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Evidence points to an indispensable function of macrophages in tissue regeneration, yet the underlying molecular mechanisms remain elusive. Here we demonstrate a protective function for the IL-33-ST2 axis in bronchial epithelial repair, and implicate ST2 in myeloid cell differentiation. ST2 deficiency in mice leads to reduced lung myeloid cell infiltration, abnormal alternatively activated macrophage (AAM) function, and impaired epithelial repair post naphthalene-induced injury. Reconstitution of wild type (WT) AAMs to ST2-deficient mice completely restores bronchial re-epithelialization. Central to this mechanism is the direct effect of IL-33-ST2 signaling on monocyte/macrophage differentiation, self-renewal and repairing ability, as evidenced by the downregulation of key pathways regulating myeloid cell cycle, maturation and regenerative function of the epithelial niche in ST2−/− mice. Thus, the IL-33-ST2 axis controls epithelial niche regeneration by activating a large multi-cellular circuit, including monocyte differentiation into competent repairing AAMs, as well as group-2 innate lymphoid cell (ILC2)-mediated AAM activation., Signaling of IL-33 via its receptor, ST2, has been implicated in macrophage function in tissue repair. Here the authors show, using genetic mouse models and single-cell transcriptomic data, that the IL-33/ST2 axis regulates both ILC2-derived IL-13 and macrophage differentiation/reparative function required for club cell regeneration.

Background This study aimed to assess, by rapid tests, the immune status against COVID-19 among Healthcare Workers (HCW) with history of symptoms, and for whom SARS-CoV-2 detection was either not documented or negative. Methods Whole blood by finger prick and serum samples were taken from HCW for use with 2 rapid lateral flow tests and an automated immunoassay. Results Seventy-two HCWs were included, median duration between symptoms onset and serology sampling was 68 days. Anti-SARS-CoV-2 antibodies were detected by rapid test in 11 HCW (15.3%) and confirmed in the 10 with available serum by the automated immunoassay. The frequency of ageusia or anosmia was higher in participants with SARS-CoV-2 antibodies (P = 0.0006 and P = 0.029, respectively). Conclusions This study, among symptomatic HCW during the first wave in France, showed that 15% had IgG anti-SARS-CoV-2, a higher seroprevalence than in the general population. Rapid lateral flow tests were highly concordant with automated immunoassay.

Bronchial thermoplasty (BT) is a non-pharmacological alternative treatment for severe asthma [1, 2]. BT consists of applying radiofrequency energy to the airways that are distal to the lobar bronchi and >3 mm, to reduce airway smooth muscle mass and bronchial hyperreactivity. However, concerns have been raised about long-term safety, especially risk of bronchial stenosis or bronchiectasis. Indeed, morphological changes in bronchial tubes, such as bronchiectasis or widening of the airways, have been occasionally described during follow-up [3–7]. However, bronchial changes have not been systematically assessed by computed tomography (CT), especially in large prospective cohorts [2, 3, 8, 9]., Focal bronchial dilatations develop after bronchial thermoplasty (BT) in 58% of patients with severe asthma. This suggests a need for systematic evaluation by CT scan after BT, with specific focus on bronchial dilatation development. https://bit.ly/2AYuhMj

International audience

Michel Aubier,1–4 Gabriel Thabut,1–3,5 Caroline Fabry-Vendrand6 1Inserm UMR1152, Physiopathology and Epidemiology of Respiratory Diseases, Paris, France; 2Faculty of Medicine, Paris Diderot University, Paris, France; 3Laboratory of Excellence, INFLAMEX, Université Sorbonne Paris Cité and DHU FIRE, Paris, France; 4Pneumology A Department, Bichat-Claude-Bernard University Hospital, Paris, France; 5Pneumology B Department, Bichat-Claude-Bernard University Hospital, Paris, France; 6Epidemiology and Research Partnerships, AstraZeneca, Courbevoie, France Background and objective: Benralizumab (Fasenra™) has recently been approved as add-on maintenance treatment for adult patients with severe eosinophilic asthma inadequately controlled despite high-dosage inhaled corticosteroids plus long-acting β2-agonists. We aimed to identify and describe the clinical characteristics and disease burden of patients with severe, uncontrolled, eosinophilic asthma in France who may be eligible for treatment with benralizumab. Patients and methods: This was a retrospective analysis of a prospective, noninterventional, observational study of patients in France enrolled in the Asthma and Bronchial Obstruction Cohort (COBRA). First, we selected adult patients with severe asthma, a documented blood eosinophil count, 12 months of baseline data, and 12 months of follow-up data. Of these study-eligible patients, we next determined the prevalence and described the clinical characteristics and disease burden of patients who would be eligible to receive benralizumab, namely those with ≥2 asthma exacerbations in the previous 12 months and a blood eosinophil count ≥300/μL who were receiving high-dosage inhaled corticosteroids/long-acting β2-agonists. Results: Of the 441 patients eligible for this study, 85 (19%) met the criteria for benralizumab therapy. At study inclusion, benralizumab-eligible patients had a smaller prebronchodilator forced expiratory volume in 1second and less effective asthma control compared with benralizumab-ineligible patients. During the 12-month follow-up period, benralizumab-eligible patients had greater frequencies of asthma exacerbations and hospitalizations compared with benralizumab-ineligible patients. Conclusion: Of patients with severe asthma, approximately 20% were qualified for benralizumab treatment. Benralizumab-eligible patients had increased bronchial obstruction, worse asthma control, and a greater frequency of asthma exacerbations and hospitalizations during follow-up care compared with benralizumab-ineligible patients, demonstrating inadequate disease control for these patients. Keywords: COBRA, benralizumab, biologic, eosinophilia, France

