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European Respiratory Journal
Journal Prestige (SJR): 3.788
Citation Impact (citeScore): 5
Number of Followers: 42  
 
  Full-text available via subscription Subscription journal
ISSN (Print) 0903-1936 - ISSN (Online) 1399-3003
Published by European Respiratory Society Homepage  [4 journals]
  • Higher throughput drug screening for rare respiratory diseases:
           readthrough therapy in primary ciliary dyskinesia

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      Authors: Lee, D. D. H; Cardinale, D, Nigro, E, Butler, C. R, Rutman, A, Fassad, M. R, Hirst, R. A, Moulding, D, Agrotis, A, Forsythe, E, Peckham, D, Robson, E, Smith, C. M, Somavarapu, S, Beales, P. L, Hart, S. L, Janes, S. M, Mitchison, H. M, Ketteler, R, Hynds, R. E, O'Callaghan, C.
      Pages: 2000455 - 2000455
      Abstract: BackgroundDevelopment of therapeutic approaches for rare respiratory diseases is hampered by the lack of systems that allow medium-to-high-throughput screening of fully differentiated respiratory epithelium from affected patients. This is a particular problem for primary ciliary dyskinesia (PCD), a rare genetic disease caused by mutations in genes that adversely affect ciliary movement and consequently mucociliary transport. Primary cell culture of basal epithelial cells from nasal brush biopsies followed by ciliated differentiation at the air–liquid interface (ALI) has proven to be a useful tool in PCD diagnostics but the technique's broader utility, including in pre-clinical PCD research, has been restricted by the limited number of basal cells that can be expanded from such biopsies.MethodsWe describe an immunofluorescence screening method, enabled by extensive expansion of basal cells from PCD patients and the directed differentiation of these cells into ciliated epithelium in miniaturised 96-well transwell format ALI cultures. As proof-of-principle, we performed a personalised investigation in a patient with a rare and severe form of PCD (reduced generation of motile cilia), in this case caused by a homozygous nonsense mutation in the MCIDAS gene.ResultsInitial analyses of ciliary ultrastructure, beat pattern and beat frequency in the 96-well transwell format ALI cultures indicate that a range of different PCD defects can be retained in these cultures. The screening system in our proof-of-principal investigation allowed drugs that induce translational readthrough to be evaluated alone or in combination with nonsense-mediated decay inhibitors. We observed restoration of basal body formation but not the generation of cilia in the patient's nasal epithelial cells in vitro.ConclusionOur study provides a platform for higher throughput analyses of airway epithelia that is applicable in a range of settings and suggests novel avenues for drug evaluation and development in PCD caused by nonsense mutations.
      Keywords: Lung biology and experimental studies, Paediatric pulmonology
      PubDate: 2021-10-14T02:10:50-07:00
      DOI: 10.1183/13993003.00455-2020
      Issue No: Vol. 58, No. 4 (2021)
       
  • The early use of Antibiotics for at Risk CHildren with InfluEnza-like
           illness (ARCHIE): a double-blind randomised placebo-controlled trial

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      Authors: Wang, K; Semple, M. G, Moore, M, Hay, A. D, Tonner, S, Galal, U, Grabey, J, Carver, T, Perera, R, Yu, L.-M, Mollison, J, Little, P, Farmer, A, Butler, C. C, Harnden, A.
      Pages: 2002819 - 2002819
      Abstract: IntroductionThe UK government stockpiles co-amoxiclav to treat bacterial complications during influenza pandemics. This pragmatic trial examines whether early co-amoxiclav use reduces reconsultation due to clinical deterioration in "at risk" children presenting with influenza-like illness (ILI) in primary or ambulatory care.Methods"At risk" children aged from 6 months to 12 years presenting within 5 days of ILI onset were randomly assigned to oral co-amoxiclav 400/57 or a placebo twice daily for 5 days (dosing based on age±weight). "At risk" groups included children with respiratory, cardiac and neurological conditions. Randomisation was stratified by region and used a non-deterministic minimisation algorithm to balance age and current seasonal influenza vaccination status. Our target sample size was 650 children which would have allowed us to detect a reduction in the proportion of children reconsulting due to clinical deterioration from 40% to 26%, with 90% power and 5% two-tailed alpha error (including allowance for 25% loss to follow-up and an inflation factor of 1.041). Participants, caregivers and investigators were blinded to treatment allocation. Intention-to-treat analysis included all randomised participants with primary outcome data on reconsultation due to clinical deterioration within 28 days. Safety analysis included all randomised participants. Trial registration: ISRCTN 70714783. EudraCT 2013-002822-21.ResultsWe recruited 271 children between February 11, 2015 and April 20, 2018. Primary outcome data were available for 265 children. Only 61 out of 265 children (23.0%) reconsulted due to clinical deterioration. No evidence of a treatment effect was observed for reconsultation due to clinical deterioration (33 out of 133 for co-amoxiclav (24.8%) and 28 out of 132 (21.2%) for placebo; adjusted risk ratio (RR) 1.16, 95% confidence interval (CI) 0.75–1.80). There was also no evidence of a difference between groups in the proportion of children for whom one or more adverse events (AEs) were reported (32 out of 136 (23.5%) for co-amoxiclav and 22 out of 135 (16.3%) for placebo; adjusted RR 1.45, 95% CI 0.90–2.34). In total, 66 AEs were reported (co-amoxiclav, n=37; placebo, n=29). Nine serious AEs were reported per group, although none were considered related to study medication.ConclusionOur trial did not find evidence that treatment with co-amoxiclav reduces risk of reconsultation due to clinical deterioration in "at risk" children who present early with ILI during influenza season. Our findings therefore do not support early co-amoxiclav use in children with seasonal ILI.
      Keywords: Respiratory infections and tuberculosis, Paediatric pulmonology
      PubDate: 2021-10-07T00:19:04-07:00
      DOI: 10.1183/13993003.02819-2020
      Issue No: Vol. 58, No. 4 (2021)
       
