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Florence Coste,1,2,* Ilyes Benlala,1–3,* Gaël Dournes,1–3 Pierre-Olivier Girodet,1–3 François Laurent,1–3,* Patrick Berger,1–3,* 1University Bordeaux, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, Bordeaux, F-33000 France; 2Inserm, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, CIC1401, Bordeaux, F-33000 France; 3CHU de Bordeaux, Service d’Imagerie Thoracique et Cardiovasculaire, Service des Maladies Respiratoires, CIC1401, Service d’Explorations Fonctionnelles Respiratoires, Pessac, F-33600 France*These authors contributed equally to this workCorrespondence: Florence CosteCentre de Recherche Cardio-thoracique de Bordeaux, INSERM U1045, Université Bordeaux, 146 rue Léo Saignat, Bordeaux Cedex 33076, FranceTel +33 55 757 4602Fax +33 55 757 1695Email florence-coste@hotmail.frAbstract: Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD) and is associated with increased morbidity and mortality. Reference standard method to diagnose PH is right heart catheterization. Several non-invasive imaging techniques have been employed in the detection of PH. Among them, computed tomography (CT) is the most commonly used for phenotyping and detecting complications of COPD. Several CT findings have also been described in patients with severe PH. Nevertheless, CT analysis is currently based on visual findings which can lead to reproducibility failure. Therefore, there is a need for quantification in order to assess objective criteria. In this review, progresses in automated analyses of CT parameters and their values in predicting PH and COPD outcomes are presented.Keywords: computed tomography, pulmonary hypertension, COPD, prediction

Florence Coste,1,2,* Ilyes Benlala,1,2,* Gaël Dournes,1–3 Claire Dromer,3 Elodie Blanchard,3 Pierre-Olivier Girodet,1–3 Michel Montaudon,1–3 Fabien Baldacci,4 François Picard,3 Roger Marthan,1–3 François Laurent,1–3,* Patrick Berger1–3,* 1Université de Bordeaux, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, F-33000 Bordeaux, France; 2Centre de Recherche Cardio-Thoracique de Bordeaux, INSERM, U1045, Université de Bordeaux, CIC1401, F-33000 Bordeaux, France; 3CHU de Bordeaux, Service d’Imagerie Thoracique et Cardiovasculaire, Service des Maladies Respiratoires, Service de Cardiologie, CIC1401, Service d’Explorations Fonctionnelles Respiratoires, F-33600 Pessac, France; 4Université de Bordeaux, LaBRI, F-33405 Talence Cedex, France *These authors contributed equally to this work Background: Little is known about in vivo alterations at bronchial and vascular levels in severe pulmonary hypertension (PH) of different etiologies. We aimed to compare quantitative computed tomography (CT) data from the following three groups of severe precapillary PH patients: COPD, idiopathic pulmonary arterial hypertension (iPAH), and chronic thromboembolic PH (CTEPH). Patients and methods: This study was approved by the institutional review board. Severe PH patients (mean pulmonary arterial pressure [mPAP] ≥35 mmHg) with COPD, iPAH, or CTEPH (n=24, 16, or 16, respectively) were included retrospectively between January 2008 and January 2017. Univariate analysis of mPAP was performed in each severe PH group. Bronchial wall thickness (WT) and percentage of cross sectional area of pulmonary vessels less than 5 mm2 normalized by lung area (%CSA

Objective: Adrenal insufficiency (AI) is a potentially life-threatening condition. It is known that high doses of inhaled corticosteroids (ICS) can induce systemic adverse effects. Currently, there are no data on the prevalence of AI associated with the use of ICS. This study aimed to investigate the prevalence and clinical presentation of AI (associated or not associated with exogenous Cushing's syndrome) in patients who were prescribed ICS by French physicians during the period 2000-5.Methods: All metropolitan French paediatricians, endocrinologists, pulmonologists and intensive care physicians (n = 11 783) were mailed questionnaires requesting information regarding cases of AI associated or not associated with exogenous Cushing's syndrome between 2000 and 2005. Data collected included patient demographics, oral corticosteroid or ICS used during the year preceding the diagnosis of AI, underlying condition(s), concomitant treatment(s), presenting clinical signs and symptoms, results of laboratory investigations and outcome. The French pharmacovigilance database was screened for spontaneous reports to determine the frequency of AI associated with the use of ICS, using the capture-recapture method.Results: Forty-six cases of AI were identified. Twenty-three cases presented with clinical symptoms of AI alone and 23 with exogenous Cushing's syndrome. ICS prescribed were fluticasone propionate (n = 24), budesonide (n = 12) and beclometasone dipropionate (n = 5). In 82% (n = 32) of cases for which data were available, ICS were prescribed at high doses. A potential drug interaction was found in 12 cases. Thirteen cases of AI were identified in the French pharmacovigilance database, one of which was common with the questionnaire survey. The capture-recapture method provided an estimation of 598 (95% CI 551, 648) cases of AI associated with the use of ICS for the 2000-5 period in France.Conclusion: The results of this study confirm the occurrence of adrenal insufficiency in patients treated with ICS. Although the prevalence of ICS-induced AI reported in this study is low, the likelihood of under-diagnosis underlines the need to consider this risk in patients when prescribing these drugs. [ABSTRACT FROM AUTHOR]

Bronchi of chronic obstructive pulmonary disease (COPD) are the site of extensive cell infiltration, allowing persistent contact between resident cells and immune cells. Tissue fibrocytes interaction with CD8 + T cells and its consequences were investigated using a combination of in situ , in vitro experiments and mathematical modeling. We show that fibrocytes and CD8 + T cells are found in the vicinity of distal airways and that potential interactions are more frequent in tissues from COPD patients compared to those of control subjects. Increased proximity and clusterization between CD8 + T cells and fibrocytes are associated with altered lung function. Tissular CD8 + T cells from COPD patients promote fibrocyte chemotaxis via the CXCL8-CXCR1/2 axis. Live imaging shows that CD8 + T cells establish short-term interactions with fibrocytes, that trigger CD8 + T cell proliferation in a CD54- and CD86-dependent manner, pro-inflammatory cytokines production, CD8 + T cell cytotoxic activity against bronchial epithelial cells and fibrocyte immunomodulatory properties. We defined a computational model describing these intercellular interactions and calibrated the parameters based on our experimental measurements. We show the model's ability to reproduce histological ex vivo characteristics, and observe an important contribution of fibrocyte-mediated CD8 + T cell proliferation in COPD development. Using the model to test therapeutic scenarios, we predict a recovery time of several years, and the failure of targeting chemotaxis or interacting processes. Altogether, our study reveals that local interactions between fibrocytes and CD8 + T cells could jeopardize the balance between protective immunity and chronic inflammation in the bronchi of COPD patients., Competing Interests: EE, EM, JS, PH, PE, TT, JD, AL, AS, HB, MT, RH, RM, FL, PV, CC No competing interests declared, MZ MZ reports personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, GlaxoSmithKline and non-financial support Lilly outside the submitted work, PG POG has a patent (EP 3050574: Use of plerixafor for treating and/or preventing acute exacerbations of chronic obstructive pulmonary disease) granted. POG reports grants, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Chiesi, personal fees and non-financial support from GlaxoSmithKline, personal fees and non-financial support from Novartis, personal fees and non-financial support from Sanofi, outside the submitted work, PB PB has a patent (EP N3050574: Use of plerixafor for treating and/or preventing acute exacerbations of chronic obstructive pulmonary disease) granted. PB reports grants from AstraZeneca, Glaxo-Smith-Kline, Novartis, Chiesi, which support COBRA during the conduct of the study; grants and personal fees from AstraZeneca, BoehringerIngelheim, Novartis, personal fees and non-financial support from Chiesi, Sanofi, Menarini, outside the submitted work, ID ID has a patent (EP 3050574: Use of plerixafor for treating and/or preventing acute exacerbations of chronic obstructive pulmonary disease) granted, (© 2023, Eyraud et al.)

