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Mustafa Abdo,1 Benjamin Waschki,2 Anne-Marie Kirsten,3 Frederik Trinkmann,4,5 Heike Biller,1 Christian Herzmann,6 Erika von Mutius,7 Matthias Kopp,8,9 Gesine Hansen,10 Klaus F Rabe,1 Thomas Bahmer,1,11,* Henrik Watz3,* On behalf of the ALLIANCE study group1LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 2Department of Cardiology and Pneumology at Hospital Itzehoe, Itzehoe, Germany; 3Pulmonary Research Institute at the LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 4Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany; 5Department of Biomedical Informatics, Heinrich-Lanz-Center, University Medical Center Mannheim, Heidelberg University, Heidelberg, Germany; 6Research Center Borstel, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Borstel, Germany; 7Dr von Hauner Children’s Hospital, Ludwig Maximilians University of Munich, Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), Munich, Germany; 8Department of Pediatric Respiratory Medicine, Inselspital, University Children’s Hospital of Bern, University of Bern, Bern, Switzerland; 9Division of Pediatric Pneumology & Allergology, University Hospital Schleswig-Holstein-Campus Luebeck, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Luebeck, Germany; 10Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany; 11University Hospital Schleswig-Holstein-Campus Kiel, Department for Internal Medicine I, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Kiel, Germany*These authors contributed equally to this workCorrespondence: Mustafa AbdoLungenClinic Grosshansdorf GmbH, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Wöhrendamm 80, Großhansdorf, 22927, GermanyTel +49 4102 601 2412Email m.abdo@lungenclinic.deRationale: Asthma, obesity and physical activity (PA) are interrelated. However, longitudinal data with objective PA measures and direct assessment of body composition are still lacking.Objective: To study the impact of symptom control on PA and body composition.Methods: In a longitudinal cohort study of the German Center for Lung Research, we assessed the body composition of 233 asthma patients and 84 healthy controls using bioelectrical impedance analysis. PA (ie average daily steps and time of at least moderate activity, steps/min) was measured by accelerometry for one week. Asthma control was assessed by ACT score, ACQ-5 score and history of severe exacerbations. After two years of follow-up, we studied changes in physical activity and body composition in relation to asthma control.Results: Patients with uncontrolled asthma had increased fat mass and decreased muscle mass compared to patients with controlled asthma or healthy controls. Both fat mass and muscle mass correlated better with asthma control than the body mass index (BMI). In multivariate regressions adjusted for age and sex, asthma control and physical activity were independent predictors of body composition (R2 = 0.61, p

This study, conducted in Germany, examines the role of maternal soothing strategies to explain the association of maternal self-efficacy with infant regulation (crying and sleeping behavior). Questionnaire data of 150 mothers, living in Germany, with mixed ethnic and educational backgrounds were collected when infants were 3 and 7 months old. Two types of maternal soothing strategies were distinguished: close soothing, involving close physical and emotional contact, and distant soothing, involving physical and emotional distancing from the infant. A cross-sectional SEM at 3 months indicated that maternal self-efficacy is associated with reported infant regulation through distant soothing strategies. Low maternal self-efficacy was associated with frequent maternal use of distant soothing, which in turn was related to reported infant regulation problems, that is, non-soothability and greater crying frequency. Frequent use of close soothing was associated with reported infant sleeping behavior, that is, frequent night-time awakenings. A longitudinal SEM further indicated that the effects of close soothing persisted at least until the infants' age of 7 months. The study showed how low maternal self-efficacy, increased use of distant soothing, and reported early infant regulation problems are intertwined and that, due to their persisting positive effect on infant soothability, close soothing better supports infant development., (© 2024 The Authors. Infant Mental Health Journal published by Wiley Periodicals LLC on behalf of Michigan Association for Infant Mental Health.)