  • The risk of community-acquired pneumonia in children using gastric acid
           suppressants

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      Authors: van der Sande, L. J. T. M; Jöbsis, Q, Bannier, M. A. G. E, van de Garde, E. M. W, Coremans, J. J. M, de Vries, F, Dompeling, E, Driessen, J. H. M.
      Pages: 2003229 - 2003229
      Abstract: BackgroundWith the increased use of acid suppressants, significant potential complications such as community-acquired pneumonia (CAP) are becoming more apparent. Paradoxically, in spite of an increased focus on potential complications, there is an increased use of acid suppressants in children and a lack of data specifically targeting the association between acid suppressants and CAP. Our main objective was to evaluate the risk of CAP in children using acid suppressants (proton pump inhibitors (PPIs) and/or histamine-2 receptor antagonists (H2RAs)).MethodsWe performed a cohort study using data from the UK Clinical Practice Research Datalink. All patients aged 1 month to 18 years with a prescription of acid suppressants were included and matched to up to four unexposed children. Time-varying Cox proportional hazards models were used to estimate the risk of CAP. The cohort consisted of 84 868 exposed and 325 329 unexposed children.ResultsCurrent use of PPIs and H2RAs was associated with an increased risk of CAP (adjusted hazard ratio 2.05 (95% CI 1.90–2.22) and 1.80 (95% CI 1.67–1.94), respectively). The risk was even greater in patients with respiratory disease. Long-term use (≥211 days) of PPIs and H2RAs led to a significantly greater risk of CAP compared with short-term use (
      Keywords: CF and non-CF bronchiectasis, Paediatric pulmonology
      PubDate: 2021-10-07T00:19:04-07:00
      DOI: 10.1183/13993003.03229-2020
      Issue No: Vol. 58, No. 4 (2021)
       
  • Multi-omics links IL-6 trans-signalling with neutrophil extracellular trap
           formation and Haemophilus infection in COPD

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      Authors: Winslow, S; Odqvist, L, Diver, S, Riise, R, Abdillahi, S, Wingren, C, Lindmark, H, Wellner, A, Lundin, S, Yrlid, L, Ax, E, Djukanovic, R, Sridhar, S, Higham, A, Singh, D, Southworth, T, Brightling, C. E, Olsson, H. K, Jevnikar, Z.
      Pages: 2003312 - 2003312
      Abstract: Background:Interleukin (IL)-6 trans-signalling (IL-6TS) is emerging as a pathogenic mechanism in chronic respiratory diseases; however, the drivers of IL-6TS in the airways and the phenotypic characteristic of patients with increased IL-6TS pathway activation remain poorly understood.Objective:Our aim was to identify and characterise COPD patients with increased airway IL-6TS and to elucidate the biological drivers of IL-6TS pathway activation.Methods:We used an IL-6TS-specific sputum biomarker profile (soluble IL-6 receptor (sIL-6R), IL-6, IL-1β, IL-8, macrophage inflammatory protein-1β) to stratify sputum data from patients with COPD (n=74; Biomarkers to Target Antibiotic and Systemic Corticosteroid Therapy in COPD Exacerbation (BEAT-COPD)) by hierarchical clustering. The IL-6TS signature was related to clinical characteristics and sputum microbiome profiles. The induction of neutrophil extracellular trap formation (NETosis) and IL-6TS by Haemophilus influenzae were studied in human neutrophils.Results:Hierarchical clustering revealed an IL-6TS-high subset (n=24) of COPD patients, who shared phenotypic traits with an IL-6TS-high subset previously identified in asthma. The subset was characterised by increased sputum cell counts (p=0.0001), persistent sputum neutrophilia (p=0.0004), reduced quality of life (Chronic Respiratory Questionnaire total score; p=0.008), and increased levels of pro-inflammatory mediators and matrix metalloproteinases in sputum. IL-6TS-high COPD patients showed an increase in Proteobacteria, with Haemophilus as the dominating genus. NETosis induced by H. influenzae was identified as a potential mechanism for increased sIL-6R levels. This was supported by a significant positive correlation between sIL-6R and NETosis markers in bronchoalveolar lavage fluid from COPD patients.Conclusion:IL-6TS pathway activation due to chronic colonisation with Haemophilus may be an important disease driver in a subset of COPD patients.
      Keywords: Lung biology and experimental studies, Respiratory infections and tuberculosis
      PubDate: 2021-10-14T02:10:50-07:00
      DOI: 10.1183/13993003.03312-2020
      Issue No: Vol. 58, No. 4 (2021)
       