Fibrocytes are monocyte-derived cells able to differentiate into myofibroblasts-like cells. We have previously shown that they are increased in the bronchi of Chronic Obstructive Pulmonary Disease (COPD) patients and associated to worse lung function. COPD is characterized by irreversible airflow obstruction, partly due to an increased cholinergic environment. Our goal was to investigate muscarinic signalling in COPD fibrocytes. Fibrocytes were isolated from 16 patients with COPD's blood and presence of muscarinic M3 receptor was assessed at the transcriptional and protein levels. Calcium signalling and collagen gels contraction experiments were performed in presence of carbachol (cholinergic agonist) ± tiotropium bromide (antimuscarinic). Expression of M3 receptor was confirmed by Western blot and flow cytometry in differentiated fibrocytes. Immunocytochemistry showed the presence of cytoplasmic and membrane-associated pools of M3. Stimulation with carbachol elicited an intracellular calcium response in 35.7% of fibrocytes. This response was significantly blunted by the presence of tiotropium bromide: 14.6% of responding cells ( p < 0.0001). Carbachol induced a significant contraction of fibrocytes embedded in collagen gels (13.6 ± 0.3% versus 2.5 ± 4.1%; p < 0.0001), which was prevented by prior tiotropium bromide addition (4.1 ± 2.7% of gel contraction; p < 0.0001). Finally, M3-expressing fibrocytes were also identified in situ in the peri-bronchial area of COPD patients' lungs, and there was a tendency to an increased density compared to healthy patient's lungs. In conclusion, around 1/3 of COPD patients' fibrocytes express a functional muscarinic M3 receptor. Cholinergic-induced fibrocyte contraction might participate in airway diameter reduction and subsequent increase of airflow resistance in patients with COPD. The inhibition of these processes could participate to the beneficial effects of muscarinic antagonists for COPD treatment., Competing Interests: PH, EE, EM, SP, GC, JFQ, PE, TT and RM report no relevant conflict of interest; ID, P-OG and PB report a patent (EP N3050574: Use of plerixafor for treating and/or preventing acute exacerbations of chronic obstructive pulmonary disease (Berger et al., 2019)) (granted); POG reports grants, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Chiesi, personal fees and non-financial support from GlaxoSmithKline, personal fees and non-financial support from Novartis, personal fees and non-financial support from Sanofi, outside the submitted work; MZ reports grants from AstraZeneca; grants “Fondation Bordeaux Université,” with funding from “Assistance Ventilatoire à Domicile” (AVAD) and “Fédération Girondine de Lutte contre les Maladies Respiratoires” (FGLMR) and personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, GlaxoSmithKline and non-financial support Lilly outside the submitted work; PB reports grants from AstraZeneca, Glaxo-Smith-Kline, Novartis, Chiesi, which support COBRA during the conduct of the study; grants and personal fees from AstraZeneca, BoehringerIngelheim, Novartis, personal fees and non-financial support from Chiesi, Sanofi, Menarini, outside the submitted work; ID reports grant from the “Fondation Bordeaux Université,” with funding from “Assistance Ventilatoire à Domicile” (AVAD) and “Fédération Girondine de Lutte contre les Maladies Respiratoires” (FGLMR) during the conduct of the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Henrot, Eyraud, Maurat, Point, Cardouat, Quignard, Esteves, Trian, Girodet, Marthan, Zysman, Berger and Dupin.)

Background: Mutations in STK11/LKB1 gene present a negative impact on tumour immune microenvironment, especially with concomitant activating KRAS mutation. These recent data may explain a decreased response to immunotherapy treatment in STK11 mutant non-small cell lung cancer (NSCLC)., Objective: The primary objective is to evaluate, in a real-life setting, overall survival (OS) in patients with NSCLC according to the presence of STK11 mutation. The secondary objective is to assess time to treatment failure (TTF) for the first-line chemotherapy or immunotherapy., Methods: This observational multicentric study was conducted in Nouvelle-Aquitaine (France), for 24 months. Clinical, histopathological and imagery data were collected in each centre while the next-generation sequencing analysis was performed in Bordeaux Hospital University. Patient's data were longitudinally followed from NSCLC diagnosis date to the occurrence of censoring events (therapeutic failure or death, as applicable) or until the study end date., Results: median OS from the first drug administration was significantly longer for STK11 wt patients than STK11 mut patients (16.2 months [11 - nr] versus 4.7 months [2.5-9.4]; Log-rank test P < 0.001). The Presence of STK11 mutation was significantly associated with shortened OS (RR = 2.26 [1.35-3.79], P = 0.002). First-line TTF was significantly shorter in STK11 mut population and the presence of the mutation was significantly associated with an increase in treatment failures (RR = 1.87 [1.21-2.89], P = 0.005). The type of treatment (chemotherapy, immunotherapy) does not influence the amplitude of reduced TTF in patients with STK11 mut ., Conclusion: The presence of STK11 mutation is associated with poor prognosis in NSCLC., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: PR, SA, CC, SGG, RV, AG, AC, LN, JPM, JB and POG have no conflicts of interest to disclose. CD has received consulting fees or honorarium from Astra-Zeneca, BMS, and accommodation and travelling expenses for meetings from Astra-Zeneca, BMS, PSD, Pfizer and Roche., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Few strategies exist for treatment of patients with small-cell lung cancer (SCLC) extended-stage after failure of first-line platinum-based chemotherapy. Lurbinectedin is a novel RNA-polymerase-II inhibitor investigated as a second-line therapy for SCLC. However, its efficacy and safety profile in real clinical practice remain to be determined., Objective: To determine the efficacy and safety of lurbinectedin in real-life among patients with SCLC previously treated with first-line platinum-based chemotherapy., Methods: We retrospectively evaluated patients who received at least one dose of lurbinectedin (3.2 mg/m 2 ) between March 2020 and November 2021, in the pulmonary department of Bordeaux University Hospital. Endpoints were time to treatment discontinuation, progression-free survival, overall survival, and safety profile., Results: Thirteen patients were included. The median age was 60 years (range: 42-77), seven (54%) were females, nine (69%) having a performance status of 0-1. Lurbinectedin was given as second-line treatment before platinum rechallenge in four (31%) patients. After a mean follow-up of 4.1 months, the objective response rate (ORR) was 17%. The median time to treatment discontinuation (TTD) was 2.3 months (interquartile range [IQR], 1.2-3.6). The median progression-free survival (PFS) and overall survival (OS) were, respectively, 1.9 (IQR, 0.1.8) and 4.1 (IQR, 2.0-3.5) months. No significant difference regarding TTD, PFS or OS was found in the two groups according to treatment history or according to chemotherapy-free intervall (CMI) 〈1 or 〉1 month. The most common adverse events (AEs) were asthenia, nausea, and anemia in nine (70%) patients. Grade 3 AEs were reported, fatigue, vomiting, nausea, anorexia, and neutropenia., Conclusions: Lurbinectedin in real clinical practice could have had a lower efficacy than in phase II trial, but a better hematological and bioclinical tolerance than previously reported. Early relapse after platinum-based chemotherapy seems to have a lower response to lurbinectedin., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Patients with severe asthma show an increase in both exacerbation frequency and bronchial smooth muscle (BSM) mass. Rhinovirus (RV) infection of the bronchial epithelium (BE) is the main trigger of asthma exacerbations. Histological analysis of biopsies shows that a close connection between BE and hypertrophic BSM is a criterion for severity of asthma., Objective: We hypothesized that RV infection of BE specifically increases BSM-cell migration from patients with asthma., Methods: Serum samples, biopsies, or BSM cells were obtained from 86 patients with severe asthma and 31 subjects without asthma. BE cells from subjects without asthma were cultured in an air-liquid interface and exposed to RV-16. Migration of BSM cells was assessed in response to BE supernatant using chemotaxis assays. Chemokine concentrations were analyzed by transcriptomics and ELISAs. Immunocytochemistry, western blotting, and flow cytometry were used to quantify CXCR3 isoform distribution. CXCR3 downstream signaling pathways were assessed by calcium imaging and western blots., Results: BSM cells from patients with severe asthma specifically migrated toward RV-infected BE, whereas those from subjects without asthma did not. This specific migration is driven by BE C-X-C motif chemokine ligand 10, which was increased in vitro in response to RV infection as well as in vivo in serum from exacerbating patients with severe asthma. The mechanism is related to both decreased expression and activation of the CXCR3-B-specific isoform in BSM cells from those with severe asthma., Conclusions: We have demonstrated a novel mechanism of BSM remodeling in patients with severe asthma following RV exacerbation. This study highlights the C-X-C motif chemokine ligand 10/CXCR3-A axis as a potential therapeutic target in severe asthma., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Clinical pharmacology is the study of drugs in humans, from first-in-human studies to randomized controlled trials (RCTs) and benefit-risk ratio assessment in large populations. The objective of this review is to present the recent innovations that may revolutionize the development of drugs in the future. On behalf of the French Society of Pharmacology and Therapeutics, we provide recommendations to address those future challenges in clinical pharmacology. Whatever the future will be, robust preliminary data on drug mechanism of action and rigorous study design will remain crucial prior to the start of pharmacological studies in human. At the present time, RCTs remain the gold standard to evaluate the efficacy of human drugs, although alternative designs (pragmatic trials, platform trials, etc.) are emerging. Innovations in healthy volunteers' studies and the contribution of new technologies such as artificial intelligence, machine learning, and internet-based trials have the potential to improve drug development. In the field of precision medicine, new disease phenotypes and endotypes will probably help to identify new pharmacological targets, responders to therapies, and patients at risk for drug adverse events. In such a moving landscape, the development of translational research through academic and private partnership, transparent sharing of clinical trial data and enhanced interactions between drug experts, patients, and the general public are priority areas for action., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Rhinovirus (RV) infection of the bronchial epithelium is implicated in the vast majority of severe asthma exacerbations. Interestingly, the susceptibility of bronchial epithelium to RV infection is increased in persons with asthma. Bronchial smooth muscle (BSM) remodeling is an important feature of severe asthma pathophysiology, and its reduction using bronchial thermoplasty has been associated with a significant decrease in the exacerbation rate. We hypothesized that asthmatic BSM can play a role in RV infection of the bronchial epithelium. Using an original co-culture model between bronchial epithelium and BSM cells, we show that asthmatic BSM cells increase RV replication in bronchial epithelium following RV infection. These findings are related to the increased production of CCL20 by asthmatic BSM cells. Moreover, we demonstrate an original downregulation of the activity of the epithelial protein kinase RNA-activated (PKR) antiviral pathway. Finally, we identify a direct bottom-up effect of asthmatic BSM cells on bronchial epithelium susceptibility to RV infection., Competing Interests: Declaration of interests, (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