Background Phenotypes and endotypes predicting optimal response to bronchial thermoplasty (BT) in patients with severe asthma remain elusive. Objective Our aim was to compare the clinical characteristics and hallmarks of airway inflammation and remodeling before and after BT in responder and partial responder patients with severe asthma refractory to oral steroids and to omalizumab. Methods In all, 23 patients with severe refractory asthma were divided into BT responders (n = 15) and BT partial responders (n = 8), according to the decrease in asthma exacerbations at 12 months after BT. Clinical parameters were compared at baseline and 12 months after BT, and hallmarks of airway inflammation and remodeling were analyzed by immunohistochemistry in bronchial biopsy specimens before and 3 months after BT. Results At baseline, the BT responders were around 8 years younger than the BT partial responders (P = .02) and they had a greater incidence of atopy, higher numbers of blood eosinophils (both P = .03) and IgE levels, higher epithelial IFN-α expression, and higher numbers of mucosal eosinophils and IL-33–positive cells (P ≤ .05). A reduction in blood eosinophil count, serum IgE level, type 2 airway inflammation, and numbers of mucosal IL-33–positive cells and mast cells associated with augmented epithelial MUC5AC and IFN-α/β immunostaining was noted after BT in responders, whereas the numbers of mucosal IL-33–positive cells were augmented in BT partial responders. Most of these changes were correlated with clinical parameters. Subepithelial membrane thickening and airway smooth muscle area were similar in the 2 patient groups at baseline and after BT. Conclusion By reducing allergic type 2 inflammation and increasing epithelial MUC5AC and anti-viral IFN-α/β expression, BT may enhance host immune responses and thus attenuate exacerbations and symptoms in BT responders. Instead, targeting IL-33 may provide a clinical benefit in BT partial responders.

Introduction MicroRNAs (miRNAs) contribute to the regulation of dendritic cell (DC) polarization, thereby influencing the balance of adaptive immune responses. Herein, we studied the expression of miRNAs in polarized DCs and analyzed whether expression of these miRNAs could be associated with allergic rhinitis and allergen immunotherapy (AIT) outcome. Method Using specific culture conditions, we differentiated immature human monocyte-derived DCs into DC1, DC2, and DCreg subsets (supporting the differentiation of TH1, TH2 or regulatory T cells, respectively). Profiling of miRNA expression was performed in these DC subpopulations using microarrays. Levels of miRNAs specific for polarized DCs were then evaluated in a cohort of 58 patients with allergic rhinitis and 25 non-allergic controls, as well as in samples from 30 subjects treated with sublingual grass pollen tablets or placebo for four months. Results We successfully identified 16 miRNAs differentially regulated between immature DCs, DC1, DC2, and DCreg cells. In allergic rhinoconjunctivitis patients, the expression of two of those miRNAs (miR-132 and miR-155), was down-regulated compared to non-allergic individuals. However, the levels of these miRNAs were not significantly modified following four months of grass pollen immunotherapy. Conclusions Studying polarized DCs and clinical samples from subjects with or without allergic rhinoconjunctivitis, we demonstrated that the expression of two miRNAs linked to effector DCs (i.e., DC1 and/or DC2 cells), was reduced in the blood of patients with allergic rhinoconjunctivitis. Nevertheless, these miRNAs did not represent relevant biomarkers to predict or follow-up AIT efficacy.