  • Blood eosinophil counts and the development of obstructive lung disease:
           the Kangbuk Samsung Health Study

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      Authors: Park, H. Y; Chang, Y, Kang, D, Hong, Y. S, Zhao, D, Ahn, J, Shin, S. H, Singh, D, Guallar, E, Cho, J, Ryu, S.
      Pages: 2003823 - 2003823
      Abstract: AimThe impact of blood eosinophil counts on the development of chronic obstructive lung disease (COPD) is unknown. We investigated whether a higher blood eosinophil count was associated with the risk of developing obstructive lung disease (OLD) in a large cohort of men and women free from lung disease at baseline.MethodsThis was a cohort study of 359 456 Korean adults without a history of asthma and without OLD at baseline who participated in health screening examinations including spirometry. OLD was defined as pre-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC)
      Keywords: COPD and smoking
      PubDate: 2021-10-07T00:19:04-07:00
      DOI: 10.1183/13993003.03823-2020
      Issue No: Vol. 58, No. 4 (2021)
       
  • Healthy versus inflamed lung environments differentially affect
           mesenchymal stromal cells

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      Authors: Rolandsson Enes, S; Hampton, T. H, Barua, J, McKenna, D. H, dos Santos, C. C, Amiel, E, Ashare, A, Liu, K. D, Krasnodembskaya, A. D, English, K, Stanton, B. A, Rocco, P. R. M, Matthay, M. A, Weiss, D. J.
      Pages: 2004149 - 2004149
      Abstract: BackgroundDespite increased interest in mesenchymal stromal cell (MSC)-based cell therapies for acute respiratory distress syndrome (ARDS), clinical investigations have not yet been successful and our understanding of the potential in vivo mechanisms of MSC actions in ARDS remains limited. ARDS is driven by an acute severe innate immune dysregulation, often characterised by inflammation, coagulation and cell injury. How this inflammatory microenvironment influences MSC functions remains to be determined.AimThe aim of this study was to comparatively assess how the inflammatory environment present in ARDS lungs versus the lung environment present in healthy volunteers alters MSC behaviour.MethodsClinical-grade human bone marrow-derived MSCs (hMSCs) were exposed to bronchoalveolar lavage fluid (BALF) samples obtained from ARDS patients or from healthy volunteers. Following exposure, hMSCs and their conditioned media were evaluated for a broad panel of relevant properties, including viability, levels of expression of inflammatory cytokines, gene expression, cell surface human leukocyte antigen expression, and activation of coagulation and complement pathways.ResultsPro-inflammatory, pro-coagulant and major histocompatibility complex (self-recognition) related gene expression was markedly upregulated in hMSCs exposed ex vivo to BALF obtained from healthy volunteers. These changes were less apparent and often opposite in hMSCs exposed to ARDS BALF samples.ConclusionThese data provide new insights into how hMSCs behave in healthy versus inflamed lung environments, and strongly suggest that the inflamed environment in ARDS induces hMSC responses that are potentially beneficial for cell survival and actions. This further highlights the need to understand how different disease environments affect hMSC functions.
      Keywords: Lung biology and experimental studies
      PubDate: 2021-10-14T02:10:50-07:00
      DOI: 10.1183/13993003.04149-2020
      Issue No: Vol. 58, No. 4 (2021)
       
  • VE-cadherin cleavage in sleep apnoea: new insights into intermittent
           hypoxia-related endothelial permeability

