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Introduction: 718 of 2283 patients with severe asthma included in the real-life, long-term German Asthma Net (GAN) registry used anti-IL5(R) antibody therapy (mepolizumab, benralizumab, reslizumab), of which 343 had started therapy after registry inclusion (56±13 yrs., 55% female, 1.7% current smokers, mean BMI 27±5 kg/m², 4.6±4.6 exacerbations per year, ACQ score 2.9±1.4). Results: In comparison to baseline, patients on anti-IL5(R) therapy showed significantly less exacerbations (rate reduction (mean±SD) at year 1: -3.0±5.3, p

IntroductionCystic fibrosis (CF), especially CF lung disease, is characterized by chronic infection, immune dysfunction including impairment of regulatory T cells (Tregs) and an exaggerated inflammatory response. CF transmembrane conductance regulator (CFTR) modulators have shown to improve clinical outcomes in people with CF (PwCF) with a wide range of CFTR mutations. However, it remains unclear whether CFTR modulator therapy also affects CF-associated inflammation. We aimed to examine the effect of elexacaftor/tezacaftor/ivacaftor therapy on lymphocyte subsets and systemic cytokines in PwCF.MethodsPeripheral blood mononuclear cells and plasma were collected before and at three and six months after the initiation of elexacaftor/tezacaftor/ivacaftor therapy; lymphocyte subsets and systemic cytokines were determined using flow cytometry.ResultsElexacaftor/tezacaftor/ivacaftor treatment was initiated in 77 PwCF and improved percent predicted FEV1 by 12.5 points (pConclusionTreatment with elexacaftor/tezacaftor/ivacaftor was associated with an increased percentage of Tregs, especially in PwCF clearing Pseudomonas aeruginosa infection. Targeting Treg homeostasis is a therapeutic option for PwCF with persistent Treg impairment.

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.

BackgroundAsthma is an incurable heterogeneous disease with variations in clinical and underlying immunological phenotype. New approaches could help to support existing therapy concepts. Neonatal infection of mice with Helicobacter pylori or administration of H. pylori-derived extracts or molecules after birth have been shown to prevent the development of allergic airway disease later in life. This study evaluated the potential therapeutic efficacy of H. pylori vacuolating cytotoxin A (VacA) in allergic airway inflammation and investigated the underlying immunological mechanisms for its actions.MethodsMurine models of allergic airway diseases, and murine and human in vitro models were used.ResultsIn both an acute model and a therapeutic house dust mite model of allergic airway disease, treatment with H. pylori-derived VacA reduced several asthma hallmarks, including airway hyperresponsiveness, inflammation and goblet cell metaplasia. Flow cytometry and ELISA analyses revealed induction of tolerogenic dendritic cells (DC) and FoxP3 positive regulatory T cells (Tregs), and a shift in the composition of allergen-specific immunoglobulins. Depletion of Tregs during treatment with VacA reversed treatment-mediated suppression of allergic airway disease. Human monocyte derived DCs (moDC) that were exposed to VacA induced Tregs in co-cultured naïve autologous T cells, replicating key observations made in vivo.ConclusionH. pylori-derived VacA suppressed allergic airway inflammation via induction of Tregs in both allergic airway disease models. These data suggest that the immunomodulatory activity of VacA could potentially be exploited for the prevention and treatment of allergic airway disease.

Introduction Chronic inflammatory lung diseases are a common cause of suffering and death. Chronic obstructive pulmonary disease (COPD) is the reason for 6% of all deaths worldwide. A total of 262 million people are affected by asthma and 461,000 people died in 2019. Idiopathic pulmonary fibrosis (IPF) is diagnosed in 3 million people worldwide, with an onset over the age of 50 with a mean survival of only 24–30 months. These three diseases have in common that remodeling of the lung tissue takes place, which is responsible for an irreversible decline of lung function. Pathological lung remodeling is mediated by a complex interaction of different, often misguided, repair processes regulated by a variety of mediators. One group of these, as has recently become known, are the Wnt ligands. In addition to their well-characterized role in embryogenesis, this group of glycoproteins is also involved in immunological and structural repair processes. Depending on the combination of the Wnt ligand with its receptors and co-receptors, canonical and noncanonical signaling cascades can be induced.Wnt5A is a mediator that is described mainly in noncanonical Wnt signaling and has been shown to play an important role in different inflammatory diseases and malignancies. Objectives In this review, we summarize the literature available regarding the role of Wnt5A as an immune modulator and its role in the development of asthma, COPD and IPF. We will focus specifically on what is known about Wnt5A concerning its role in the remodeling processes involved in the chronification of the diseases. Conclusion Wnt5A has been shown to be involved in all three inflammatory lung diseases. Since the ligand affects both structural and immunological processes, it is an interesting target for the treatment of lung diseases whose pathology involves a restructuring of the lung tissue triggered in part by an inflammatory immune response.