Background Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by an unpredictable course. Prognostic markers and disease activity markers are needed. The purpose of this single-center retrospective study was to evaluate the prognostic value of lung fluorodeoxyglucose ([18F]-FDG) uptake assessed by standardized uptake value (SUV), metabolic lung volume (MLV) and total lesion glycolysis (TLG) in patients with IPF. Methods We included 27 IPF patients (IPF group) and 15 patients with a gastrointestinal neuroendocrine tumor without thoracic involvement (control group). We quantified lung SUV mean and SUV max, MLV and TLG and assessed clinical data, high-resolution CT (HRCT) fibrosis and ground-glass score; lung function; gender, age, physiology (GAP) stage at inclusion and during follow-up; and survival. Results Lung SUV mean and SUV max were higher in IPF patients than controls (p

Introduction La thermoplastie bronchique (TB) est une technique endobronchique pour le traitement des asthmes severes, qui consiste a delivrer dans les parois des bronches, de calibres superieurs a 3 mm, une energie thermique controlee. Plusieurs etudes ont montre son efficacite sur le controle et les exacerbations de l’asthme. L’application de chaleur (65 °C) sur la muqueuse pose la question de l’induction de lesions de la paroi bronchique avec apparition de stenose ou de bronchectasies. L’objectif de ce travail est de decrire chez les patients traites dans notre centre les modifications bronchiques observees a distance de la procedure et d’en evaluer l’impact sur la reponse clinique. Methodes Etude retrospective incluant 26 patients asthmatiques severes suivis sur une periode moyenne de 31 ± 20 mois, ayant beneficie d’une TB et d’au moins un scanner avant et apres traitement. Les scanners ont ete analyses visuellement en aveugle par 3 operateurs dont un radiologue specialise. Resultats Une ou plusieurs dilatations de bronches (DDB) focales sont apparues chez 15 (58 %) des patients et une augmentation globale du calibre des bronches a ete observee chez 3 (11,5 %) des patients apres TB. Le nombre de DDB focales etait en moyenne de 4 ± 2,7 par patient, localisees dans le lobe inferieur gauche dans 40 % des cas et le lobe superieur droit dans 30 %. Leur diametre moyen etait de 4,5 ± 0,9 mm et elles etaient stables lors des scanners successifs chez 86 % des patients. Le nombre d’activations etait equivalent chez les patients ayant developpe ou non des DDB focales. La reponse clinique a 12 mois n’etait pas differente entre les deux groupes en termes d’amelioration du score ACT (+4,8 ± 2,4 versus + 7,3 ± 2,1, p = 0,4), de reduction du nombre d’exacerbations (−51 ± 15 % versus −19 ± 33 %, p = 0,4), de variation du VEMS (−0,04 ± 0,1, p > 0,9), de proportion de patients sous corticoides oraux sevres (25 % versus 22 % des patients, p = 0,9). La survenue d’hemoptysie (chez 1 patient sur 15 soit 6 % versus 1 sur 11 soit 9 %, p = 0,8) ou d’infection respiratoire (chez 4 patients sur 10 soit 40 % versus 2 sur 9 soit 22 %, p = 0,22) a 12 mois etait equivalente. Conclusion Des modifications bronchiques focales sont observees chez la moitie des patients apres TB. Ces modifications ne semblent pas modifier la reponse clinique ni s’accompagner de complications.

Background: Bronchial Thermoplasty (BT) reduces exacerbations and improves asthma quality of life questionnaire (AQLQ) scores in asthma [1]. Studies have shown reductions in airway smooth muscle (ASM) mass and reticular basement membrane (RBM) thickness after BT, but are limited by small sample size. Aims: To investigate airway remodeling responses to BT, and compare these to clinical outcomes. Methods: Pre- and post-BT data was pooled for 99 patients at 7 centres. ASM mass and RBM thickness were measured on bronchial biopsies, and compared to clinical outcomes. Results: Mean (SD) age was 48.4 years (11.7) and BMI was 29.0 kg/m2 (6.4). Baseline FEV1 was 68.8% predicted (23.1) and blood eosinophils were 0.25x10-9/L (0.26). 59 of 99 patients were taking maintenance oral Prednisolone (mean dose 25.7mg). In response to BT, mean (SD) annual exacerbation rate decreased from 6.4 (5.5) to 1.1 (1.7) (p= Conclusion: ASM mass and RBM thickness reduce rapidly following BT, and effects persist beyond 1 year. The observed improvements in airway remodeling parameters are not related to improvements in clinical outcomes. Other bronchial mucosal changes or mechanisms may play a role in the clinical response to BT. Reference: 1) Castro et al, AJRCCM. 2010;181(2):116-24