DIPNECH is a differential diagnosis of severe asthma with no specific biomarkers. Chronic cough and multiple nodules on CT should prompt clinicians to consider this diagnosis. Differentiating DIPNECH from severe asthma remains crucial. https://bit.ly/3mmFbQn., Competing Interests: Conflict of interest: C. Hurabielle has nothing to disclose. Conflict of interest: C. Taillé reports grants, personal fees and nonfinancial support from GSK, Sanofi and AstraZeneca, personal fees from Novartis and Stallergenes, and participation on a data safety monitoring or advisory board for AstraZeneca, GSK, Sanofi and Novartis. Conflict of interest: G. Prévot has nothing to disclose. Conflict of interest: M. Russier has nothing to disclose. Conflict of interest: A. Didier has nothing to disclose. Conflict of interest: P-O. Girodet has nothing to disclose. Conflict of interest: M. Colombat has nothing to disclose. Conflict of interest: J. Mazières has nothing to disclose. Conflict of interest: L. Guilleminault has nothing to disclose., (Copyright ©The authors 2022.)

Competing Interests: Conflict of interest: I. Benlala has a patent “Method for generating a biomarker system” (PCT/EP2020/065380) pending. Conflict of interest: G. Dournes has a patent “Method for geometrical characterisation of the airways of the lung by MRI” (EP number 17726309.2) issued and a patent “Method for generating a biomarker system” (PCT/EP2020/065380) pending. Conflict of interest: P-O. Girodet reports grants, personal fees and non-financial support from AstraZeneca, and personal fees and non-financial support from GSK, Novartis and Sanofi, outside the submitted work; and has a patent “New compositions and methods of treating and/or preventing COPD” (EP number 3050574, PCT/EP2016/051771) issued and a patent “New compositions and methods of treating COVID-19 disease” (EP number 20173595.8) pending. Conflict of interest: T. Benkert is an employee of Siemens Healthcare GmbH. Conflict of interest: F. Laurent reports personal fees and non-financial support from Chiesi, Boehringer, AstraZeneca, Bayer, Gilead and GSK, outside the submitted work; and has a patent “Method for geometrical characterisation of the airways of the lung by MRI” (EP number 17726309.2) issued and a patent “Method for generating a biomarker system” (PCT/EP2020/065380) pending. Conflict of interest: P. Berger reports grants from Novartis SAS, France, during the conduct of the study; grants, personal fees and non-financial support from AstraZeneca, GSK, Novartis, Chiesi and Boehringer, and personal fees and non-financial support from Menarini and Sanofi, outside the submitted work; and has a patent “New compositions and methods of treating and/or preventing COPD” (EP number 3050574, PCT/EP2016/051771) issued, a patent “Method for geometrical characterisation of the airways of the lung by MRI” (EP number 17726309.2) issued, a patent “Method for generating a biomarker system” (PCT/EP2020/065380) pending and a patent “New compositions and methods of treating COVID-19 disease” (EP number 20173595.8) pending.

Background: Bronchial smooth muscle (BSM) remodelling in asthma is related to an increased mitochondrial biogenesis and enhanced BSM cell proliferation in asthma. Since mitochondria produce the highest levels of cellular energy and fatty acid β-oxidation is the most powerful way to produce ATP, we hypothesised that, in asthmatic BSM cells, energetic metabolism is shifted towards the β-oxidation of fatty acids., Objectives: We aimed to characterise BSM cell metabolism in asthma both in vitro and ex vivo to identify a novel target for reducing BSM cell proliferation., Methods: 21 asthmatic and 31 non-asthmatic patients were enrolled. We used metabolomic and proteomic approaches to study BSM cells. Oxidative stress, ATP synthesis, fatty acid endocytosis, metabolite production, metabolic capabilities, mitochondrial networks, cell proliferation and apoptosis were assessed on BSM cells. Fatty acid content was assessed in vivo using matrix-assisted laser desorption/ionisation spectrometry imaging., Results: Asthmatic BSM cells were characterised by an increased rate of mitochondrial respiration with a stimulated ATP production and mitochondrial β-oxidation. Fatty acid consumption was increased in asthmatic BSM both in vitro and ex vivo . Proteome remodelling of asthmatic BSM occurred via two canonical mitochondrial pathways. The levels of carnitine palmitoyl transferase (CPT)2 and low-density lipoprotein (LDL) receptor, which internalise fatty acids through mitochondrial and cell membranes, respectively, were both increased in asthmatic BSM cells. Blocking CPT2 or LDL receptor drastically and specifically reduced asthmatic BSM cell proliferation., Conclusion: This study demonstrates a metabolic switch towards mitochondrial β-oxidation in asthmatic BSM and identifies fatty acid metabolism as a new key target to reduce BSM remodelling in asthma., Competing Interests: Conflict of interest: P. Esteves reports other (postdoctoral salary) from Fondation pour la Recherche Médicale, grants from Fondation Bordeaux université (FGLMR/AVAD), during the conduct of the study. Conflict of interest: L. Blanc reports other (salary) from Fondation pour la Recherche Médicale, during the conduct of the study. Conflict of interest: A. Celle has nothing to disclose. Conflict of interest: I. Dupin has a delivered patent (EP 15152886 “New compositions and methods of treating and/or preventing chronic obstructive pulmonary disease”), and a submitted patent (EP 20173595.8 “New compositions and methods of treating COVID-19 disease”), all outside the submitted work. Conflict of interest: E. Maurat has nothing to disclose. Conflict of interest: N. Amoedo has nothing to disclose. Conflict of interest: G. Cardouat has nothing to disclose. Conflict of interest: O. Ousova has nothing to disclose. Conflict of interest: L. Gales has nothing to disclose. Conflict of interest: F. Bellvert has nothing to disclose. Conflict of interest: H. Begueret has nothing to disclose. Conflict of interest: M. Thumerel has nothing to disclose. Conflict of interest: J-W. Dupuy has nothing to disclose. Conflict of interest: N. Desbenoit has nothing to disclose. Conflict of interest: R. Marthan has nothing to disclose. Conflict of interest: P-O. Girodet reports grants, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Chiesi, GlaxoSmithKline, Novartis and Sanofi, outside the submitted work. Conflict of interest: R. Rossignol has nothing to disclose. Conflict of interest: P. Berger reports grants from Fondation pour la Recherche Médicale, during the conduct of the study; grants and personal fees from Novartis, grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from Chiesi, AstraZeneca and Sanofi, non-financial support from Menarinni and TEVA, outside the submitted work; and has a patent EP 15152886.6 “New compositions and methods of treating and/or preventing chronic obstructive pulmonary disease” issued, a patent 22605-FR “Geometric characterization of airways using MRI” pending, and a patent EP 20173595.8 “New compositions and methods of treating COVID-19 disease” pending. Conflict of interest: T. Trian reports grants from Agence Nationale pour la Recherche, during the conduct of the study., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: The links between microbial environmental exposures and asthma are well documented, but no study has combined deep sequencing results from pulmonary and indoor microbiomes of patients with asthma with spirometry, clinical, and endotype parameters., Objective: The goal of this study was to investigate the links between indoor microbial exposures and pulmonary microbial communities and to document the role of microbial exposures on inflammatory and clinical outcomes of patients with severe asthma (SA)., Methods: A total of 55 patients with SA from the national Cohort of Bronchial Obstruction and Asthma cohort were enrolled for analyzing their indoor microbial flora through the use of electrostatic dust collectors (EDCs). Among these patients, 22 were able to produce sputum during "stable" or pulmonary "exacerbation" periods and had complete pairs of EDC and sputum samples, both collected and analyzed. We used amplicon targeted metagenomics to compare microbial communities from EDC and sputum samples of patients according to type 2 (T2)-asthma endotypes., Results: Compared with patients with T2-low SA, patients with T2-high SA exhibited an increase in bacterial α-diversity and a decrease in fungal α-diversity of their indoor microbial florae, the latter being significantly correlated with fraction of exhaled nitric oxide levels. The β-diversity of the EDC mycobiome clustered significantly according to T2 endotypes. Moreover, the proportion of fungal taxa in common between the sputum and EDC samples was significantly higher when patients exhibited acute exacerbation., Conclusion: These results illustrated, for the first time, a potential association between the indoor mycobiome and clinical features of patients with SA, which should renew interest in deciphering the interactions between indoor environment, fungi, and host in asthma., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Aims: Pictograms on medicine boxes warn of potential drug-related driving hazard; we studied their association with serious accidents., Methods: Prospective study in emergency departments of the hospitals in Bordeaux and Périgueux (France), of drivers with serious (admitted at least 24 hours) or nonserious vehicular accidents. Minors, passengers, pedestrians or subjects incapable of answering an interview were excluded. Interviews ascertained driver and accident characteristics, use of drugs with or without pictograms, use of alcohol and abuse substances, sleepiness, distractions, and mind wandering at the time of the accident, RESULTS: Between 18 October 2016 and 26 December 2018, 1200 of the 6212 drivers admitted to the hospital emergency rooms, 741 nonserious, 459 serious, were interviewed. Serious accidents were associated with male sex (odds ratio 1.89, 95% confidence interval [1.36-2.64]), age above 60 years (3.64 [2.21-6.00]), driving on local roads (3.34 [2.34-4.76]), driving a motorcycle (3.39 [2.29-5.00]), having drunk alcohol within 6 hours (2.89 [1.85-4.51]) and using a drug with a pictogram during the 24 hours previous to the accident (1.57 [1.06-2.32]). From 207 police reports, 101 drivers were not responsible, and 106 were responsible, associated with age below 40 years, driving in overcast or rainy weather (2.62 [1.29-5.33]), on local roads (3.89 [1.90-7.95]), and use of at least 1 pictogram drug in the previous week (3.12 [1.31-7.41])., Conclusion: The known risks of alcohol and pictogram drugs, of riding motorcycles and using local roads were confirmed. As measured, behavioural sleepiness did not predict accidents., (© 2020 The British Pharmacological Society.)