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.

Poster-Abstract

Background: Anti-IL-5 antibodies represent an established therapy for severe eosinophilic asthma (SEA), but some patients show inadequate response. The objective of this study was to assess the effects of a switch to anti-IL-5Rα therapy in patients with inadequate response to anti-IL-5 therapy. Methods: In this retrospective multi-centre, real-life study, we analysed all SEA patients switched from anti-IL-5 to anti-IL-5Rα therapy due to inadequate response or intolerability. Pulmonary function tests, blood gas analyses, asthma control tests (ACT) and oral corticos-teroid (OCS) usage were analysed and compared at three timepoints: baseline (BL, before anti-IL-5 therapy), timepoint 1 (T1, under anti-IL-5 therapy) and timepoint 2 (T2, under anti-IL-5Rα therapy). Results: Of 665 patients treated with anti-IL-5 antibodies, 70 were switched to anti-IL-5Rα and 60 were included in the analysis. Median treatment duration was 8 months [IQR 5; 15] for anti-IL-5 and 5 months [IQR 4; 6] for anti-IL-5Rα therapy. FEV₁ was 61% of predicted at BL [IQR 41; 74], 61% [IQR 43; 79] at T1 and 68% [IQR 49; 87] at T2 (pT₁₋T₂=0.011). ACT score was 10 [IQR 8; 13], 16 [IQR 10; 19] and 19 [IQR 14; 22], respectively (both p

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.

Poster-Abstract

Background: Pneumonia after thoracic surgery considerably contributes to perioperative morbidity and mortality. So far, the forced expiratory volume in one second and diffusing capacity of the lungs for carbon dioxide are the most common validated prognosticators to estimate individual risk. Beyond functional parameters, modifiable risk factors for respiratory complications like pneumonia are poorly investigated in a prospective way. Thus, we aimed to assess the impact of oral health status in patients undergoing thoracic surgery and its correlation to perioperative outcomes. Methods: A prospective observational study included adult patients undergoing elective thoracic surgery from October 2, 2018 to April 29, 2020. The day before surgery, patients were examined by a dentist. Oral health status (caries, periodontal disease, tooth loss, and regular dental visits) was correlated with perioperative outcomes. Results: During the study period, 230 consecutive patients were included. Oral health status was poor in the study population. Postoperative complications were associated with active caries [odds ratio (OR) 2.5, P

Poster-Abstract

The authors regret that Sanofi, one of the funders of the German Asthma Net, was omitted from the acknowledgements and funding section of the manuscript. The full disclosure should read: The GAN Severe Asthma Registry is supported by the German Asthma Net e.V., a German nonprofit society, and is funded by the German Ministry for Education and Research in the CHAMP consortium (BMBF, 01GL1742D); the GAN is also being funded by AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi, and Teva. The authors would like to apologise for any inconvenience caused.