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      Authors: Harki, O; Tamisier, R, Pepin, J.-L, Bailly, S, Mahmani, A, Gonthier, B, Salomon, A, Vilgrain, I, Faury, G, Briancon-Marjollet, A.
      Pages: 2004518 - 2004518
      Abstract: BackgroundObstructive sleep apnoea (OSA) causes intermittent hypoxia that in turn induces endothelial dysfunction and atherosclerosis progression. We hypothesised that VE-cadherin cleavage, detected by its released extracellular fragment solubilised in the blood (sVE), may be an early indicator of emergent abnormal endothelial permeability. Our aim was to assess VE-cadherin cleavage in OSA patients and in in vivo and in vitro intermittent hypoxia models to decipher the cellular mechanisms and consequences.MethodsSera from seven healthy volunteers exposed to 14 nights of intermittent hypoxia, 43 OSA patients and 31 healthy control subjects were analysed for their sVE content. Human aortic endothelial cells (HAECs) were exposed to 6 h of intermittent hypoxia in vitro, with or without an antioxidant or inhibitors of hypoxia-inducible factor (HIF)-1, tyrosine kinases or vascular endothelial growth factor (VEGF) pathways. VE-cadherin cleavage and phosphorylation were evaluated, and endothelial permeability was assessed by measuring transendothelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC)–dextran flux.ResultssVE was significantly elevated in sera from healthy volunteers submitted to intermittent hypoxia and OSA patients before treatment, but conversely decreased in OSA patients after 6 months of continuous positive airway pressure treatment. OSA was the main factor accounting for sVE variations in a multivariate analysis. In in vitro experiments, cleavage and expression of VE-cadherin increased upon HAEC exposure to intermittent hypoxia. TEER decreased and FITC–dextran flux increased. These effects were reversed by all of the pharmacological inhibitors tested.ConclusionsWe suggest that in OSA, intermittent hypoxia increases endothelial permeability in OSA by inducing VE-cadherin cleavage through reactive oxygen species production, and activation of HIF-1, VEGF and tyrosine kinase pathways.
      Keywords: Sleep medicine
      PubDate: 2021-10-07T00:19:04-07:00
      DOI: 10.1183/13993003.04518-2020
      Issue No: Vol. 58, No. 4 (2021)
       
  • Measurement of hypoxia in the lung in idiopathic pulmonary fibrosis: an
           F-MISO PET/CT study

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      Authors: Porter, J. C; Win, T, Erlandsson, K, Fraioli, F, Rashidnasab, A, Holman, B, Ganeshan, B, Screaton, N. J, Maher, T. M, Endozo, R, Hoath, J, Shortman, R. I, Emond, E, Thielemans, K, Hutton, B. F, Lukey, P. T, Aigbirhio, F, Khan, S, Rodriguez-Justo, M, Groves, A. M.
      Pages: 2004584 - 2004584
      Abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease, with an incidence of ~1 per 10 000 per year, and a poor prognosis with limited treatments [1]. The role of hypoxia in disease progression is unclear.
      PubDate: 2021-10-07T00:19:04-07:00
      DOI: 10.1183/13993003.04584-2020
      Issue No: Vol. 58, No. 4 (2021)
       
  • Impact of baseline patient characteristics on dupilumab efficacy in type 2
           asthma

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      Authors: Busse, W. W; Paggiaro, P, Munoz, X, Casale, T. B, Castro, M, Canonica, G. W, Douglass, J. A, Tohda, Y, Daizadeh, N, Ortiz, B, Pandit-Abid, N.
      Pages: 2004605 - 2004605
      Abstract: Severe asthma affects an estimated 5–10% of the total asthma patient population [1]. Various demographic factors, such as sex, age, obesity and age of onset, have been associated with asthma disease severity [2, 3], and the efficacy of asthma treatments has previously been found to vary depending on patient demographics [4, 5].
      PubDate: 2021-10-07T00:19:04-07:00
      DOI: 10.1183/13993003.04605-2020
      Issue No: Vol. 58, No. 4 (2021)
       
  • Perspectives on palliative oxygen for breathlessness: systematic review
           and meta-synthesis

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      Authors: Kochovska, S; Ferreira, D. H, Garcia, M. V, Phillips, J. L, Currow, D. C.
      Pages: 2004613 - 2004613
      Abstract: Oxygen therapy is frequently prescribed for the palliation of breathlessness, despite lack of evidence for its effectiveness in people who are not hypoxaemic. This study aimed to compare and contrast patients’, caregivers’ and clinicians’ experiences of palliative oxygen use for the relief of chronic breathlessness in people with advanced life-limiting illnesses, and how this shapes prescribing.A systematic review and meta-synthesis of qualitative data was conducted. MEDLINE, CINAHL and PsycINFO were searched for peer-reviewed studies in English (2000–April 2019) reporting perspectives on palliative oxygen use for reducing breathlessness in people with advanced illnesses in any healthcare setting. After data extraction, thematic synthesis used line-by-line coding of raw data (quotes) to generate descriptive and analytical themes.Of 457 articles identified, 22 met the inclusion criteria by reporting perspectives of patients (n=337), caregivers (n=91) or clinicians (n=616). Themes common to these perspectives were: 1) benefits and burdens of palliative oxygen use, 2) knowledge and perceptions of palliative oxygen use beyond the guidelines, and 3) longitudinal trajectories of palliative oxygen use.There are differing perceptions regarding the benefits and burdens of using palliative oxygen. Clinicians should be aware that oxygen use may generate differing goals of therapy for patients and caregivers. These perceptions should be taken into consideration when prescribing oxygen for the symptomatic relief of chronic breathlessness in patients who do not quality for long-term oxygen therapy.
      Keywords: Respiratory clinical practice
      PubDate: 2021-10-07T00:19:04-07:00
      DOI: 10.1183/13993003.04613-2020
      Issue No: Vol. 58, No. 4 (2021)
       