Background: Dupilumab is a monoclonal anti-IL-4Rα antibody developed for the treatment of severe asthma (SA). An early access programme for dupilumab was opened in France in SA patients experiencing unacceptable steroids side-effects and/or life-threatening exacerbations., Objective: To assess changes in asthma control between baseline and 12 months of treatment., Methods: Multi-centre (n = 13) retrospective real-life cohort study. This study is registered on ClinicalTrials.gov (NCT04022447)., Results: Overall, 64 patients with SA (median age 51, interquartile range [44-61]; 53% females) received dupilumab as add-on therapy to maximal standard of care; and 76% were on oral daily steroids at baseline. After 12 months, median asthma control test score improved from 14 [7-16] to 22 [17-24] (P < .001); median forced expiratory volume in 1 seconds increased from 58% [47-75] to 68% [58-88] (P = .001); and daily prednisone dose was reduced from 20 [10-30] to 5 [0-7] mg/d (P < .001). Annual exacerbations decreased from 4 [2-7] to 1 [0-2] (P < .001). Hypereosinophilia ≥1500/mm 3 was observed at least once during follow-up in 16 patients (25%), persisting after 6 months in 8 (14%) of them. Increase in blood eosinophil count did not modify the clinical response during the study period. Injection-site reaction was the most common side effect (14%). Three deaths were observed, none related to treatment by investigators., Conclusion & Clinical Relevance: In this first real-life cohort study of predominantly steroid-dependent SA, dupilumab significantly improved asthma control and lung function and reduced oral steroids use and exacerbations rate. Despite limitations due to the retrospective study, these results are consistent with controlled trials efficacy data. Further studies are required to assess the clinical significance and long-term prognosis of sustained dupilumab-induced hypereosinophilia., (© 2020 John Wiley & Sons Ltd.)

Competing Interests: P. Rosellini et D. Berdaï déclarent n’avoir aucun lien d’intérêts. M. Molimard déclare les liens d’intérêts suivants : activités de consultance sur le développement de médicaments dans les domaines des maladies respiratoires (ALK-Abelló, AstraZeneca, Boehringer Ingelheim, Novartis, GSK, Stallergenes). P.-O. Girodet déclare les liens d’intérêts suivants : investigateur d’essais cliniques (ALK-Abelló, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis Pharma, Sanofi). Interventions ponctuelles, telles que conférences invitées, enseignements postuniversitaires, groupes de travail (ALK-Abelló, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis). Grants pour projets de recherche fondamentale et clinique (AstraZeneca, Novartis). Absence d’intérêt financier et absence de liens durables ou permanents.

Asthma exacerbations, a major concern in therapeutic strategies, are most commonly triggered by viral respiratory infections, particularly with human rhinovirus (HRV). Infection of bronchial epithelial (BE) cells by HRV triggers inflammation, notably monocyte recruitment. The increase of bronchial smooth muscle (BSM) mass in asthma, a hallmark of bronchial remodeling, is associated with the annual rate of exacerbations. The aim of the present study was to assess whether or not BSM could increase monocyte migration induced by HRV-infected BE. We used an advanced in vitro model of co-culture of human BE cells in air-liquid interface with human BSM cells from control and asthmatic patients. Inflammation triggered by HRV infection (HRV-16, MOI 0.1, 1 h) was assessed at 24 h with transcriptomic analysis and multiplex ELISA. In vitro CD14 + monocyte migration was evaluated with modified Boyden chamber. Results showed that HRV-induced monocyte migration was substantially increased in the co-culture model with asthmatic BSM, compared with control BSM. Furthermore, the well-known monocyte migration chemokine, CCL2, was not involved in this increased migration. However, we demonstrated that CCL5 was further increased in the asthmatic BSM co-culture and that anti-CCL5 blocking antibody significantly decreased monocyte migration induced by HRV-infected BE. Taken together, our findings highlight a new role of BSM cells in HRV-induced inflammation and provide new insights in mucosal immunology which may open new opportunities for prevention and/or treatment of asthma exacerbation., (Copyright © 2020 Allard, Levardon, Esteves, Celle, Maurat, Thumerel, Girodet, Trian and Berger.)