Einleitung Mit weit mehr als 1400 stationär behandelten COVID-19-Patienten ist die Universitätsmedizin Essen der größte COVID-19-Versorger der Region Rhein-Ruhr. Wir präsentieren die Daten unserer Patienten aus den ersten 12 Monaten der Pandemie und die hieraus entstandenen praktischen Konzepte. Methode Retrospektive Analyse aller 1396 stationären COVID-19-Patienten, die zwischen dem 1. März 2020 und 28. Februar 2021 versorgt wurden, im Hinblick auf Komorbiditäten, Überleben und Komplikationen im Verlauf. Es erfolgte ein Gruppenvergleich zwischen Patienten auf Normalstation und Überwachungs-/ Intensivstation. Ergebnisse Bei einer Gesamtmortalität von 19,8 % (277/1396) starben 10,6 % (93/877) der Patienten auf Normalstation und 35,5 % (184/519) der Patienten auf Intensiv- und Überwachungsstationen im klinischen Verlauf. Hierbei waren ein Alter über 60 Jahre, Adipositas, maschinelle Beatmung, NO-Therapie, ECMO-Therapie sowie akutes Nierenversagen und Apoplex im Therapieverlauf unabhängige Prädiktoren für Mortalität. Fazit Die Mortalität unseres Kollektivs auf Normal- bzw. Intensivstationen liegt im Rahmen international publizierter Daten. Sowohl die hohe Rate von Komplikationen bei schwerem Verlauf als auch die große Bedeutung einfacher Komorbiditäten kann eindrücklich gezeigt werden. Das mittlere Alter der Patienten ist mit 60 Jahren auf Normalstation und 63 Jahren auf Intensivstationen überraschend niedrig. Maximaler Patienten- und Personalschutz, eine rasche und effektive Teststrategie im Rahmen der primären Triage, standardisierte Abläufe von der Notaufnahme bis zur Intensivstation sowie eine dynamische tagesaktuelle Anpassung der Ressourcen können eine hohe Versorgungsqualität, auch während der Pandemie, sichern.

Poster Abstract

Antibiotics, among the most used medications in children, affect gut microbiome communities and metabolic functions. These changes in microbiota structure can impact host immunity. We hypothesized that early-life microbiome alterations would lead to increased susceptibility to allergy and asthma. To test this, mouse pups between postnatal days 5-9 were orally exposed to water (control) or to therapeutic doses of azithromycin or amoxicillin. Later in life, these mice were sensitized and challenged with a model allergen, house dust mite (HDM), or saline. Mice with early-life azithromycin exposure that were challenged with HDM had increased IgE and IL-13 production by CD4