The nuclear long non-coding RNA LUCAT1 has previously been identified as a negative feedback regulator of type I interferon and inflammatory cytokine expression in human myeloid cells. Here, we define the mechanistic basis for the suppression of inflammatory gene expression by LUCAT1. Using comprehensive identification of RNA-binding proteins by mass spectrometry as well as RNA immunoprecipitation, we identified proteins important in processing and alternative splicing of mRNAs as LUCAT1-binding proteins. These included heterogeneous nuclear ribonucleoprotein C, M, and A2B1. Consistent with this finding, cells lacking LUCAT1 have altered splicing of selected immune genes. In particular, upon lipopolysaccharide stimulation, the splicing of the nuclear receptor 4A2 (NR4A2) gene was particularly affected. As a consequence, expression of NR4A2 was reduced and delayed in cells lacking LUCAT1. NR4A2-deficient cells had elevated expression of immune genes. These observations suggest that LUCAT1 is induced to control the splicing and stability of NR4A2, which is in part responsible for the anti-inflammatory effect of LUCAT1. Furthermore, we analyzed a large cohort of patients with inflammatory bowel disease as well as asthma and chronic obstructive pulmonary disease. In these patients, LUCAT1 levels were elevated and in both diseases, positively correlated with disease severity. Collectively, these studies define a key molecular mechanism of LUCAT1-dependent immune regulation through post-transcriptional regulation of mRNAs highlighting its role in the regulation of inflammatory disease.

Background: Comprehensive studies investigated the role of T-cells in asthma which led to personalised treatment options targeting severe eosinophilic asthma. However, little is known about the contribution of B-cells to this chronic inflammatory disease. In this study we investigated the contribution of various B-cell populations to specific clinical features in asthma., Methods: In the All Age Asthma Cohort (ALLIANCE), a subgroup of 154 adult asthma patients and 28 healthy controls were included for B-cell characterisation by flow cytometry. Questionnaires, lung function measurements, blood differential counts and allergy testing of participants were analysed together with comprehensive data on B-cells using association studies and multivariate linear models., Results: Patients with severe asthma showed decreased immature B-cell populations while memory B-cells were significantly increased compared with both mild-moderate asthma patients and healthy controls. Furthermore, increased frequencies of IgA + memory B-cells were associated with impaired lung function and specifically with parameters indicative for augmented resistance in the peripheral airways. Accordingly, asthma patients with small airway dysfunction (SAD) defined by impulse oscillometry showed increased frequencies of IgA + memory B-cells, particularly in patients with mild-moderate asthma. Additionally, IgA + memory B-cells significantly correlated with clinical features of SAD such as exacerbations., Conclusions: With this study we demonstrate for the first time a significant association of increased IgA + memory B-cells with asthma and SAD, pointing towards future options for B-cell-directed strategies in preventing and treating asthma., Competing Interests: Conflict of interest: C. Happle reports grants from Novartis and Pari, outside the submitted work. M.V. Kopp reports grants from Allergopharma GmbH and Vertex GmbH; honoraria for lectures from Allergopharma GmbH, Sanofi GmbH, Infectopharm GmbH, Vertex GmbH and Leti GmbH; advisory board membership at Allergopharma GmbH and Sanofi GmbH; outside the submitted work. E. von Mutius reports royalties from Elsevier GmbH, Georg Thieme Verlag, Springer-Verlag GmbH and Elsevier Ltd; consulting fees from the Chinese University of Hong Kong, European Commission, HiPP GmbH & Co KG and AstraZeneca; lecture honoraria from Massachusetts Medical Society, Springer-Verlag GmbH, Elsevier Ltd, Boehringer Ingelheim International GmbH, European Respiratory Society, Universiteit Utrecht – Faculteit Diergeneeskunde, Universität Salzburg, Springer Medizin Verlag GmbH, Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), Klinikum Rechts der Isar, University of Colorado, Paul-Martini-Stiftung and Imperial College London; travel support from Verein zur Förderung der Pneumologie am Krankenhaus Großhansdorf eV, Pneumologie Développement, Mondial Congress & Events GmbH & Co. KG, American Academy of Allergy, Asthma & Immunology, Imperial College London, Margaux Orange, Volkswagen Stiftung, Boehringer Ingelheim International GmbH, European Respiratory Society, Universiteit Utrecht – Faculteit Diergeneeskunde, Österreichische Gesellschaft für Allergologie und Immunologie, Massachusetts Medical Society, OM Pharma SA, Hanson Wade Ltd, iKOMM GmbH, DSI Dansk Borneastma Center, American Thoracic Society, HiPP GmbH & Co. KG and Universiteit Utrecht – Faculteit Bètawetenschappen; outside the submitted work. In addition, E. von Mutius has patent LU101064 (Barn dust extract for the prevention and treatment of diseases) pending, royalties paid to ProtectImmun for patent EP2361632 (Specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders, granted on 19 March 2014), and patents EP1411977 (Composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases, granted on 18 April 2007), EP1637147 (Stable dust extract for allergy protection, granted on 10 December 2008) and EP1964570 (Pharmaceutical compound to protect against allergies and inflammatory diseases, granted on 21 November 2012) licensed to ProtectImmun. In addition, E. von Mutius is a member of the EXPANSE (funded by European Commission) Scientific Advisory Board, member of the BEAMS External Scientific Advisory Board (ESAB), member of the Editorial Board of the Journal of Allergy and Clinical Immunology: In Practice, member of the Scientific Advisory Board of the Children's Respiratory and Environmental Workgroup (CREW), member of the International Scientific and Societal Advisory Board (ISSAB) of Utrecht Life Sciences (ULS), University of Utrecht, member of the External Review Panel of the Faculty of Veterinary Science, University of Utrecht, member of the Selection Committee for the Gottfried Wilhelm Leibniz Programme (DFG), member of the International Advisory Board of the Asthma UK Centre for Applied Research (AUKCAR), member of the International Advisory Board of The Lancet Respiratory Medicine, and member of the Scientific Advisory Board of the CHILD (Canadian Healthy Infant Longitudinal Development) study, McMaster University, Hamilton, Canada. T. Bahmer reports grants from Network University Medicine (NUM): National Pandemic Cohort Network (NAPKON); consulting fees and lecture honoraria from AstraZeneca, Novartis, GlaxoSmithKline, Roche and Chiesi; travel support from Chiesi and AstraZeneca; outside the submitted work. K.F. Rabe reports lecture honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi Pharmaceuticals, Novartis, Sanofi Regeneron, GlaxoSmithKline, Berlin-Chemie and Roche; advisory board membership at AstraZeneca and Sanofi Regeneron; leadership roles with the German Center for Lung Research (DZL), German Chest Society (DGP) and American Thoracic Society; outside the submitted work. A. Meyer-Bahlburg reports lecture honoraria from Pfizer; travel support from CSL Behring; advisory board membership with Pfizer; outside the submitted work. G. Hansen reports consulting fees from Sanofi GmbH; lecture honoraria from MedUpdate and AbbVie; outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2022.)

Rationale: In adults, personalised asthma treatment targets patients with type 2 (T2)-high and eosinophilic asthma phenotypes. It is unclear whether such classification is achievable in children., Objectives: To define T2-high asthma with easily accessible biomarkers and compare resulting phenotypes across all ages., Methods: In the multicentre clinical All Age Asthma Cohort (ALLIANCE), 1125 participants (n=776 asthmatics, n=349 controls) were recruited and followed for 2 years (1 year in adults). Extensive clinical characterisation (questionnaires, blood differential count, allergy testing, lung function and sputum induction (in adults)) was performed at baseline and follow-ups. Interleukin (IL)-4, IL-5 and IL-13 were measured after stimulation of whole blood with lipopolysaccharide (LPS) or anti-CD3/CD28., Measurements and Main Results: Based on blood eosinophil counts and allergen-specific serum IgE antibodies, patients were categorised into four mutually exclusive phenotypes: "atopy-only", "eosinophils-only", "T2-high" (eosinophilia + atopy) and "T2-low" (neither eosinophilia nor atopy). The T2-high phenotype was found across all ages, even in very young children in whom it persisted to a large degree even after 2 years of follow-up. T2-high asthma in adults was associated with childhood onset, suggesting early