The remodelling mechanism and cellular players causing persistent airflow limitation in COPD remain largely elusive. We have recently demonstrated that circulating fibrocytes, a rare population of fibroblast-like cells produced by the bone marrow stroma, are increased in COPD patients during an exacerbation. We aimed to quantify fibrocyte density in situ in bronchial specimens from both control subjects and COPD patients, to define associations with relevant clinical, functional and computed tomography (CT) parameters, and to investigate the effect of the epithelial microenvironment on fibrocyte survival in vitro ("Fibrochir" study).A total of 17 COPD patients and 25 control subjects, all requiring thoracic surgery, were recruited. Using co-immunostaining and image analysis, we identified CD45 + FSP1 + cells as tissue fibrocytes, and quantified their density in distal and proximal bronchial specimens. Fibrocytes, cultured from the blood samples of six COPD patients, were exposed to primary bronchial epithelial cell secretions from control subjects or COPD patients.We demonstrate that fibrocytes are increased in both distal and proximal tissue specimens of COPD patients. The density of fibrocytes is negatively correlated with lung function parameters and positively correlated with bronchial wall thickness as assessed by CT scan. A high density of distal bronchial fibrocytes predicts the presence of COPD with a sensitivity of 83% and a specificity of 70%. Exposure of fibrocytes to COPD epithelial cell supernatant favours cell survival.Our results thus demonstrate an increased density of fibrocytes within the bronchi of COPD patients, which may be promoted by epithelial-derived survival-mediating factors., Competing Interests: Conflict of interest: I. Dupin reports grants from Fondation Bordeaux Université, during the conduct of the study. In addition, she has a patent (EP 15152886.6: New compositions and methods of treating and/or preventing Chronic Obstructive Pulmonary Disease) pending. Conflict of interest: M. Thumerel has nothing to disclose. Conflict of interest: E. Maurat has nothing to disclose. Conflict of interest: F. Coste has nothing to disclose. Conflict of interest: E. Eyraud has nothing to disclose. Conflict of interest: H. Begueret has nothing to disclose. Conflict of interest: T. Trian has nothing to disclose. Conflict of interest: M. Montaudon has nothing to disclose. Conflict of interest: R. Marthan has nothing to disclose. Conflict of interest: P-O. Girodet reports personal fees from Novartis, Chiesi, Boehringer Ingelheim, AstraZeneca and GlaxoSmithKline, outside the submitted work. In addition, he has a patent (EP 15152886.6: New compositions and methods of treating and/or preventing Chronic Obstructive Pulmonary Disease) pending. Conflict of interest: P. Berger reports grants from Nycomed, Takeda and Fondation du Souffle–Fonds de dotation Recherche en Santé Respiratoire, during the conduct of the study; grants and personal fees from Novartis, personal fees and nonfinancial support from AstraZeneca, Sanofi, and Chiesi, grants, personal fees and nonfinancial support from Boehringer Ingelheim, and personal fees from Menarinni and Teva, outside the submitted work. In addition, he has a patent (EP 15152886.6: New compositions and methods of treating and/or preventing Chronic Obstructive Pulmonary Disease) pending., (Copyright ©ERS 2019.)

Aim of the Study: To provide a tool for drug misuse or potential misuse monitoring by using a healthcare insurance database., Methods: A cross-sectional study repeated quarterly from 2007 to 2014 was conducted using data from a 1/97th random sample of the French national healthcare reimbursement system. For each drug studied, ad hoc indicators were designed to assess drug misuse, defined as prescriptions that did not comply with the label stipulated in the summary of product characteristics, in terms of the drug (e.g., interactions) or the patient (age, medical history). We focused on specifically identified situations of drug misuse involving non-steroidal anti-inflammatory drugs (NSAIDs), antiemetics in patients with Parkinson's disease and antipsychotics in pediatrics; we also focused on direct anticoagulants, asthma and oral antidiabetic drugs but results for these latter are only shown in supplementary materials., Results: At-risk prescribing of NSAIDs in patients treated by diuretics or renin-angiotensin system inhibitors always remained higher than 14% over the study (maximum: 19%; 2014 quarter 4: 15.4%). Off-label prescribing of contraindicated anti-dopaminergic antiemetics with dopaminergic antiparkinson drugs was marginal (maximum: 2.2%; 2014 quarter 4: 0.5%) but represented at least 5.5% of antiemetic prescriptions. Despite the rise in antipsychotic prescriptions in pediatrics, no dramatic increase in misuse related to age was observed during the study period (2007 quarter 1: 16.1%; 2014 quarter 4: 11.1%). The highest degree of misuse was observed for aripiprazole and for second-generation antipsychotics other than risperidone and aripiprazole., Conclusion: This study provides a simple tool to monitor drug misuse or potential misuse using information from a health insurance database. The results highlight the need for the Regulator to rethink risk management information campaigns and to modify the official information on products., (Copyright © 2019 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background The validity of three-dimensional (3D) ultrashort echo time (UTE) MRI for the assessment of emphysema in patients with chronic obstructive pulmonary disease (COPD) at high spatial resolution is, to the knowledge of the authors, unknown. Purpose To assess whether noncontrast agent-enhanced 3D UTE MRI at submillimeter spatial resolution can be used to determine the extent of emphysema by using both qualitative visual scoring and fully automated volumetric quantification. Materials and Methods Twenty-eight participants with COPD and 10 control participants (mean age, 70 years ± 7 [standard deviation] and 64 years ± 4, respectively) were prospectively enrolled between 2015 and 2017. Participants underwent pulmonary function testing, CT, and MRI. CT was used as the reference standard. Qualitative scoring of emphysema extent was performed by two readers. Fully automated quantification of percentage of low-attenuation volume by using a threshold of -950 HU (%LAV -950HU ) at CT and percentage of low-signal-intensity volume by using an adaptive threshold of 0.20 (%LSV 0.20 ) at MRI were the respective emphysema indexes. Comparison of means was performed by using Student t test, correlation was determined by using Pearson test, agreement was found by using weighted κ index, and reproducibility was determined by using intraclass correlation coefficient. Diagnostic performance was assessed by calculating the area under the receiver operating characteristics curve (AUC). Results With qualitative scoring, agreement between UTE MRI and CT was good (weighted κ, 0.79; 95% confidence interval: 0.71, 0.83). With automated volumetric quantification, %LSV 0.20 was significantly correlated with %LAV -950HU in participants with COPD ( r , -0.80; P < .001) and correlated with forced expiratory volume in 1 second percentage predicted ( r , -0.55; P = .002). %LSV 0.20 was significantly higher in participants with COPD than in control participants ( P < .001). The diagnostic performance and reproducibility of %LSV 0.20 were good (AUC, 1.00 [95% confidence interval: 0.88, 1.00], and intraclass correlation coefficient, > 0.99, respectively). Conclusion A fully automated method with three-dimensional ultrashort echo time MRI reproducibly quantified the volumetric extent of emphysema in participants with chronic obstructive pulmonary disease. © RSNA, 2019 Online supplemental material is available for this article.

Pharmacoepidemiology studies are of particular interest in the respiratory field and especially for inhaled drugs. In real-life, excessive use of rescue medications and under- or inappropriate-prescribing of preventer medications has been shown. In asthma and chronic obstructive pulmonary disease (COPD), the poor use of inhalation device is associated with uncontrolled diseases and occurrence of exacerbations. Inhalation treatments are directly delivered within the lung and are generally considered as safe. However, systemic adverse drug reactions that were not evidenced in clinical trials may be observed after a long-term treatment., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Rationale: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, and development of novel therapeutics requires an understanding of pathophysiologic phenotypes., Objectives: The purpose of the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study was to correlate clinical features and biomarkers with molecular characteristics in a well-profiled COPD cohort., Methods: A total of 67 COPD subjects (forced expiratory volume in the first second of expiration [FEV 1 ]: 45%-80% predicted) and 63 healthy smoking and nonsmoking controls underwent multiple assessments including patient questionnaires, lung function, and clinical biomarkers including fractional exhaled nitric oxide (FENO), induced sputum, and blood., Measurements and Main Results: The impact of inhaled corticosteroids (ICSs), and to a lesser extent current smoking, was more associated with symptom control, exacerbation rates, and clinical biomarkers, than severity by FEV 1 . The ICS-treated smoking subjects were most symptomatic, with significantly elevated scores on patient-reported outcomes and more annual exacerbations ( P  < .05). Inhaled corticosteroid users had greater airflow obstruction and air trapping compared with non-ICS users, regardless of smoking status. Smoking, regardless of ICS use, was associated with significantly lower FENO ( P  < .05). Smoking, in non-ICS users, was associated with an elevated proportion of sputum neutrophils and reduced sputum macrophages. Increased serum C-reactive protein was observed in smokers but not in ICS and nonsmoking ICS users ( P  < .05). In contrast, only air trapping and neutrophilic inflammation increased with severity, defined by postbronchodilator FEV 1 ., Conclusions: Compared with COPD severity by FEV 1 , ICS use and current smoking were better determinants of clinical characteristics and biomarkers. Use of the ADEPT COPD data promises to prove useful in defining biological phenotypes to facilitate personalized therapeutic approaches., Competing Interests: Declaration of conflicting interests:The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The non-Janssen authors (D.S., J.M.F., A.E., A.L-S., G.C.C., V.B., C.P., P-O.G., M.T.D.) declare that they have no competing interests regarding the ADEPT data set. The Janssen employees (P.E.S., F.B., V.S.S., M.J.L.) were full-time employees at the time of the study and own stock in the company; however, Janssen Research & Development is no longer pursuing COPD indications.