Hintergrund: Die anhaltend hohe Prävalenz allergischer Erkrankungen in westlichen Industrienationen und die eingeschränkten Möglichkeiten einer kausalen Therapie machen eine evidenzbasierte Primärprävention notwendig. Methoden: Die Empfehlungen der in letzter Fassung 2014 veröffentlichten S3-Leitlinie Allergieprävention wurden auf der Basis einer aktuellen systematischen Literatursuche überarbeitet und konsentiert. Die Evidenzsuche erfolgte für den Zeitraum 06/2013 – 11/2020 in den elektronischen Datenbanken Cochrane und MEDLINE, sowie in den Referenzlisten von aktuellen Übersichtsarbeiten und durch Hinweise von Experten. Die aufgefundene Literatur wurde in zwei Filterprozessen zunächst nach Titel und Zusammenfassung und die verbliebenen Arbeiten im Volltext auf Relevanz hin überprüft. Die danach eingeschlossenen Studien wurden nach Evidenzgrade geordnet und die Studienqualität i.S. des Verzerrungspotenzials (niedrig/hoch) angegeben. Die überarbeiteten Empfehlungen wurden unter Beteiligung von Vertretern der relevanten Fachgesellschaften und (Selbsthilfe-)Organisationen formal abgestimmt und konsentiert (nominaler Gruppenprozess). Von 5.681 Treffern wurden 286 Studien eingeschlossen und bewertet. Ergebnisse: Einen wichtigen Stellenwert in der aktualisierten Leitlinie nehmen wieder Empfehlungen zur Ernährung der Mutter während der Schwangerschaft und Stillzeit sowie des Säuglings in den ersten Lebensmonaten ein: Dabei wurden viele der bisherigen Empfehlungen durch die aktuelle Datenlage bestätigt. Präzisiert wurde, dass für den Zeitraum der ersten 4 – 6 Monate nach Geburt nach Möglichkeit ausschließlich gestillt werden soll und auch mit Einführung von Beikost weitergestillt werden soll. Neu ist die Empfehlung, dass eine Zufütterung von kuhmilchbasierter Formulanahrung in den ersten Lebenstagen bei Stillwunsch der Mutter vermieden werden sollte. Ferner wurde festgestellt, dass die Evidenz für eine klare positive Empfehlung für hydrolysierte Säuglingsnahrung bei nicht gestillten Risikokindern aktuell nicht mehr ausreicht. Aktuell wird daher empfohlen zu prüfen, ob bis zur Einführung von Beikost eine Säuglingsanfangsnahrung mit in Studien zur Allergieprävention nachgewiesener Wirksamkeit verfügbar ist. Schließlich wurden auf Basis der EAACI-Leitlinie zur Prävention der Hühnereiallergie die Empfehlung ausgesprochen, durcherhitztes (zum Beispiel verbackenes oder hartgekochtes), aber nicht „rohes“ Hühnerei (auch kein Rührei) mit der Beikost einzuführen und regelmäßig weiter zu geben. Die Empfehlung zur Einführung von Erdnuss in der Beikost wurde für den deutschsprachigen Raum zurückhaltend formuliert: In Familien mit bereits bestehendem regelmäßigem Erdnusskonsum kann zur Prävention einer Erdnussallergie bei Säuglingen mit atopischer Dermatitis die regelmäßige Gabe von erdnusshaltigen Nahrungsmitteln in altersgerechter Form (zum Beispiel Erdnussbutter) mit der Beikost erwogen werden. Vor der Einführung muss insbesondere bei Säuglingen mit moderater bis schwerer AD eine klinisch relevante Erdnussallergie ausgeschlossen werden. Für eine allergiepräventive Wirksamkeit von Präbiotika oder Probiotika, Vitamin D oder anderen Vitaminen in Form von Präparaten fehlt weiterhin ausreichende Evidenz, sodass in der aktuellen Leitlinie erstmals Empfehlungen gegen deren Supplementierung verabschiedet wurden. Die Biodiversität spielt für die Entwicklung einer immunologischen Toleranz gegenüber Umwelt- und Nahrungsmittelallergenen eine wichtige Rolle: So gibt es deutliche Hinweise darauf, dass das Aufwachsen auf dem Bauernhof mit einem geringeren Risiko für die Entwicklung von Asthma und allergischen Erkrankungen assoziiert ist. Dies wird mit einer frühzeitigen unspezifischen Immunstimulation unter anderem durch die größere mikrobielle Biodiversität des Hausstaubs in diesem Lebensraum in Verbindung gebracht. Dieser Aspekt spiegelt sich auch in den Empfehlungen zur Tierhaltung wider, zu der eine differenzierte Stellungnahme erfolgte: In Familien ohne erkennbares erhöhtes Allergierisiko soll die Haustierhaltung mit Katzen oder Hunden nicht generell eingeschränkt werden. Familien mit erhöhtem Allergierisiko (d. h. Vater, Mutter oder Geschwisterkind sind von einer atopischen Erkrankung betroffen) oder bei Kindern mit bereits bestehender atopischer Dermatitis sollten eine Katze nicht neu anschaffen – im Gegensatz dazu sollte von einer Hundehaltung jedoch nicht abgeraten werden. Interventionen zur Reduktion der Exposition gegenüber Hausstaubmilbenallergenen im Haushalt, zum Beispiel die Verwendung milbenallergendichter Matratzenüberzüge („encasings“), sollten nicht mit dem Ziel einer primären Allergieprävention erfolgen. Kinder, die durch einen Kaiserschnitt geboren wurden, haben ein geringfügig erhöhtes Asthmarisiko – dies soll bei der Beratung zum Geburtsmodus außerhalb von Notfallsituationen berücksichtigt werden. Auch aktuelle Arbeiten stützen die Empfehlungen zu Luftschadstoffen: Die aktive und passive Exposition gegenüber Tabakrauch erhöhen das Allergierisiko und sind deshalb zu vermeiden. Die Exposition gegenüber Stickoxiden, Ozon und Feinstaub der Partikelgröße < 2,5 Mikrometer (PM 2,5) ist mit einem erhöhten Risiko, besonders für Asthma, verbunden. Daher sollte die Exposition gegenüber Emissionen gegenüber Stickoxiden, Ozon und Feinstaub (PM 2,5) gering gehalten werden. Die Autor/-innen dieser Leitlinie sprechen sich einhellig für den Erlass entsprechender Verordnungen zur Minimierung dieser Luftschadstoffe aus. Es gibt keine Belege, dass Impfungen das Allergierisiko erhöhen, umgekehrt aber Hinweise, dass Impfungen das Allergierisiko senken können. Alle Kinder, auch Risikokinder, sollen auch aus Gründen der Allergieprävention nach den aktuellen Empfehlungen der ­STIKO geimpft werden. Schlussfolgerung: Die Konsentierung von Empfehlungen in dieser Leitlinie beruht auf einer umfangreichen Evidenzgrundlage. Die Aktualisierung der Leitlinie ermöglicht evidenzbasierte und aktuelle Empfehlungen zur Prävention allergischer Erkrankungen.