  • A large-scale genome-wide association analysis of lung function in the
           Chinese population identifies novel loci and highlights shared genetic
           aetiology with obesity

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      Authors: Zhu, Z; Li, J, Si, J, Ma, B, Shi, H, Lv, J, Cao, W, Guo, Y, Millwood, I. Y, Walters, R. G, Lin, K, Yang, L, Chen, Y, Du, H, Yu, B, Hasegawa, K, Camargo, C. A, Moffatt, M. F, Cookson, W. O. C, Chen, J, Chen, Z, Li, L, Yu, C, Liang, L.
      Pages: 2100199 - 2100199
      Abstract: BackgroundLung function is a heritable complex phenotype with obesity being one of its important risk factors. However, knowledge of their shared genetic basis is limited. Most genome-wide association studies (GWASs) for lung function have been based on European populations, limiting the generalisability across populations. Large-scale lung function GWASs in other populations are lacking.MethodsWe included 100 285 subjects from the China Kadoorie Biobank (CKB). To identify novel loci for lung function, single-trait GWAS analyses were performed on forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC in the CKB. We then performed genome-wide cross-trait analysis between lung function and obesity traits (body mass index (BMI), BMI-adjusted waist-to-hip ratio and BMI-adjusted waist circumference) to investigate the shared genetic effects in the CKB. Finally, polygenic risk scores (PRSs) of lung function were developed in the CKB and their interaction with BMI's association on lung function were examined. We also conducted cross-trait analysis in parallel with the CKB using up to 457 756 subjects from the UK Biobank (UKB) for replication and investigation of ancestry-specific effects.ResultsWe identified nine genome-wide significant novel loci for FEV1, six for FVC and three for FEV1/FVC in the CKB. FEV1 and FVC showed significant negative genetic correlation with obesity traits in both the CKB and UKB. Genetic loci shared between lung function and obesity traits highlighted important biological pathways, including cell proliferation, embryo, skeletal and tissue development, and regulation of gene expression. Mendelian randomisation analysis suggested significant negative causal effects of BMI on FEV1 and on FVC in both the CKB and UKB. Lung function PRSs significantly modified the effect of change in BMI on change in lung function during an average follow-up of 8 years.ConclusionThis large-scale GWAS of lung function identified novel loci and shared genetic aetiology between lung function and obesity. Change in BMI might affect change in lung function differently according to a subject's polygenic background. These findings may open new avenues for the development of molecular-targeted therapies for obesity and lung function improvement.
      Keywords: Lung structure and function, Genetics
      PubDate: 2021-10-14T02:10:50-07:00
      DOI: 10.1183/13993003.00199-2021
      Issue No: Vol. 58, No. 4 (2021)
       
  • Impact of obstructive sleep apnoea and intermittent hypoxia on blood
           rheology: a translational study

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      Authors: Waltz, X; Beaudin, A. E, Belaidi, E, Raneri, J, Pepin, J.-L, Pialoux, V, Hanly, P. J, Verges, S, Poulin, M. J.
      Pages: 2100352 - 2100352
      Abstract: BackgroundHaemorheological alterations are reported in obstructive sleep apnoea (OSA) and reversed with continuous positive airway pressure (CPAP), observations potentially explained by intermittent hypoxia (IH)-induced oxidative stress. Our objective was to investigate whether IH causes haemorheological alterations via oxidative stress.MethodsWistar rats were exposed to normoxia (n=7) or IH (n=8) for 14 days. 23 moderate-to-severe OSA patients were assessed at three time-points: baseline, after randomisation to either 2 weeks of nocturnal oxygen (n=13) or no treatment (n=10) and after 1 month of CPAP treatment (n=17). Furthermore, an OSA-free control group (n=13) was assessed at baseline and after time-matched follow-up. We measured haemorheological parameters (haematocrit, blood viscosity, plasma viscosity (rats only), erythrocyte aggregation and deformability (humans only)) and redox balance (superoxide dismutase (SOD), glutathione peroxidase, protein oxidation (advanced oxidation protein products (AOPPs)) and lipid peroxidation (malondialdehyde)). We also tested the haemorheological sensitivity of erythrocytes to reactive oxygen species (ROS) in our human participants using the oxidant t-butyl hydroperoxide (TBHP).ResultsIn rats, IH increased blood viscosity by increasing haematocrit without altering the haemorheological properties of erythrocytes. IH also reduced SOD activity and increased AOPPs. In humans, baseline haemorheological properties were similar between patients and control participants, and properties were unaltered following oxygen and CPAP, except erythrocyte deformability was reduced following oxygen therapy. Redox balance was comparable between patients and control participants. At baseline, TBHP induced a greater reduction of erythrocyte deformability in patients while CPAP reduced TBHP-induced increase in aggregation strength.ConclusionsIH and OSA per se do not cause haemorheological alterations despite the presence of oxidative stress or higher sensitivity to ROS, respectively.
      Keywords: Sleep medicine
      PubDate: 2021-10-07T00:19:04-07:00
      DOI: 10.1183/13993003.00352-2021
      Issue No: Vol. 58, No. 4 (2021)
       