Background: The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects., Objective: We explored this data set to define type 2 inflammation based on airway mucosal IL-13-driven gene expression and how this related to clinically accessible biomarkers., Methods: IL-13-driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (Feno) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression., Results: Expression of airway mucosal CCL26, periostin, and IL-13-IVS all facilitated segregation of subjects into type 2-high and type 2-low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had Feno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm 3 ) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of Feno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26-high status. Clinical variables did not differ between subjects with type 2-high and type 2-low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression., Conclusion: A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13-IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Although the prevalence of chronic obstructive pulmonary disease (COPD) increases with age, no specific therapeutic approaches are available till date for the elderly population., Aim: To assess the efficacy and safety of once-daily indacaterol 150 and 300 μg in elderly patients with moderate to severe COPD., Methods: Data were pooled from 11 randomized, double-blind, placebo- and active-controlled studies (8445 patients with COPD). The patient population was stratified into age groups: young (≥40-<65 years; 52.3%), elderly (≥65-<75 years; 36.4%), and very elderly (≥75 years; 11.4%). The efficacy outcomes included improvements in trough forced expiratory volume in 1 s (FEV 1 ), transition dyspnea index (TDI), and health status (St. George's Respiratory Questionnaire [SGRQ]); safety was also assessed at 12 weeks., Results: At Week 12, the mean improvement in FEV 1 with indacaterol 150 μg versus placebo was comparable in the elderly (150 mL), very elderly (160 mL), and young (170 mL) groups (p < 0.001 for all comparisons). Similar improvement in FEV 1 was observed with indacaterol 300 μg versus placebo in each group (p < 0.001). This improvement was also significantly higher with indacaterol than formoterol, salmeterol, and tiotropium in all groups (p < 0.01). Both TDI and SGRQ scores significantly improved with indacaterol versus placebo across age groups (p < 0.001) and were significantly higher than that for tiotropium (p < 0.001). Incidences of adverse events among indacaterol- or placebo-treated patients were similar, regardless of the age group., Conclusions: This pooled analysis suggests that the efficacy and safety of indacaterol treatment is similar between elderly and younger patients with COPD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Acute exacerbations of chronic obstructive pulmonary disease (COPD) can be prevented by inhaled treatment. Errors in inhaler handling, not taken into account in clinical trials, could impact drug delivery and minimise treatment benefit. We aimed to assess real-life inhaler device handling in COPD patients and its association with COPD exacerbations.To this end, 212 general practitioners and 50 pulmonologists assessed the handling of 3393 devices used for continuous treatment of COPD in 2935 patients. Handling errors were observed in over 50% of handlings, regardless of the device used. Critical errors compromising drug delivery were respectively made in 15.4%, 21.2%, 29.3%, 43.8%, 46.9% and 32.1% of inhalation assessment tests with Breezhaler® (n=876), Diskus® (n=452), Handihaler® (n=598), pressurised metered-dose inhaler (pMDI) (n=422), Respimat® (n=625) and Turbuhaler® (n=420).The proportion of patients requiring hospitalisation or emergency room visits in the past 3 months for severe COPD exacerbation was 3.3% (95% CI 2.0-4.5) in the absence of error and 6.9% (95% CI 5.3-8.5) in the presence of critical error (OR 1.86, 95% CI 1.14-3.04, p<0.05).Handling errors of inhaler devices are underestimated in real life and are associated with an increased rate of severe COPD exacerbation. Training in inhaler use is an integral part of COPD management., (Copyright ©ERS 2017.)

The immune responses of type 2 T helper cells (Th2) play an important role in asthma and promote the differentiation of alternatively activated (M2) macrophages. M2 macrophages have been increasingly understood to contribute to Th2 immunity. We hypothesized that M2 macrophages are altered in asthma and modulate Th2 responses. The aim of this study was to characterize the phenotype and function of human monocyte-derived M2 and bronchoalveolar lavage fluid (BALF) macrophages from healthy control subjects and subjects with asthma. Phenotypic characteristics and effector function of M2 macrophages were examined using monocyte-derived and BALF macrophages obtained from subjects with asthma (n = 28) and healthy volunteers (n = 9) by flow cytometry and quantitative PCR. Resting monocyte-derived (M0) and M2 macrophages were generated by the addition of macrophage colony-stimulating factor or macrophage colony-stimulating factor plus IL-4, respectively. M2 macrophage cytokine expression and their impact on dendritic and CD4 + T cell activation were examined in vitro. High levels of CD206 and major histocompatibility complex class II expression identify macrophages with an M2 phenotype that are increased 2.9-fold in the BALF of subjects with asthma compared with control subjects. M2 macrophages have elevated IL-6, IL-10, and IL-12p40 production compared with conventional macrophages and modulate dendritic and CD4 + T cell interactions. Histamine receptor 1 and E-cadherin expression identify M2 macrophage subsets associated with increased airflow obstruction. M2 macrophages have a distinct cell surface and effector phenotype and are found in increased numbers in subjects with asthma. These findings suggest that M2 macrophages may play an important role in allergic asthma through their bidirectional interactions with immune and structural cells, and inflammatory mediators.