Background: Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts. Research Question: What is the prevalence of eosinophilic and noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables? Study Design and Methods: This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a predefined gradient eosinophilic algorithm based on highest BEC, long-term oral corticosteroid use, elevated fractional exhaled nitric oxide, nasal polyps, and adult-onset asthma. Demographic and clinical characteristics were defined at baseline (ie, 1 year before or closest to date of BEC). Results: One thousand seven hundred sixteen patients with prospective data were included; 83.8% were identified as most likely (grade 3), 8.3% were identified as likely (grade 2), and 6.3% identified as least likely (grade 1) to have an eosinophilic phenotype, and 1.6% of patients showed a noneosinophilic phenotype (grade 0). Eosinophilic phenotype patients (ie, grades 2 or 3) showed later asthma onset (29.1 years vs 6.7 years; P < .001) and worse lung function (postbronchodilator % predicted FEV1, 76.1% vs 89.3%; P = .027) than those with a noneosinophilic phenotype. Patients with noneosinophilic phenotypes were more likely to be women (81.5% vs 62.9%; P = .047), to have eczema (20.8% vs 8.5%; P = .003), and to use anti-IgE (32.1% vs 13.4%; P = .004) and leukotriene receptor antagonists (50.0% vs 28.0%; P = .011) add-on therapy. Interpretation: According to this multicomponent, consensus-driven, and evidence-based eosinophil gradient algorithm (using variables readily accessible in real life), the severe asthma eosinophilic phenotype was more prevalent than previously identified and was phenotypically distinct. This pragmatic gradient algorithm uses variables readily accessible in primary and specialist care, addressing inherent issues of phenotype heterogeneity and phenotype instability. Identification of treatable traits across phenotypes should improve therapeutic precision. publishedVersion

Supplemental Digital Content is available in the text., Objectives The RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19). Cell entry is mediated by the human angiotensin-converting enzyme II (ACE2). ACE2 and its close homolog angiotensin-converting enzyme I (ACE) are currently discussed candidate genes, in which single-nucleotide polymorphisms (SNPs) could alter binding or entry of SARS-CoV-2 and enhance tissue damage in the lung or other organs. This could increase the susceptibility for SARS-CoV-2 infection and the severity of COVID-19. Patients and methods We performed genotyping of SNPs in the genes ACE2 and ACE in 297 SARS-CoV-2-positive and 253 SARS-CoV-2-negative tested patients. We analyzed the association of the SNPs with susceptibility for SARS-CoV-2 infection and the severity of COVID-19. Results SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding demographics and clinical characteristics. For ACE2 rs2285666, the GG genotype or G-allele was significantly associated with an almost two-fold increased SARS-CoV-2 infection risk and a three-fold increased risk to develop serious disease or COVID-19 fatality. In contrast, the ACE polymorphism was not related to infection risk or severity of disease. In a multivariable analysis, the ACE2 rs2285666 G-allele remained as an independent risk factor for serious disease besides the known risk factors male gender and cardiovascular disease. Conclusions In summary, our report appears to be the first showing that a common ACE2 polymorphism impacts the risk for SARS-CoV-2 infection and the course of COVID-19 independently from previously described risk factors.

