Pharma and has received research grants from Deutsche Forschungsgesellschaft, Land Mecklenburg-Vorpommern, GSK, MSD and is a full time employee of the Universitätsmedizin Rostock. The authors report no other conflicts of interest in this work., (© 2022 Bergmann et al.)

Background: Asthma is one of the most common chronic diseases in Germany. While many patients achieve asthma control under standard therapies, some patients still experience exacerbations and persistent airway obstructions. Thus, further pharmacological treatment is needed, and biologics could fill this gap, as they have shown clinical benefit in patients with severe asthma. Therefore, this real-world study aimed to compare healthcare resource utilization (HCRU) and associated costs before and after biologic therapy initiation., Methods: A retrospective claims data analysis has been conducted on adult asthma patients who initiated a long-term biologic therapy between January 2015 and June 2018. Patients were therapy-naïve to biologics for at least 12 months. HCRU and cost incurred by patients during 12 months before and after therapy initiation were compared., Results: Overall, 571 asthma patients initiated a biologic therapy during the observational period (316 omalizumab, 232 mepolizumab, 16 benralizumab, and 7 reslizumab). Patients had a mean age of 54.86 (62.70% female), and the majority (93.70%) received at least one follow-up prescription of their index-biologic agent within one year. During baseline, patients received on average 2.75 OCS prescriptions compared to 2.17 during follow-up. Most patients received less or the same amount of OCS after therapy initiation. Moreover, hospitalizations and asthma-related sick leave days decreased significantly. The average total costs per patient were €6618.90 during baseline and €22,832.33 during follow-up. Biologics mainly drove the increase; however, hospitalization costs were reduced significantly (€2443.37 vs €1941.93; p<0.001)., Conclusion: Our study demonstrates an improved asthma control due to the initiation of a biologic therapy in terms of decreased hospitalization frequency, OCS consumption, and sick leave days. However, biologics are associated with high costs for healthcare providers during the first year after initiation. Therefore, short- and long-term clinical benefits and financial burden must be considered in the overall context of healthcare., Competing Interests: Fränce Hardtstock and Julia Krieger participated in this study as staff members of IPAM; the work of IPAM in this study was financed by GlaxoSmithKline GmbH & Co. KG. Thomas Wilke is the founder of IPAM e.V., and has received honoraria from various pharmaceutical companies, including Novo Nordisk, Janssen Pharmaceutica, Boehringer Ingelheim Pharma, Bayer Health Care, Novartis, Sanofi, Pfizer and GlaxoSmithKline. Marco Lukas, Bernhard Ultsch and Robert Welte are GlaxoSmithKline employees and shareholders. Renate Quinzler is an employee of AOK Baden-Württemberg. Ulf Maywald is an employee of AOK PLUS. Hartmut Timmermann is affiliated with Schwerpunktpraxis Colonnaden and has received consultancy fees and grants from several pharmaceutical companies, including AstraZenica, Takeda, Bayer Health Care, Almirall, Astrellas Pharma, Novartis, Sanofi, Leti Pharma, Boehringer Ingelheim Pharma, Meda Pharmaceuticals, Mundipharma, Pfizer, Nycomed, Berlin-Chemie, Teva and GlaxoSmithKline. The authors report no other conflicts of interest in this work., (© 2022 Hardtstock et al.)