  • A phase 2 multiple ascending dose study of the inhaled pan-JAK inhibitor
           nezulcitinib (TD-0903) in severe COVID-19

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      Authors: Singh, D; Bogus, M, Moskalenko, V, Lord, R, Moran, E. J, Crater, G. D, Bourdet, D. L, Pfeifer, N. D, Woo, J, Kaufman, E, Lombardi, D. A, Weng, E. Y, Nguyen, T, Woodcock, A, Haumann, B, Saggar, R.
      Pages: 2100673 - 2100673
      Abstract: Severe coronavirus disease 2019 (COVID-19) is characterised by pneumonia with excessive systemic inflammation, referred to as a "cytokine storm" [1–3]. Dexamethasone treatment decreases mortality in patients with COVID-19 receiving respiratory support and is standard of care for severe COVID-19 [4, 5]. However, pulmonary inflammation, which drives COVID-19 morbidity and mortality [3], can persist despite corticosteroid use [6, 7]. Janus kinase (JAK) inhibition blocks signalling by many cytokines in diverse cell types, offering broad immunomodulation [8]. The oral JAK-1/2 inhibitor baricitinib combined with the antiviral remdesivir shows clinical efficacy in patients with severe COVID-19 [9]. Direct delivery of JAK inhibition to the lung via inhalation could overcome corticosteroid-resistant pulmonary inflammation [10], offering the potential for improved responses while minimising risk of excessive systemic immunosuppression. The novel inhaled pan-JAK inhibitor nezulcitinib (TD-0903) was designed to target all JAK isoforms (JAK1, JAK2, JAK3, TYK2; –log inhibition constant ≥9.2) and optimise delivery to the lungs while limiting systemic exposure (R. Sana and co-workers; unpublished results: abstract submitted to ERS International Congress, 2021). We report results from the completed part 1 of a 2-part phase 2 trial (NCT04402866) in hospitalised patients with severe COVID-19.
      PubDate: 2021-10-14T02:10:50-07:00
      DOI: 10.1183/13993003.00673-2021
      Issue No: Vol. 58, No. 4 (2021)
       
  • Unravelling the unmet needs of patients with severe dyspnoea: a case for
           palliative oxygen

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      Authors: Yohannes A. M.
      Pages: 2100775 - 2100775
      Abstract: The number of people over the age of 65 years living with chronic diseases is exponentially rising worldwide. In 2008, the World Health Organization estimated physicians diagnosed approximately 210 million people worldwide with COPD and millions of others with another respiratory disease (e.g. asthma or interstitial lung disease) [1]. Many among these millions of patients with advanced, chronic non-malignant respiratory diseases often experience disabling (intractable) dyspnoea, cough and pain. Dyspnoea (breathlessness) is an "air hunger" comprising a multifaceted, subjective symptom with significant impact on patients’ quality of life, ensuing disability, increasing social isolation and loneliness [1]. Untreated dyspnoea on exertion creates unprecedented fear and stress of "fighting for breath" to a patient. Furthermore incessant dyspnoea frequently causes patients to impose burdens of worry to their caregivers, and patients experience emergency healthcare utilisation, hospital admissions, and premature mortality [2, 3]. Suffering with dyspnoea may escalate to uncontrollable anxiety [4] and all these adverse consequences create a sea of misery for patients with advanced, chronic non-malignant respiratory diseases.
      PubDate: 2021-10-07T00:19:04-07:00
      DOI: 10.1183/13993003.00775-2021
      Issue No: Vol. 58, No. 4 (2021)
       
  • Digital-Rapid On-site Examination in Endobronchial Ultrasound-Guided
           Transbronchial Needle Aspiration (DEBUT): a proof of concept study for the
           application of artificial intelligence in the bronchoscopy suite