origins of this asthma phenotype. In both children and adults, the T2-high phenotype was characterised by excessive production of specific IgE to allergens (p<0.0001) and, from school age onwards, by increased production of IL-5 after anti-CD3/CD28 stimulation of whole blood., Conclusions: Using easily accessible biomarkers, patients with T2-high asthma can be identified across all ages delineating a distinct phenotype. These patients may benefit from therapy with biologicals even at a younger age., Competing Interests: Conflict of interest: N. Maison, J. Omony, S. Illi, D. Thiele, A.M. Dittrich, C. Happle, M. Meyer, S. Foth and R. Grychtol have nothing to disclose. C. Skevaki reports grants and personal fees from Hycor Biomedical, Bencard Allergie, Thermo Fisher Scientific as well as grants from Mead Johnson Nutrition (MJN), Universities Giessen and Marburg Lung Centre, the German Centre for Lung Research (DZL), University Hospital Giessen and Marburg, Deutsche Forschungsgemeinschaft (DFG). T. Bahmer reports grants from the Federal Ministry for Education and Research (BMBF) for the German Center for Lung Research (DZL) and personal fees from AstraZeneca, GlaxoSmithKline, Novartis, Roche and Chiesi. M. Weckmann reports grants from Federal Ministry for Education and Research (BMBF), University of Luebeck and German Academic Exchange Service. B. Schaub reports grants from DFG, BMBF, the EU as well from GlaxoSmithKline, Sanofi and Novartis. H. Renz reports grants from German Center for Lung Disease (DZL) and Universities Giessen Marburg Lung Center. M.V. Kopp reports grants and personal fees from Allergopharma GmbH and Vertex GmbH; additional, personal fees from Sanofi GmbH, Infectopharm GmbH and Leti GmbH. E. Rietschel reports personal lecture payments for Nutricia Milupa GmbH and Novartis Pharma, and honoraria for participation in advisory boards for MICE-Mylan, Novartis Pharma GmbH and Boehringer Ingelheim GmbH. K.F. Rabe recieved personal payments or honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi Pharmaceuticals, Novartis, Sanofi & Regeneron, GlaxoSmithKline, Berlin Chemie and Roche; K.F. Rabe also discloses participation on data safety monitoring boards/advisory boards for AstraZeneca and Sanofi Regeneron, and leadership or fiduciary role in the German Center for Lung Research (DZL), German Chest Society (DGP) and American Thoracic Society (ATS). G. Hansen reports grants from German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG) as well as personal fees from Sanofi GmbH, MedUpdate, and Abbvie. E. von Mutius reports grants from the German Center for Lung Research (DZL) as well as royalties/licenses held by Elsevier GmbH, Gerog Thieme Verlag, Springer Verlag GmbH, Elsevier Ltd; furthermore, consultation fees were received from the Chinese University of Hong Kong, European Commission, HiPP GmbH and AstraZeneca; E. von Mutius also received payments and/or support for meetings/travel from the Massachusetts Medical Society, Springer-Verlag GmbH, Elsevier Ltd, Böhringer Ingelheim International GmbH, European Respiratory Society (ERS), University Utrecht, Salzburg, Colorado and Imperial College London, Springer Medizin Verlag GmbH, Japanese Society of Pediatric Allergy and Clinical Immunology, Klinkum Rechts der Isar, Paul-Martini-Stiftung; further support for meetings/travel was granted by Verein zur Förderung der Pneumologie am Krankenhaus Groshansdorf, Pneumologie Development Mondial Congress & Events GmbH, American Academy of Allergy, Asthma & Immunology, Margaux Orange, Volkswagen Stiftung, Österreichische Gesellschaft für Allergologie & Immunologie, OM Pharma SA, Hanson Wade Ltd, iKOMM GmbH, DSI Dansk Bornestma Center, American Thoracic Society, HiPP GmbH; E. von Mutius has patent EP2361632, EP1411977, EP1637147 and EP 1964570 (licensed to Protectimmun), furthermore patent LU101064 is pending; E. von Mutius participates in the following data monitoring or advisory boards: EXPANSE, BEAMS External Scientific Advisory Board, Journal of Allergy and Clinical Immunology: in Practice, Children's Respiratory and Environmental Workgroup (CREW), International Scientific & Societal Advisory Board of Utrecht Life Sciences, External Review Panel of the Faculty of Veterinary Science (University of Utrecht), Gottfried Wilhelm Leibniz Programme, Asthma UK for Applied Research, Advisory Board of The Lancet Respiratory Medicine, CHILD (Canadian Healthy Infant Longitudinal Development Study)., (Copyright ©The authors 2022.)