BackgroundRegulatory bodies have approved five biologics for severe asthma. However, regional differences in accessibility may limit the global potential for personalized medicine.ObjectiveTo compare global differences in ease of access to biologics.MethodsIn April 2021, national prescription criteria for omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab were reviewed by severe asthma experts collaborating in the International Severe Asthma Registry. Outcomes (per country, per biologic) were (1) country-specific prescription criteria and (2) development of the Biologic Accessibility Score (BACS). The BACS composite score incorporates 10 prescription criteria, each with a maximum score of 10 points. Referenced to European Medicines Agency marketing authorization specifications, a higher score reflects easier access.ResultsBiologic prescription criteria differed substantially across 28 countries from five continents. Blood eosinophil count thresholds (usually ≥300 cells/μL) and exacerbations were key requirements for anti-IgE/anti–IL-5/5R prescriptions in around 80% of licensed countries. Most countries (40% for dupilumab to 54% for mepolizumab) require two or more moderate or severe exacerbations, whereas numbers ranged from none to four. Moreover, 0% (for reslizumab) to 21% (for omalizumab) of countries required long-term oral corticosteroid use. The BACS highlighted marked between-country differences in ease of access. For omalizumab, mepolizumab, benralizumab, and dupilumab, only two, one, four, and seven countries, respectively, scored equal or higher than the European Medicines Agency reference BACS. For reslizumab, all countries scored lower.ConclusionsAlthough some differences were expected in country-specific biologic prescription criteria and ease of access, the substantial differences found in the current study present a challenge to implementing precision medicine across the world.

The transmembrane serine protease 2 (TMPRSS2) is the major host protease that enables entry of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) into host cells by spike (S) protein priming. Single nucleotide polymorphisms (SNPs) in the gene TMPRSS2 have been associated with susceptibility to and severity of H1N1 or H1N9 influenza A virus infections. Functional variants may influence SARS-CoV-2 infection risk and severity of Coronavirus disease 2019 (COVID-19) as well. Therefore, we analyzed the role of SNPs in the gene TMPRSS2 in a German case-control study. We performed genotyping of the SNPs rs2070788, rs383510, and rs12329760 in the gene TMPRSS2 in 239 SARS-CoV-2-positive and 253 SARS-CoV-2-negative patients. We analyzed the association of the SNPs with susceptibility to SARS-CoV-2 infection and severity of COVID-19. SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding their demographics. The CC genotype of TMPRSS2 rs383510 was associated with a 1.73-fold increased SARS-CoV-2 infection risk, but was not correlated to severity of COVID-19. Neither TMPRSS2 rs2070788 nor rs12329760 polymorphisms were related to SARS-CoV-2 infection risk or severity of COVID-19. In a multivariable analysis (MVA), the rs383510 CC genotype remained an independent predictor for a 2-fold increased SARS-CoV-2 infection risk. In summary, our report appears to be the first showing that the intron variant rs383510 in the gene TMPRSS2 is associated with an increased risk to SARS-CoV-2 infection in a German cohort. OA Förderung 2021

Thymic epithelial tumors are the most common mediastinal tumors. Surgery is the mainstay of treatment and complete resection provides the best survival rate. However, advanced tumors often require multimodality treatment and thus we analyzed the prognostic potential of routine circulating biomarkers that might help to risk-stratify patients beyond tumor stage and histology. Preoperative values for white blood cell count (WBC), C-reactive protein (CRP) and lactate dehydrogenase (LDH) were analyzed in 220 thymic epithelial tumor patients operated between 1999 and 2018. Increased CRP levels (>1 mg/dl) were significantly more often measured in thymic carcinoma and neuroendocrine tumors when compared to thymoma. LDH serum activity was higher in thymic neuroendocrine tumors when compared to thymoma or thymic carcinoma. The median disease specific survival was significantly longer in thymoma cases than in thymic carcinoma and neuroendocrine tumors. Increased preoperative LDH level (>240 U/L) associated with shorter survival in thymus carcinoma (HR 4.76, p = 0.0299). In summary, higher CRP associated with carcinoma and neuroendocrine tumors, while LDH increased primarily in neuroendocrine tumors suggesting that biomarker analysis should be performed in a histology specific manner. Importantly, preoperative serum LDH might be a prognosticator in thymic carcinoma and may help to risk stratify surgically treated patients in multimodal treatment regimens. OA Förderung 2021

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.Das vorliegende Addendum zur Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma (2017) ergänzt wichtige neue Erkenntnisse zur Diagnostik und Therapie von Asthma sowie zu neu für die Therapie des Asthmas zugelassenen Medikamenten. Es werden sowohl für Kinder und Jugendliche als auch für Erwachsene mit Asthma die aktuellen, Evidenz-basierten diagnostischen und therapeutischen Empfehlungen dargelegt.