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      Authors: Asfahan, S; Elhence, P, Dutt, N, Niwas Jalandra, R, Chauhan, N. K.
      Pages: 2100915 - 2100915
      Abstract: Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) has become the standard of care for sampling mediastinal and hilar lesions and is finding increased acceptance for diagnostic as well as staging purposes [1]. EBUS-TBNA is an expensive procedure due to the high cost of equipment [2]. A repeat procedure in case of an inconclusive outcome adds to the burgeoning expenditure. To circumvent this, rapid on-site examination (ROSE) has been adopted to reduce the number of needle punctures and decrease the requirement for additional procedures [3]. However, ROSE requires presence of a pathologist or cyto-technicians in the bronchoscopy suite.
      PubDate: 2021-10-14T02:10:50-07:00
      DOI: 10.1183/13993003.00915-2021
      Issue No: Vol. 58, No. 4 (2021)
       
  • Steroid use in elderly critically ill COVID-19 patients

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      Authors: Jung; C., Wernly, B., Fjolner, J., Bruno, R. R., Dudzinski, D., Artigas, A., Bollen Pinto, B., Schefold, J. C., Wolff, G., Kelm, M., Beil, M., Sigal, S., van Heerden, P. V., Szczeklik, W., Czuczwar, M., Elhadi, M., Joannidis, M., Oeyen, S., Zafeiridis, T., Marsh, B., Andersen, F. H., Moreno, R., Cecconi, M., Leaver, S., Boumendil, A., De Lange, D. W., Guidet, B., Flaatten, H., the COVIP study group
      Pages: 2100979 - 2100979
      Abstract: More than a year after the onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, treating patients with coronavirus disease 2019 (COVID-19) remains a challenge. In contrast to the rapid development of effective vaccines against SARS-CoV-2, the development of specific and effective therapeutics against COVID-19 remains largely unresolved.
      PubDate: 2021-10-07T00:19:04-07:00
      DOI: 10.1183/13993003.00979-2021
      Issue No: Vol. 58, No. 4 (2021)
       
  • Understanding the impact of the lung microenvironment to enhance the
           therapeutic potential of mesenchymal stromal cells for acute respiratory
           distress syndrome

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      Authors: Masterson, C; Gonzalez, H, Laffey, J. G.
      Pages: 2100986 - 2100986
      Abstract: Acute respiratory distress syndrome (ARDS) is a clinical syndrome of severe acute hypoxaemic respiratory failure with clinical features including reduced lung compliance and permeability-induced pulmonary oedema, which can frequently progress to multiple organ failure [1, 2]. ARDS occurs in 10% of all critically patients in ICU and nearly one quarter of all mechanically ventilated patients [3]. Common underlying causes of ARDS include bacterial or viral pneumonia, sepsis, pulmonary aspiration and trauma [4]. The burden of ARDS is substantial, with hospital mortality rates varying, depending on ARDS severity, from 30–45% of affected patients [5]. Of further concern, ARDS survivors are often left with debilitating long-term sequelae which reduces their quality of life.
      PubDate: 2021-10-14T02:10:50-07:00
      DOI: 10.1183/13993003.00986-2021
      Issue No: Vol. 58, No. 4 (2021)
       
  • Standard pleural interventions are not high-risk aerosol generating
           procedures

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      Authors: Arnold, D. T; Gregson, F. K. A, Sheikh, S, Hamilton, F. W, Welch, H, Dipper, A, Nava, G. W, AERATOR group, Dodd, J. W, Clive, A. O, Bzdek, B. R, Reid, J. P, Maskell, N. A.
      Pages: 2101064 - 2101064
      Abstract: The nosocomial spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has focused attention on the risk of aerosol generating procedures (AGPs) in healthcare [1]. SARS-CoV-2 has been isolated from pleural fluid, which has the potential to infect staff or patients if viraemic fluid is aerosolised during procedures [2, 3]. However, evidence for aerosol generation from pleural procedures is very limited. Current guidelines for appropriate use of personal protective equipment (PPE) while performing pleural procedures are based on expert opinion and application of the precautionary principle [4]. We set out to quantify if pleural procedures generated appreciable aerosol (aerosolised liquid particles that have the potential to carry virus) compared to aerosol sampled during normal respiratory activities of breathing and coughing.
      PubDate: 2021-10-14T02:10:50-07:00
      DOI: 10.1183/13993003.01064-2021
      Issue No: Vol. 58, No. 4 (2021)
       
  • A new piece in the puzzle: the eosinophil and the development of COPD

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      Authors: Petousi, N; Wooden, A, Russell, R. E. K.
      Pages: 2101105 - 2101105
      Abstract: COPD is associated with high morbidity and mortality worldwide, with overall high personal, societal and economic impact [1].
      PubDate: 2021-10-07T00:19:04-07:00
      DOI: 10.1183/13993003.01105-2021
      Issue No: Vol. 58, No. 4 (2021)
       
  • Human experimental models: seeking to enhance multiscale research in sleep
           apnoea