Background: Pulmonary Tuberculosis (TB) is diagnosed through sputum samples. As sputum sampling is challenging in children and cachexic patients, the development of diagnostic tests using saliva appears promising but has been discouraged due to low bacterial load and poor sensitivity. Here, we present a novel and rapid method to enrich Mycobacterium tuberculosis (Mtb) from saliva, which may serve as a basis for a diagnostic saliva test., Methods: Lipobiotin-functionalized magnetic beads (LMBs) were incubated with Mtb-spiked PBS and saliva from healthy donors as well as with saliva from TB patients. Flow cytometry was used to evaluate the capacity of the beads to bind Mtb, while real-time quantitative polymerase chain reaction (qPCR) was utilized to detect Mtb and determine the amount of mycobacterial DNA in different sample types., Results: We found that LMBs bind Mtb efficiently when compared to non-functionalized beads. The development of an qPCR assay based on the use of LMBs (LMB assay) allowed us to enrich mycobacterial DNA in spiked sample types, including PBS and saliva from healthy donors (enrichment of up to ~8.7 fold). In Mtb-spiked saliva samples, we found that the LMB assay improved the detection rate of 102 bacteria in a volume of 5 ml from 0 out of 15 (0%) to 6 out of 15 (40%). Consistent with that, the LMB assay increased the rate of correctly identified saliva samples from TB patients in two independent cohorts., Conclusions: Implementation of the principle of the LMB-based assay may improve the sensitivity of existing diagnostic techniques, e.g. by functionalizing materials that facilitate Mtb sampling from the oral cavity., Competing Interests: CH reports that he obtains personal fees from Janssen outside the submitted work. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

One-fourth of the global human population is estimated to be infected with strains of the Mycobacterium tuberculosis complex (MTBC), the causative agent of tuberculosis (TB). Using lipidomic approaches, we show that tuberculostearic acid (TSA)-containing phosphatidylinositols (PIs) are molecular markers for infection with clinically relevant MTBC strains and signify bacterial burden. For the most abundant lipid marker, detection limits of ∼10 2 colony forming units (CFUs) and ∼10 3 CFUs for bacterial and cell culture systems were determined, respectively. We developed a targeted lipid assay, which can be performed within a day including sample preparation─roughly 30-fold faster than in conventional methods based on bacterial culture. This indirect and culture-free detection approach allowed us to determine pathogen loads in infected murine macrophages, human neutrophils, and murine lung tissue. These marker lipids inferred from mycobacterial PIs were found in higher levels in peripheral blood mononuclear cells of TB patients compared to healthy individuals. Moreover, in a small cohort of drug-susceptible TB patients, elevated levels of these molecular markers were detected at the start of therapy and declined upon successful anti-TB treatment. Thus, the concentration of TSA-containing PIs can be used as a correlate for the mycobacterial burden in experimental models and in vitro systems and may prospectively also provide a clinically relevant tool to monitor TB severity.

Respiratory infections by Gram-negative bacteria are a major cause of global morbidity and mortality. Alveolar macrophages (AMs) play a central role in maintaining lung immune homeostasis and host defense by sensing pathogens via pattern recognition receptors (PRR). The PRR Toll-like receptor (TLR) 4 is a key sensor of lipopolysaccharide (LPS) from Gram-negative bacteria. Pulmonary surfactant is the natural microenvironment of AMs. Surfactant protein A (SP-A), a multifunctional host defense collectin, controls LPS-induced pro-inflammatory immune responses at the organismal and cellular level via distinct mechanisms. We found that SP-A post-transcriptionally restricts LPS-induced TLR4 protein expression in primary AMs from healthy humans, rats, wild-type and SP-A -/- mice by further decreasing cycloheximide-reduced TLR4 protein translation and enhances the co-localization of TLR4 with the late endosome/lysosome. Both effects as well as the SP-A-mediated inhibition of LPS-induced TNF-α release are counteracted by pharmacological inhibition of the small GTPase Rab7. SP-A-enhanced Rab7 expression requires β-arrestin2 and, in β-arrestin2 -/- AMs and after intratracheal LPS challenge of β-arrestin2 -/- mice, SP-A fails to enhance TLR4/lysosome co-localization and degradation of LPS-induced TLR4. In SP-A -/- mice, TLR4 levels are increased after pulmonary LPS challenge. SP-A-induced activation of mechanistic target of rapamycin complex 1 (mTORC1) kinase requires β-arrestin2 and is critically involved in degradation of LPS-induced TLR4. The data suggest that SP-A post-translationally limits LPS-induced TLR4 expression in primary AMs by lysosomal degradation comprising Rab7, β-arrestin2, and mTORC1. This study may indicate a potential role of SP-A-based therapeutic interventions in unrestricted TLR4-driven immune responses to lower respiratory tract infections caused by Gram-negative bacteria.