Background: Seasonality is a characteristic of some respiratory viruses. The aim of our study was to evaluate the seasonality and the potential effects of different meteorological factors on the detection rate of the non-SARS coronavirus detection by PCR. Methods: We performed a retrospective analysis of 12,763 respiratory tract sample results (288 positive and 12,475 negative) for non-SARS, non-MERS coronaviruses (NL63, 229E, OC43, HKU1). The effect of seven single weather factors on the coronavirus detection rate was fitted in a logistic regression model with and without adjusting for other weather factors. Results: Coronavirus infections followed a seasonal pattern peaking from December to March and plunged from July to September. The seasonal effect was less pronounced in immunosuppressed patients compared to immunocompetent patients. Different automatic variable selection processes agreed on selecting the predictors temperature, relative humidity, cloud cover and precipitation as remaining predictors in the multivariable logistic regression model, including all weather factors, with low ambient temperature, low relative humidity, high cloud cover and high precipitation being linked to increased coronavirus detection rates. Conclusions: Coronavirus infections followed a seasonal pattern, which was more pronounced in immunocompetent patients compared to immunosuppressed patients. Several meteorological factors were associated with the coronavirus detection rate. However, when mutually adjusting for all weather factors, only temperature, relative humidity, precipitation and cloud cover contributed independently to predicting the coronavirus detection rate. OA Förderung 2021

Mit den Biologika stehen zunehmend mehr Therapeutika zur Verfugung, die zielgerichtet bestimmte Schaltstellen im Pathomechanismus immunologisch dominierter Erkrankungen adressieren Damit steht mehr die individuelle Krankheitsauspragung des einzelnen Patienten im Fokus der Diagnostik und Therapie (Prazisionsmedizin) Bezuglich der unterschiedlichen Phanotypen atopischer Erkrankungen war das schwere Asthma die erste Entitat, fur die Biologika zugelassen wurde, gefolgt von Urtikaria, und schlieslich der atopischen Dermatitis und der chronischen Rhinosinusitis mit nasalen Polypen Die Erfahrungen in der Therapie des schweren Asthma bronchiale machten deutlich, dass die Intensitat des Ansprechens auf eine Biologikatherapie entscheidend von der Qualitat der klinischen und immunologischen Phanotypisierung der Patienten abhangt, wobei diese Unterscheidung z T schwierig sein kann und sich verschiedene Phanotypen durchaus uberlagern konnen Das gilt auch fur unterschiedliche Erkrankungen des atopischen Formenkreises, da Patienten in jeweils entsprechend unterschiedlicher Auspragung unter mehreren atopischen Krankheiten gleichzeitig leiden konnen Es bilden sich bereits Biologika heraus, die eine geeignete Therapie fur das allergische Asthma bronchiale, das haufig gemeinsam mit einer schweren Neurodermitis auftritt, sowie die chronische Rhinosinusitis mit nasalen Polypen darstellen konnen In der Praxis stellt sich dennoch zunehmend die Frage nach moglichen Biologika-Kombinationen zur Therapie komplexer Krankheitsbilder einzelner Patienten Dabei gilt es, das Nebenwirkungsprofil zu beachten, zu denen auch Hypersensitivitatsreaktionen gehoren, deren diagnostisches und logistisches Management eine sichere und effiziente Therapie der Grunderkrankung zum Ziel haben muss Erhohte Aufmerksamkeit gilt auch fur eine Biologikatherapie bei Schwangerschaften und geplanten (planbaren) Impfungen sowie bestehenden Infektionen, wie zum Beispiel die SARS-CoV-2-Infektion Vor dem Start einer Biologikatherapie sollten der Immunstatus in Bezug auf chronische Virusund bakterielle Infektionen gepruft und gegebenenfalls vor Therapieeinleitung der Impfstatus aufgefrischt bzw fehlende Impfungen nachgeholt werden Derzeit liegen verlassliche Daten zum Effekt von Biologika auf die immunologische Situation der SARS-CoV-2-Infektion und COVID-19 nicht vor Daher ist die Erforschung und Entwicklung geeigneter Diagnostikverfahren zur Erfassung immunologisch bedingter Nebenwirkungen sowie der Erfassung potenzieller Therapie-Responder und -Non-Responder von groser BedeutungAlternate abstract:With the advent of biologicals, more and more therapeutics are available that specifically address specific switch points in the pathomechanism of immunologically dominated diseases Thus, the focus of diagnostics and therapy (precision medicine) is more on the individual disease characteristics of the individual patient Regarding the different phenotypes of atopic diseases, severe asthma was the first entity for which biologicals were approved, followed by urticaria, and finally atopic dermatitis and chronic rhinosinusitis with nasal polyps Experience in the treatment of severe bronchial asthma has shown that the intensity of the response to biological therapy depends on the quality of clinical and immunological phenotyping of the patients This also applies to different diseases of the atopic form, as patients can suffer from several atopic diseases at the same time, each with different characteristics Biologics are already emerging that may represent a suitable therapy for allergic bronchial asthma, which often occurs together with severe neurodermatitis, and chronic rhinosinusitis with nasal polyps In practice, however, the question of possible combinations of biologicals for the therapy of complex clinical pictures of individual patients is increasingly arising In doing so, the side effect profile must be taken into account, including hypersensitivity reactions, whose diagnostic and logistical management must aim at a safe and e ficient therapy of the underlying disease Increased attention must also be paid to biological therapy in pregnancy and planned (predictable) vaccinations as well as existing infections, such as SARS-CoV-2 infection Before starting a biological therapy, the immune status should be checked with regard to chronic viral and bacterial infections and, if necessary, the vaccination status should be refreshed or missing vaccinations should be made up for before starting therapy Currently, reliable data on the effect of biologicals on the immunological situation of SARS-CoV-2 infection and COVID-19 are not available Therefore, research and development of suitable diagnostic methods for detection of immunologically caused side effects as well as detection of potential therapy responders and non-responders is of great importance