Rationale: Severe pulmonary hypertension (PH) is very uncommon in COPD, and a distinct phenotype has been hypothesised. We aimed to evaluate whether CT can help to recognise this condition non-invasively by measuring small pulmonary vessels., Material and Methods: Patients with COPD who underwent pulmonary function tests, unenhanced CT of the chest and right heart catheterisation (RHC) during a period of stability were included in the study. From 105 included patients, 20 patients with COPD with severe PH (mean pulmonary arterial pressure, mPAP>35 mm Hg) were compared with 20 FEV1-matched and age-matched patients with COPD with mild or without PH (mPAP<35 mm Hg). The percentage of total cross-sectional area of vessels less than 5 mm(2) normalised by lung area (%CSA<5) and 5-10 mm(2) (%CSA5-10), the mean number of cross-sectioned vessels (CSNs) and bronchial wall thickness (WT) were measured on CT examination and compared between groups. Paw scores combining PaO2 measurement and CT parameters best correlated with mPAP were compared by receiver operating characteristic analysis to predict severe PH in COPD., Results: Patients with severe PH COPD had higher %CSA and CSN values than those of patients with COPD without severe PH. Using multiple regression analysis, %CSA<5 and WT were the best predictors of mPAP in patients with and without severe PH, respectively. A score combining %CSA<5, PaO2 and WT best predicted severe PH in patients with COPD., Conclusions: CT measurements of small vessels support a distinct vessel-related phenotype in patients with COPD with severe PH, and combined with WT and PaO2 parameters in the paw score, which may offer a non-invasive tool to select patients for RHC., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Increase of bronchial smooth muscle (BSM) mass is a crucial feature of asthma remodeling. The mechanisms of such an increased BSM mass are complex but involve enhanced mitochondrial biogenesis, leading to increased proliferation of BSM cells in asthmatic patients. The major tumor suppressor protein p53 is a key cell regulator involved in cell proliferation and has also been implicated in mitochondrial biogenesis. However, the role of p53 in BSM cell proliferation and mitochondrial biogenesis has not been investigated thus far., Objective: We sought to evaluate the role of p53 in proliferation of BSM cells in asthmatic patients and mitochondrial biogenesis., Methods: The expression of p53 was assessed both in vitro by using flow cytometry and Western blotting and ex vivo by using RT-PCR after laser microdissection. The role of p53 was assessed with small hairpin RNA lentivirus in both asthmatic patients and control subjects with BSM cell proliferation by using 5-bromo-2'-deoxyuridine and cell counting and in the expression of p21, BCL2-associated X protein, mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)., Results: Twenty-nine patients with moderate-to-severe asthma and 26 control subjects were enrolled in the study. p53 expression was increased in BSM from asthmatic patients both ex vivo and in vitro, with a decreased interaction with mouse double minute 2 homolog (Mdm2) and an increased phosphorylation of serine 20. p53 did not inhibit the transcription of both TFAM and PGC-1α in BSM cells from asthmatic patients. As a consequence, p53 is unable to slow the increased mitochondrial biogenesis and hence the subsequent increased proliferation of BSM cells in asthmatic patients., Conclusion: This study suggests that p53 might act as a new potential therapeutic target against BSM remodeling in asthmatic patients., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Asthma is a biologically heterogeneous disease and development of novel therapeutics requires understanding of pathophysiologic phenotypes. There is uncertainty regarding the stability of clinical characteristics and biomarkers in asthma over time. This report presents the longitudinal stability over 12 months of clinical characteristics and clinically accessible biomarkers from ADEPT., Methods: Mild, moderate, and severe asthma subjects were assessed at 5 visits over 12 months. Assessments included patient questionnaires, spirometry, bronchodilator reversibility, fractional exhaled nitric oxide (FENO), and biomarkers measured in induced sputum., Results: Mild (n = 52), moderate (n = 55), and severe (n = 51) asthma cohorts were enrolled from North America and Western Europe. For all clinical characteristics and biomarkers, group mean data showed no significant change from visit to visit. However, individual data showed considerable variability. FEV1/FVC ratio showed excellent reproducibility while pre-bronchodilator FEV1 and FVC were only moderately reproducible. Of note bronchodilator FEV1 reversibility showed low reproducibility, with the nonreversible phenotype much more reproducible than the reversible phenotype. The 7-item asthma control questionnaire (ACQ7) demonstrated moderate reproducibility for the combined asthma cohorts, but the uncontrolled asthma phenotype (ACQ7 > 1.5) was inconstant in mild and moderate asthma but stable in severe asthma. FENO demonstrated good reproducibility, with the FENO-low phenotype (FENO < 35 ppb) more stable than the FENO-high phenotype (FENO ≥ 35 ppb). Induced sputum inflammatory phenotypes showed marked variability across the 3 sputum samples taken over 6 months., Conclusions: The ADEPT cohort showed group stability, individual stability in some parameters e.g. low FEV1/FVC ratio, and low FENO, but marked individual variability in other clinical characteristics and biomarkers e.g. type-2 biomarkers over 12 months. This variability is possibly related to seasonal variations in climate and allergen exposure, medication changes and acute exacerbations. The implications for patient selection strategies based on clinical biomarkers may be considerable.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by peribronchial fibrosis. The chronic course of COPD is worsened by recurrent acute exacerbations., Objective: The aim of the study was to evaluate the recruitment of blood fibrocytes in patients with COPD during exacerbations and, subsequently, to identify potential mechanisms implicated in such recruitment., Methods: Using flow cytometry, we quantified circulating fibrocytes and characterized their chemokine receptor expression in 54 patients with COPD examined during an acute exacerbation (V1) and 2 months afterward (V2) and in 40 control subjects. The role of the chemokines CXCL12 and CCL11 in fibrocyte migration was investigated by using a chemotaxis assay. Patients were followed for up to 3 years after V1., Results: We demonstrated a significantly increased number of circulating fibrocytes at V1 compared with control subjects. The number of circulating fibrocytes decreased at V2. A high percentage of circulating fibrocytes during exacerbation was associated with increased risk of death. The percentage of fibrocytes at V2 was negatively correlated with FEV1, forced vital capacity, FEV1/forced vital capacity ratio, transfer lung capacity of carbon monoxide, and Pao2. Fibrocytes highly expressed CXCR4 and CCR3, the chemokine receptors for CXCL12 and CCL11, respectively. Fibrocytes collected from patients with COPD at V1 had increased chemotactic migration in response to CXCL12 but not to CCL11 compared with those from control subjects. Plerixafor, a CXCR4 antagonist, decreased fibrocyte migration to plasma from patients with exacerbating COPD., Conclusion: Blood fibrocytes are recruited during COPD exacerbations and related to mortality and low lung function. The CXCL12/CXCR4 axis is involved in such fibrocyte recruitment (Firebrob study; ClinicalTrials NCT01196832)., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Rationale: Increased bronchial smooth muscle (BSM) mass is a key feature of airway remodeling that classically distinguishes severe from nonsevere asthma. Proliferation of BSM cells involves a specific mitochondria-dependent pathway in individuals with severe asthma. However, BSM remodeling and mitochondrial biogenesis have not been examined in nonsevere asthma., Objectives: We aimed to assess whether an increase in BSM mass was also implicated in nonsevere asthma and its relationship with mitochondria and clinical outcomes., Methods: We enrolled 34 never-smoker subjects with nonsevere asthma. In addition, we recruited 56 subjects with nonsevere asthma and 19 subjects with severe asthma as comparative groups (COBRA cohort [Cohorte Obstruction Bronchique et Asthme; Bronchial Obstruction and Asthma Cohort; sponsored by the French National Institute of Health and Medical Research, INSERM]). A phenotypic characterization was performed using questionnaires, atopy and pulmonary function testing, exhaled nitric oxide measurement, and blood collection. Bronchial biopsy specimens were processed for immunohistochemistry and electron microscopy analysis. After BSM remodeling assessment, subjects were monitored over a 12-month period., Measurements and Main Results: We identified characteristic features of remodeling (BSM area >26.6%) and increased mitochondrial number within BSM in a subgroup of subjects with nonsevere asthma. The number of BSM mitochondria was positively correlated with BSM area (r = 0.78; P < 0.001). Follow-up analysis showed that subjects with asthma with high BSM had worse asthma control and a higher rate of exacerbations per year compared with subjects with low BSM., Conclusions: This study reveals that BSM remodeling and mitochondrial biogenesis may play a critical role in the natural history of nonsevere asthma (Mitasthme study). Clinical trial registered with www.clinicaltrials.gov (NCT00808730).

The objective of this study was to evaluate the performance of the ICD-10 (International Classification of Diseases and Related Health Problems, 10(th) Edition) coding in the French hospitalization database (PMSI) to identify acute coronary syndrome (ACS) occurrence. Eligible hospitalizations were those that occurred at the Bordeaux teaching hospitals between 1 January 2011 and 31 December 2011 and had one of the ICD-10 codes related to ischaemic heart diseases (I20 to I25, excluding I23 and I25.2). Among these, 100 hospitalizations were randomly selected; for each case, the ACS diagnosis was confirmed/excluded after medical file examination by an independent events validation committee and the performance of codes, and combinations of codes, to identify ACS was evaluated by calculating the positive predictive value (PPV). Of the individual codes, I20.0, I21 and I24 had the highest PPV; 100.0% for I24 (95%CI [15.8-100.0]); 90.0% for I21 (95%CI [76.3-97.2]); and 66.7% for I20.0 (95%CI [38.4-88.2]). The combination of I20.0 or I24 codes was able to identify 12 of the 56 validated ACS cases with a PPV of 70.6% (95%CI [44.0-89.7]), the combination of I21 or I24 identified 38 cases with a PPV of 90.5% (95%CI [77.4-97.3]), the combination of I20.0 or I21 identified 46 cases with a PPV of 83.6% (95%CI [71.2-92.2]), and the combination of I20.0, I21 or I24 identified 48 cases with a PPV of 84.2% (95%CI [72.1-92.5]). The combination of I20.0, I21 or I24 codes had the best performance to identify occurrence of ACS in the French hospitalization database., (© 2015 Société Française de Pharmacologie et de Thérapeutique.)

Background: Asthma is a heterogeneous disease and development of novel therapeutics requires an understanding of pathophysiologic phenotypes. The purpose of the ADEPT study was to correlate clinical features and biomarkers with molecular characteristics, by profiling asthma (NCT01274507). This report presents for the first time the study design, and characteristics of the recruited subjects., Methods: Patients with a range of asthma severity and healthy non-atopic controls were enrolled. The asthmatic subjects were followed for 12 months. Assessments included history, patient questionnaires, spirometry, airway hyper-responsiveness to methacholine, fractional exhaled nitric oxide (FENO), and biomarkers measured in induced sputum, blood, and bronchoscopy samples. All subjects underwent sputum induction and 30 subjects/cohort had bronchoscopy., Results: Mild (n = 52), moderate (n = 55), severe (n = 51) asthma cohorts and 30 healthy controls were enrolled from North America and Western Europe. Airflow obstruction, bronchodilator response and airways hyperresponsiveness increased with asthma severity, and severe asthma subjects had reduced forced vital capacity. Asthma control questionnaire-7 (ACQ7) scores worsened with asthma severity. In the asthmatics, mean values for all clinical and biomarker characteristics were stable over 12 months although individual variability was evident. FENO and blood eosinophils did not differ by asthma severity. Induced sputum eosinophils but not neutrophils were lower in mild compared to the moderate and severe asthma cohorts., Conclusions: The ADEPT study successfully enrolled asthmatics across a spectrum of severity and non-atopic controls. Clinical characteristics were related to asthma severity and in general asthma characteristics e.g. lung function, were stable over 12 months. Use of the ADEPT data should prove useful in defining biological phenotypes to facilitate personalized therapeutic approaches.