To examine the role of smoking on the bacterial community composition of the upper and the lower respiratory tract, a monocentric, controlled prospective study was performed, including healthy smokers, ex-smokers and never-smokers. Smokers were further grouped according to their smoking history. Bacterial diversity was analysed using a molecular barcoding approach based on directly extracted DNA. Our study shows for the first time distinct bacterial response patterns in the upper and lower respiratory tract to cigarette smoking leading to a higher abundance of opportunistic pathogens. The clinical significance of these dysbioses for health needs to be further explored., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Non-invasive ventilation (NIV) is a recommended treatment for COPD patients suffering from chronic hypercapnic respiratory failure. Prolonged dyspnea after mask removal in the morning, often referred to as deventilation syndrome, is a common side effect but has been poorly characterized yet. This study aimed to explore the pathomechanism, identify risk factors and possible treatment strategies for the deventilation syndrome., Methods: A prospective, controlled, non-blinded study was conducted. After a night with established NIV therapy, the patients underwent spirometry, blood gas analyses and 6-min walking tests (6MWT) directly, at 2 and 4 h after mask removal. Dyspnea was measured by the modified Borg scale. Bodyplethysmography and health-related quality of life (HRQoL) questionnaires were used. Patients suffering from deventilation syndrome (defined as dyspnea of at least three points on the Borg scale after mask removal) were treated with non-invasive pursed lip breathing ventilation (PLBV) during the second night of the study., Results: Eleven of 31 patients included (35%) met the given criteria for a deventilation syndrome. They reported significantly more dyspnea on the Borg scale directly after mask removal (mean: 7.2 ± 1.0) compared to measurement after 2 h (4.8 ± 2.6; p = 0.003). Initially, mean inspiratory vital capacity was significantly reduced (VCmax: 46 ± 16%) compared to 2 h later (54 ± 15%; p = 0.002), while no changes in pulse oximetry or blood gas analysis were observed. Patients who suffered from a deventilation syndrome had a significantly higher mean airway resistance (Reff: 320 ± 88.5%) than the patients in the control group (253 ± 147%; p = 0.021). They also scored significantly lower on the Severe Respiratory Insufficiency Questionnaire (SRI; mean: 37.6 ± 10.1 vs 50.6 ± 16.7, p = 0.027). After one night of ventilation in PLBV mode, mean morning dyspnea decreased significantly to 5.6 ± 2.0 compared to 7.2 ± 1.0 after established treatment (p = 0.019) and mean inspiratory vital capacity increased from 44 ± 16.0% to 48 ± 16.3 (p = 0.040)., Conclusions: The deventilation syndrome is a serious side effect of NIV in COPD patients, characterized by increase of dyspnea. It is associated with decrease in vital capacity, exercise tolerance after mask removal and lower HRQoL. Patients with high airway resistance are at greater risk of suffering from morning dyspnea. Ventilation in PLBV mode may prevent or improve the deventilation syndrome., Trial Registration: The study was registered in the German Clinical Trials Register (DRKS00016941) on 09 April 2019., (© 2022. The Author(s).)

Background: Little is known about the role of small airway dysfunction (SAD) and its complex relation with asthma control and physical activity (PA)., Objective: To investigate the interrelations among SAD, risk factors for asthma severity, symptom control, and PA., Methods: We assessed SAD by impulse oscillometry and other sophisticated lung function measures including inert gas washout in adults with asthma (mild to moderate, n = 140; severe, n = 128) and 69 healthy controls from the All Age Asthma Cohort. We evaluated SAD prevalence and its interrelation with risk factors for asthma severity (older age, obesity, and smoking), type 2 inflammation (sputum and blood eosinophils, fractional exhaled nitric oxide), systemic inflammation (high-sensitivity C-reactive protein), asthma control (AC), and PA (accelerometer for 1 week). We applied a clinical model based on structural equation modeling that integrated causal pathways among these clinical variables., Results: The prevalence of SAD ranged from 75% to 90% in patients with severe asthma and from 53% to 64% in mild to moderate asthma. Severe SAD was associated with poor AC and low PA. Structural equation modeling indicated that age, obesity, obesity-related systemic inflammation, T2 inflammation, and smoking are independent predictors of SAD. Small airway dysfunction was the main determinant factor of AC, which in turn affected PA. Obesity affected AC directly and through its contribution to SAD and low PA. In addition, PA had bidirectional associations with obesity, SAD, and AC. Structural equation modeling also indicated interrelations among distal airflow limitation, air trapping, and ventilation heterogeneity., Conclusions: Small airway dysfunction is a highly prevalent key feature of asthma that interrelates a spectrum of distal lung function abnormalities with risk factors for asthma severity, asthma control, and physical activity., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite efforts to improve tuberculosis (TB) detection, limitations in access, quality and timeliness of diagnostic services in low- and middle-income countries are challenging for current TB diagnostics. This study aimed to identify and characterise a metabolic profile of TB in urine by high-field nuclear magnetic resonance (NMR) spectrometry and assess whether the TB metabolic