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      Authors: Farre, R; Gozal, D, Almendros, I.
      Pages: 2101169 - 2101169
      Abstract: Obstructive sleep apnoea (OSA) is a prevalent respiratory disease associated with important comorbidities, such as obesity, metabolic syndrome, cancer, and cognitive and cardiovascular alterations [1, 2]. Unfortunately, determining cause–effect relationships that definitively link OSA to these comorbidities and establishing whether OSA treatment may reduce the comorbidity risk have emerged as conundrums that have proven very difficult to disentangle in spite of major research efforts [3–5]. These difficulties have emerged as particularly relevant when focusing on the potential relationship between OSA and cardiocirculatory diseases [6, 7]. Indeed, a simple search (12 April, 2021) in PubMed for the past 12 months using the tags "sleep apnoea AND cardiovascular" (563 publications) and "sleep apnoea" (3300 publications) indicates that 17% of all the research in the field of OSA is focused on its putative relationship with cardiovascular dysfunction.
      PubDate: 2021-10-07T00:19:04-07:00
      DOI: 10.1183/13993003.01169-2021
      Issue No: Vol. 58, No. 4 (2021)
       
  • Improving ethnic diversity in respiratory genomics research

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      Authors: Tobin, M. D; Izquierdo, A. G.
      Pages: 2101615 - 2101615
      Abstract: In this issue of the European Respiratory Journal, Zhu et al. [1] report findings from a genomic study of lung function in the China Kadoorie Biobank.
      PubDate: 2021-10-14T02:10:50-07:00
      DOI: 10.1183/13993003.01615-2021
      Issue No: Vol. 58, No. 4 (2021)
       
  • The search for realistic evidence on the outcomes of obstructive sleep
           apnoea

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      Authors: Schiza, S; Levy, P, Martinez-Garcia, M. A, Pepin, J.-L, Simonds, A, Randerath, W.
      Pages: 2101963 - 2101963
      Abstract: The burden and societal impact of obstructive sleep apnoea (OSA) needs to be more widely understood to guide health policies and improve value-based care. OSA affects one billion people worldwide, representing a major and still under-recognised health problem. Its prevalence is expected to continue to increase, owing to the obesity epidemic and the increase in life expectancy [1]. OSA has been associated with numerous long-term consequences, including cardiovascular and metabolic disorders, and neuropsychiatric diseases [2–4]. Also, OSA impairs quality of life, cognitive function, and productivity in the workplace, and causes road traffic accidents, resulting in injuries and fatalities [5].
      PubDate: 2021-10-07T00:19:04-07:00
      DOI: 10.1183/13993003.01963-2021
      Issue No: Vol. 58, No. 4 (2021)
       
  • The Cochrane review of electronic cigarettes for smoking cessation:
           remaining focused on the evidence

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      Authors: Notley, C; Butler, A. R, Lindson, N, Bullen, C, Theodoulou, A, Begh, R, McRobbie, H, Hajek, P, Rigotti, N, Hartman-Boyce, J.
      Pages: 2102117 - 2102117
      Abstract: We are grateful for the opportunity to reply to the commentary on our Cochrane review of electronic cigarettes (EC) for smoking cessation [1] posed by Pisinger and Vestbo [2] with subsequent commentary by McAlinden et al. [3].
      PubDate: 2021-10-07T00:19:04-07:00
      DOI: 10.1183/13993003.02117-2021
      Issue No: Vol. 58, No. 4 (2021)
       
  • IL-6 trans-signalling: how Haemophilus surfs the NET to amplify
           inflammation in COPD

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      Authors: Keir, H. R; Chalmers, J. D.
      Pages: 2102143 - 2102143
      Abstract: COPD is characterised by neutrophilic inflammation in the majority of patients [1–3]. Neutrophils represent a key second line of defence against infection and are rapidly recruited to the airway if pathogens are able to evade first line defences, which include mucociliary clearance and resident immune cells such as macrophages [3]. Neutrophils typically clear infection through ingestion of invading microbes (phagocytosis) and through the internal generation of reactive oxygen species, serine proteases such as neutrophil elastase, cathepsin G and proteinase-3, and antimicrobial proteins [4]. These processes aim to clear infection without damage to host tissues, but in COPD there is a failure of these normal antimicrobial processes. Mucociliary clearance is impaired, macrophage phagocytosis is less effective, and pro-inflammatory cytokines signal recruitment and survival of neutrophils which fail to effectively kill bacteria, leading to chronic neutrophilic inflammation and chronic infection [3–6]. Recent data suggests that a distinct form of neutrophil behaviour in which neutrophils release a DNA scaffold decorated with granule proteins (such as proteases) and termed neutrophil extracellular trap (NET) formation is associated with worse symptoms, frequent exacerbations and lung infections in a subset of patients [7–9]. The precise drivers and implications of NETosis in COPD are, however, unclear.
      PubDate: 2021-10-14T02:10:50-07:00
      DOI: 10.1183/13993003.02143-2021
      Issue No: Vol. 58, No. 4 (2021)
       
 
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