Purpose: To assess lung magnetic resonance (MR) imaging with a respiratory-gated pointwise encoding time reduction with radial acquisition (PETRA) sequence at 1.5 T and compare it with imaging with a standard volumetric interpolated breath-hold examination (VIBE) sequence, with extra focus on the visibility of bronchi and the signal intensity of lung parenchyma., Materials and Methods: The study was approved by the local ethics committee, and all subjects gave written informed consent. Twelve healthy volunteers were imaged with PETRA and VIBE sequences. Image quality was evaluated by using visual scoring, numbering of visible bronchi, and quantitative measurement of the apparent contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR). For preliminary clinical assessment, three young patients with cystic fibrosis underwent both MR imaging and computed tomography (CT). Comparisons were made by using the Wilcoxon signed-rank test for means and the McNemar test for ratios. Agreement between CT and MR imaging disease scores was assessed by using the κ test., Results: PETRA imaging was performed with a voxel size of 0.86 mm(3). Overall image quality was good, with little motion artifact. Bronchi were visible consistently up to the fourth generation and in some cases up to the sixth generation. Mean CNR and SNR with PETRA were 32.4% ± 7.6 (standard deviation) and 322.2% ± 37.9, respectively, higher than those with VIBE (P < .001). Good agreement was found between CT and PETRA cystic fibrosis scores (κ = 1.0)., Conclusion: PETRA enables silent, free-breathing, isotropic, and submillimeter imaging of the bronchi and lung parenchyma with high CNR and SNR and may be an alternative to CT for patients with cystic fibrosis.

Rationale: Severe asthma is a major public health issue throughout the world. Increased bronchial smooth muscle (BSM) mass, a characteristic feature of airway remodeling in severe asthma, is associated with resistance to high-intensity treatment and poor prognosis. In vitro, the Ca(2+)-channel blocker gallopamil decreased the proliferation of BSM cells from patients with severe asthma., Objectives: We conducted a double-blind, randomized, placebo-controlled study to evaluate the effect of gallopamil on airway remodeling in patients with severe asthma., Methods: Subjects received either gallopamil (n = 16) or placebo (n = 15) for 1 year and were monitored for an additional 3-month period. Airway remodeling was analyzed at baseline and after treatment phase using both fiberoptic bronchoscopy and computed tomography scan. The primary end point was the BSM area. Secondary end points included normalized BSM thickness and frequency of asthma exacerbations., Measurements and Main Results: BSM area was reduced in the gallopamil group (baseline vs. end of treatment) but was unchanged in the placebo group. Between-group differences in BSM area were not significantly different in gallopamil versus placebo groups. By contrast, between-group differences in normalized BSM thickness were significantly different between the two groups. The mean number of exacerbations per month was not different during the treatment phase in gallopamil versus placebo group but was significantly lower in patients previously treated with gallopamil during the follow-up period. There were no differences between the groups with respect to overall side effects., Conclusions: Gallopamil treatment for 12 months reduces BSM remodeling and prevents the occurrence of asthma exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT 00896428).

Rationale: Asthma is a frequent airway disease, and asthma control determinants have been associated with indoor allergen sensitization. The most frequent allergens are house dust mites (HDM), which act in vivo on the bronchial epithelial layer. Severe asthma has also been associated with bronchial remodeling and more specifically with increased mass of bronchial smooth muscle (BSM). However, the relationship between HDM stimulation of the bronchial epithelial layer and BSM remodeling is unknown., Objectives: To evaluate whether epithelial stimulation with HDM induces BSM cell proliferation in subjects with severe asthma., Methods: A total of 22 subjects with severe asthma and 27 subjects with no asthma were recruited. We have developed an in vitro culture model combining an epithelium layer in air-liquid interface (ALI) interacting with BSM. We assessed BSM proliferation using BrdU incorporation. We explored the role of epithelium-derived mediators using reverse-transcriptase polymerase chain reaction (RT-PCR) and ELISA in vitro and in vivo. Finally, leukotrienes receptor expression was assessed in vitro by flow cytometry and RT-PCR and ex vivo by laser microdissection and RT-PCR., Measurements and Main Results: We found that epithelial stimulation by HDM selectively increased the proliferation of asthmatic BSM cells and not that of nonasthmatic cells. The mechanism involved epithelial protease-activated receptor-2-dependent production of leukotrienes C4 associated with an overexpression of leukotrienes receptor CysLTR1 by asthmatic BSM cells in vitro and ex vivo., Conclusions: This work demonstrates the selective role of HDM on BSM remodeling in patients with severe asthma and points out different therapeutic targets at epithelial and smooth muscle levels.

Rationale: Pulmonary hypertension (PH) is an established complication of advanced chronic obstructive pulmonary disease (COPD) associated with increased mortality. The mechanisms coupling PH and bronchial obstruction are unknown; in particular, PH appears to be unrelated to emphysema. We hypothesized that computed tomographic (CT) measurement of airway remodeling instead of emphysema may correlate with PH in COPD., Objectives: We aimed to describe the clinical and CT characteristics of patients with COPD with or without PH and to correlate CT measurements of airway remodeling and emphysema with PH., Methods: Data were retrieved from 60 COPD patients who underwent both right heart catheterization and computed tomography in a period of stability and had no other disease known to cause PH. CT measurement of airway wall thickness (WT-Pi10) was used to assess airway remodeling and low lung area percentage (LAA%) to quantify emphysema extent., Measurements and Main Results: Thirty-four of the sixty patients with COPD had PH (mean pulmonary arterial pressure [PAPm] ≥ 25 mm Hg). There was no difference between the two groups regarding age, sex, and spirometric results, whereas there was more profound hypoxemia in the PH group. WT-Pi10 was increased in the patients with COPD and PH and correlated with PAPm (ρ = 0.62; P < 0.001). Conversely, there was no difference or correlation between PAPm and LAA% (ρ = 0.12; P = 0.33). In multivariate analysis (R(2) = 0.53), WT-Pi10 was the independent predictor most associated with PAPm elevation, as compared to hypoxia (PaO2) or pulmonary arterial enlargement (diameter ratio between the pulmonary arterial truncus and the ascending aorta)., Conclusions: This study demonstrates, for the first time to our knowledge, an association between structural alterations of bronchi and PH in COPD. Unlike quantification of emphysema, CT measurement of airway remodeling correlates with PAPm and could be used to estimate the severity of PH in COPD. Airway remodeling burden is not limited to airflow limitation in the assessment of COPD severity and mortality.

Background: Mycoplasma pneumoniae has been implicated in asthma exacerbations and chronic asthma. A 2-year longitudinal study has been conducted to investigate the role of M. pneumoniae infections in 168 and 20 hospitalized children and adults, respectively, with asthma exacerbation compared with outpatients (88 children and 48 adults) with chronic asthma (without an exacerbation). The prevalence of Chlamydia pneumoniae and respiratory viruses was also assessed in these 2 populations., Methods: Lung function testing, blood sampling and microbiological testing (polymerase chain reaction, culture and serology) were performed for 256 children and 68 adults followed by a 7-week, follow-up visit with repeated blood sampling for serological testing and phone interviews at 6 and 12 months later., Results: M. pneumoniae infection was more prevalent in children with chronic asthma (13.6%) compared with children with exacerbation (7.1%), while the reverse was true in adults (6.3 vs. 10.0%, respectively). However, these differences were not statistically significant. Acute C. pneumoniae infection was identified in 3.9% of children and 7.4% adults. Children seen for chronic asthma were significantly more likely to be infected with C. pneumoniae than children hospitalized for an asthma exacerbation. Viruses were the most prevalent microorganisms detected in children with an asthma exacerbation. No differences in the outcome parameters were identified between M. pneumoniae-infected and noninfected patients., Conclusions: The present study suggests that M. pneumoniae does not play a direct role in the pathogenicity of acute or chronic asthma in most children.