profile is also detected by a low-field benchtop NMR spectrometer. We included 189 patients with tuberculosis, 42 patients with pneumococcal pneumonia, 61 individuals infected with latent tuberculosis and 40 uninfected individuals. We acquired the urine spectra from high and low-field NMR. We characterised a TB metabolic fingerprint from the Principal Component Analysis. We developed a classification model from the Partial Least Squares-Discriminant Analysis and evaluated its performance. We identified a metabolic fingerprint of 31 chemical shift regions assigned to eight metabolites (aminoadipic acid, citrate, creatine, creatinine, glucose, mannitol, phenylalanine, and hippurate). The model developed using low-field NMR urine spectra correctly classified 87.32%, 85.21% and 100% of the TB patients compared to pneumococcal pneumonia patients, LTBI and uninfected individuals, respectively. The model validation correctly classified 84.10% of the TB patients. We have identified and characterised a metabolic profile of TB in urine from a high-field NMR spectrometer and have also detected it using a low-field benchtop NMR spectrometer. The models developed from the metabolic profile of TB identified by both NMR technologies were able to discriminate TB patients from the rest of the study groups and the results were not influenced by anti-TB treatment or TB location. This provides a new approach in the search for possible biomarkers for the diagnosis of TB.

Purpose: Long-term non-invasive ventilation (NIV) is recommended for patients with stable chronic obstructive lung disease (COPD) and chronic hypercapnia. High inspiratory pressure NIV (hiNIV) and a significant reduction of arterial pCO2 have been shown to prolong survival. Often, patients on hiNIV describe severe respiratory distress, known as "deventilation syndrome", after removal of the NIV mask in the morning. Mechanical pursed lips breathing ventilation (PLBV) is a new non-invasive ventilation mode that mimics the pressure-curve of pursed lips breathing during expiration. The clinical impact of switching patients from standard NIV to PLBV has not been studied so far., Patients and Methods: In this hypothesis generating study, we retrospectively analysed the effects of switching COPD patients (stage GOLD III-IV) from conventional NIV to PLBV. Medical records of all patients who had an established NIV and were switched to PLBV between March 2016 and October 2017 were screened. Patients were included if they complained of shortness of breath on mask removal, used their conventional NIV regularly, and had a documented complete diagnostic workup including lung function testing, blood gas analysis and 6-minute walk test (6MWT) before and after 3-7 days of PLBV., Results: Six male and 10 female patients (median age 65.4 years; IQR 64.0-71.3) with a previous NIV treatment duration of 38 months (median; IQR 20-42) were analysed. After PLVB initiation, the median inspiratory ventilation pressure needed to maintain the capillary pre-switch pCO2 level was reduced from 19.5 mbar (IQR 16.0-26.0) to 13.8 mbar (IQR 12.5-14.9; p<0.001). The median 6MWT distance increased from 200m (IQR 153.8-266.3) to 270m (IQR 211.3-323.8; p<0.001). Median forced vital capacity (FVC) increased from 49.5% to 53.0% of the predicted value (p = 0.04), while changes in FEV1 and residual volume (RV) were non-significant., Conclusion: Based on this small retrospective analysis, we hypothesise that switching patients with COPD GOLD III-IV and chronic hypercapnia from conventional NIV to PLBV may increase exercise tolerance and FVC in the short term., Competing Interests: SR invented the PLBV and has co-developed the Vigaro within the scope of a consulting contract with FLO medical. CL reports personal fees from Chiesi, Gilead, Janssen, Lucane, Novartis, Oxoid, Berlin Chemie and Thermofisher outside the submitted work. CH reports personal fees from Janssen outside the submitted work. CJ, KIG and LK have no conflicting interests to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Originally, the neuropeptide α-melanocyte-stimulating hormone (α-MSH) has been described as a mediator of skin pigmentation. However, recent studies have shown that α-MSH is able to modulate inflammation in various tissues including the lung. So far, it is still not clear whether α-MSH also plays a role in allergic bronchial asthma., Objective: This study aimed at investigating the role and regulatory mechanisms of α-MSH in asthma pathogenesis., Methods: α-MSH levels were measured in bronchoalveolar lavage (BAL) fluid of asthmatic and non-asthmatic individuals as well as of healthy mice and mice with experimental asthma. Wild-type mice were sensitized to ovalbumin (OVA) and exposed to an OVA aerosol in order to induce experimental allergic asthma. α-MSH was administrated intratracheally, the α-MSH antibody intraperitoneally prior each OVA challenge. Airway inflammation, cytokine production, mucus production, airway hyperresponsiveness and receptor expression were assessed., Results: α-MSH levels in BAL of asthmatic individuals and mice were significantly higher compared to healthy controls. In a mouse model of experimental asthma, α-MSH neutralization increased airway inflammation and mucus production, whereas local administration of α-MSH significantly reduced inflammation of the airways. The beneficial effects were further associated with decreased levels of eosinophilic chemoattractant factors that are released by MC5R-positive T helper 2 and airway epithelial cells., Conclusion and Clinical Relevance: α-MSH acts as a regulatory factor to maintain local immune homeostasis in allergic bronchial asthma., (© 2019 John Wiley & Sons Ltd.)