Background: Bronchoscopic lung volume reduction (BLVR) via valve implantation can be achieved by targeting severely hyperinflated and emphysematously destructed lung areas in patients with chronic obstructive lung disease. Lack of collateral ventilation (CV) is important for good outcomes with BLVR. CV can be measured using the catheter-based Chartis system. The aim of this study was to evaluate the correlation between total exhaled volume drained from the target lobe measured by Chartis and clinical outcomes after BLVR in CV-negative patients. Methods: From January 2016 to March 2019, 60 patients were included in this retrospective single-center analysis. Drained volume (TVol) measured by Chartis was recorded and compared with lung function and physical performance parameters. Outcome variables included the percentage change in lung function [forced expiratory volume in 1 s (FEV 1 ), residual volume (RV), and inspiratory vital capacity (IVC)]. Secondary outcomes were the degree of target lobe volume reduction (TLVR), change in 6-min walk distance (6MWD), and change in chronic obstructive pulmonary disease (COPD) assessment test (CAT) score. Results: Drained volume correlated significantly with post-BLVR change in FEV 1 ( r = 0.663), IVC ( r = 0.611), RV ( r = −0.368), and TLVR ( r = 0.635) (all p 400 ml ( n = 8)]; mean changes in FEV 1 were 2.6%, 17.4%, and 51.3%; in RV were −3.9%, −10.6%, and −23.8%; in IVC were −4.0%, 10.6%, and 62.4%; and in TLVR were 525 ml (39%), 1375 ml (73%) and 1760 ml (100%), respectively. There were no significant correlations between absolute and percentage changes in 6MWD and the CAT score. Lung volume reduction was diagnosed in 32 (53%) cases. Conclusion: Drained volume measured by the Chartis system correlated with functional improvement in CV-negative patients undergoing BLVR. The reviews of this paper are available via the supplemental material section.

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.

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