Introduction: The German Asthma Net Severe Asthma Registry is collecting long-term data from a large cohort of patients aged ≥6 years with severe asthma. This manuscript presents their baseline characteristics, and identifies relationships with exacerbations and/or poor asthma control., Methods: The registry is collecting routine clinical parameters including: demographics and medical history; disease characteristics (Asthma Control Questionnaire [ACQ]-5, forced expiratory volume in 1 s [FEV 1 ]); exacerbations; and biomarkers (eosinophils, immunoglobulin E [IgE], fractional exhaled nitric oxide [FeNO])., Results: These analyses include data from 2011 patients at 72 sites (91.9% adult). Children (6-17 years) were more likely to be male, whereas more adults were female (males: children/adults 62%/41%). Most were receiving inhaled corticosteroid/long-acting β 2 -agonist combinations (78%/81%); 38.0% of adults were receiving systemic steroids. Asthma control was suboptimal in both groups: 21.5%/13.3% were controlled; 10.4%/49.1% were symptomatic; 33.1%/37.2% received emergency asthma treatment in the previous year. Median blood eosinophil (400/238 cells/μL) and IgE levels (494/186 IU/mL) were higher in children; FeNO was lower (19/35 ppb). Patients with ≥2 exacerbations in the previous year had lower FEV 1 (absolute and % predicted) and IgE, and higher ACQ-5, FeNO and blood eosinophil levels (all p < 0.05). There was a weak, negative correlation between ACQ-5 and FEV 1 % predicted in adults (p < 0.001)., Conclusions: These analyses characterise the typical German patient with severe asthma, and provide information on their overall care. Their planned long-term follow-up will assess whether asthma control can be optimised, how best to do so, and most importantly how such optimisation can benefit patients., (Copyright © 2022. Published by Elsevier Ltd.)

Background: There exists a range of treatments in the management of asthma. Non-adherence to these medications has been identified as a factor negatively impacting the effects of treatment., Objective: The objective of this study was to identify the potential barriers to medication adherence among adult patients with asthma in Germany., Patients and Methods: A multi-center observational study was conducted addressing adult patients with asthma who were prescribed regular maintenance medication between 2014 and 2016. Data were derived from physicians' documentation as well as claims data, which were linked to the above primary observational data, and patient survey data. Adherence barriers were assessed by the validated Adherence Barriers Questionnaire, both descriptively and in a logistic regression framework. Cluster analysis identified distinct patient groups with respect to the relevance of specific adherence barriers., Results: We included 524 patients with asthma (mean age 53.1 years, 74.6% female, 43.1% allergic asthma, 37.6% nonallergic, 19.3% mixed). Most of the participants reported to face at least three barriers (61.1%). Frequently reported barriers were the perception that medications are all harmful (53.6% of the participants), the burden of medication co-payment (44.1%), positive perception about current health status (39.9%), feeling of depression (30.9%), and the fear of side effects (27.5%). Four distinct patient clusters could be identified: cluster 1 with a low number of barriers (28.6% of participants), cluster 2 (11.6%) with a comparably high number of existing barriers, cluster 3 with high importance of depression as a barrier (27.3% of participants), and cluster 4 that was dominated by the perception that medications are all harmful (32.5% of participants)., Conclusions: Results of this study provide important insights for further development of adherence programs, which should focus on distinct patients' clusters that differ substantially in the relevance of specific adherence barriers.

Background: Peripheral neuropathy is a common comorbidity in COPD. We aimed to investigate associations between alterations commonly found in COPD and peripheral neuropathy, with particular emphasize on the distinction between direct and indirect effects., Methods: We used visit 4 data of the COPD cohort COSYCONET, which included indicators of polyneuropathy (repeated tuning fork and monofilament testing), excluding patients with diabetes a/o increased HbA1c. These indicators were analysed for the association with COPD characteristics, including lung function, blood gases, 6-min walk distance (6-MWD), timed-up-and-go-test (TUG), exacerbation risk according to GOLD, C-reactive protein (CRP), and ankle-brachial index (ABI). Based on the results of conventional regression analyses adjusted for age, BMI, packyears and gender, we utilized structural equation modelling (SEM) to quantify the network of direct and indirect relationships between parameters., Results: 606 patients were eligible for analysis. The indices of polyneuropathy were highly correlated with each other and related to base excess (BE), ABI and TUG. ABI was linked to neuropathy and 6-MWD, exacerbations depended on FEV 1 , 6-MWD and CRP. The associations could be summarized into a SEM comprising polyneuropathy as a latent variable (PNP) with three measured indicator variables. Importantly, PNP was directly dependent on ABI and particularly on BE. When also including patients with diabetes and/or elevated values of HbA1c (n = 742) the SEM remained virtually the same., Conclusion: We identified BE and ABI as major determinants of peripheral neuropathy in patients with COPD. All other associations, particularly those with lung function and physical capacity, were indirect. These findings underline the importance of alterations of the micromilieu in COPD, in particular the degree of metabolic compensation and vascular status.