Background: Diagnosis of chronic pulmonary aspergillosis (CPA) is challenging. Symptoms are unspecific or missing, radiological findings are variable and proof of mycological evidence is limited by the accuracy of diagnostic tests. The goal of this study was to investigate diagnostic performance of galactomannan (GM), the newly formatted Aspergillus -specific lateral-flow-device test (LFD), and a number of cytokines in bronchoalveolar lavage fluid (BALF) samples obtained from patients with CPA, patients with respiratory disorders without CPA and healthy individuals. Methods: Patients with CPA ( n = 27) and controls ( n = 27 with underlying respiratory diseases but without CPA, and n = 27 healthy volunteers) were recruited at the Medical University of Graz, Austria and the Research Center Borstel, Germany between 2010 and 2018. GM, LFD and cytokine testing was performed retrospectively at the Research Center Borstel. Results: Sensitivity and specificity of GM testing from BALF with a cut off level of ≥0.5 optical density index (ODI) was 41 and 100% and 30 and 100% with a cut off level of ≥1.0 ODI. ROC curve analysis showed an AUC 0.718 (95% CI 0.581-0.855) for GM for differentiating CPA patients to patients with other respiratory diseases without CPA. The LFD resulted positive in only three patients with CPA (7%) and was highly specific. CPA patients did not differ significantly in the BALF cytokine profile compared to patients with respiratory disorders without CPA, but showed significant higher values for IFN-γ, IL-1b, IL-6, IL-8, and TNF-α compared to healthy individuals. Conclusion: Both GM and LFD showed insufficient performance for diagnosing CPA, with sensitivities of BALF GM below 50%, and sensitivity of the LFD below 10%. The high specificities may, however, result in a high positive predictive value and thereby help to identify semi-invasive or invasive disease.

Tuberculosis is transmitted by inhalation of Mycobacterium tuberculosis -containing aerosols; 75 % of all patients show pulmonary manifestation. Immune responses after exposure that lead to clinical symptoms occur mainly in the respiratory tract and are only poorly understood. In most cases, cells of the innate immune system are believed to control the growth of or eradicate inhaled mycobacteria. However, this cannot be verified in vivo using standard methods. Subsequently, CD4 + and CD8 + T cell-driven adaptive immune responses are induced that attempt to control bacterial growth. The humoral defence appears to be less important. This article gives an overview of the current understanding of pulmonary immune mechanisms during exposure, latent infection, active disease and therapy of tuberculosis., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Assessing language development in the first postnatal year is difficult, as receptive and expressive skills are rudimentary. Although outward manifestations of change are limited, the auditory language system is thought to undergo critical development at this age, as the foundations are laid for the rapid onset of spoken language in the second and third years. We recruited 11 infants, 7 healthy controls (gestational age = 40.69 ± 0.56; range from 40 to 41.43) and preterm babies (gestational age = 28.04 ± 0.95; range from 27.43 to 29.43) who underwent a Magnetic Resonance Imaging study during the first postnatal year (age at scan = 194.18 ± 97.98). We assessed white matter tracts using diffusion-weighted magnetic resonance imaging with probabilistic tractography. Fractional anisotropy was found to be largely mature even at one month, although there was a little further increase during the first postnatal year in both the acoustic radiation and the direct brainstem-Heschl's pathway., (© 2018 Wiley Periodicals, Inc.)