ARIETTA was a prospective, single-arm, noninterventional, multicenter study in patients with severe asthma.To examine the predictive and prognostic abilities of type 2 biomarkers for severe asthma outcomes.Adult patients with severe asthma receiving daily inhaled corticosteroids (fluticasone propionate ≥500 μg or equivalent) and ≥1 second controller medication were enrolled. Biomarker, clinical, and safety data were collected over 52 weeks. The primary endpoint was the asthma exacerbation rate over 52 weeks in serum periostin-high (≥50 ng/mL at baseline) versus periostin-low subgroups (50 ng/mL). Correlations between biomarker levels (periostin, blood eosinophils, IgE, and fractional exhaled nitric oxide [FeNO]) and between central and local laboratory measurements (blood eosinophils and IgE) were assessed. The study was terminated before planned enrollment was completed.Of 465 patients, 66.5% were female, 13.3% were receiving oral corticosteroids, 42.4% had ≥1 exacerbation in the previous year, 52.0% were periostin-high, and 87.5% had type 2 inflammation (blood eosinophils ≥150 cells/μL and/or FeNO ≥25 ppb and/or positive skin allergen test). Biomarker levels correlated poorly with each other. Central and local laboratory blood eosinophil and IgE measurements generally agreed. No difference was observed in exacerbation rates over 52 weeks between periostin-high and periostin-low patients (rate ratio, 0.93; 95% confidence interval, 0.67-1.28; P = .642). Results suggested higher exacerbation rates in patients with blood eosinophils ≥300 cells/μL and FeNO ≥25 ppb.No prognostic value for serum periostin related to exacerbations was detected. Higher blood eosinophils combined with increased FeNO were potentially associated with increased exacerbation rates.

International audience; We previously showed that patients with severe allergic asthma have high numbers of circulating ILC2s expressing CCR10.METHOD:Herein, CCR10+ ILC2s were further analyzed in the blood of healthy individuals or patients with allergic and non-allergic asthma. Characteristics of human CCR10+ and CCR10- ILC2s were assessed by flow cytometry as well as single-cell multiplex RT-qPCR. The role of CCR10+ ILC2s in asthma pathophysiology was studied in allergen-treated mice.RESULTS:When compared to healthy controls, CCR10+ ILC2s are enriched in the blood of both allergic and non-allergic severe asthmatic patients, and these cells are recruited to the lungs. Plasma concentrations of the CCR10 ligand CCL27 are significantly increased in severe asthmatics when compared to non-asthmatic patients. CCR10+ ILC2s secrete little TH 2 cytokines, but exhibit ILC1-like properties, including a capacity to produce IFN-γ. Also, single-cell analysis reveals that the CCR10+ ILC2 subset is enriched in cells expressing amphiregulin. CCR10+ ILC2 depletion, as well as blocking of IFN-γ activity, exacerbates airway hyperreactivity in allergen-challenged mice, providing evidence for a protective role of these cells in allergic inflammation.CONCLUSIONS:Frequencies of circulating CCR10+ ILC2s and CCL27 plasma concentrations represent candidate markers of asthma severity. The characterization of CCR10+ ILC2s in human samples and in mouse asthma models suggests that these cells downregulate allergic inflammation through IFN-γ production.

International audience; Anaphylaxis is a systemic acute hypersensitivity reaction that is considered to depend on allergen-specific immunoglobulin E (IgE) antibodies and histamine release by mast cells and basophils. Nevertheless, allergen-specific IgG antibodies have been proposed to contribute when the allergen is an abundant circulating large molecule, e.g., after infusions of therapeutic antibodies or dextran. Data from animal models demonstrate a pathway involving platelet-activating factor (PAF) release by monocytes/macrophages and neutrophils activated via their Fc gamma receptors (FcγRs). We hypothesized that such a pathway may also apply to small drugs and could be responsible for non-IgE-mediated anaphylaxis and influence anaphylaxis severity in humans. We prospectively conducted a multicentric study of 86 patients with suspected anaphylaxis to neuromuscular-blocking agents (NMBAs) during general anesthesia and 86 matched controls. We found that concentrations of anti-NMBA IgG and markers of FcγR activation, PAF release, and neutrophil activation correlated with anaphylaxis severity. Neutrophils underwent degranulation and NETosis early after anaphylaxis onset, and plasma-purified anti-NMBA IgG triggered neutrophil activation ex vivo in the presence of NMBA. Neutrophil activation could also be observed in patients lacking evidence of classical IgE-dependent anaphylaxis. This study supports the existence of an IgG-neutrophil pathway in human NMBA-induced anaphylaxis, which may aggravate anaphylaxis in combination with the IgE pathway or underlie anaphylaxis in the absence of specific IgE. These results reconcile clinical and experimental data on the role of antibody classes in anaphylaxis and could inform diagnostic approaches to NMBA-induced acute hypersensitivity reactions.

Background Bronchial Thermoplasty (BT) is a bronchoscopic treatment for severe asthma. Following research trials there remains a need to guide BT treatment in clinical practice, specifically in the fields of patient assessment, selection and positioning of BT within the range of treatment modalities, BT treatment protocols and post-BT management and follow-up. Consensus statements can bridge the gap between evidence-based medicine and real world clinical practice. Methods We performed a modified RAND consensus analysis using a baseline list of statements derived from ATS/ERS Guidelines on Severe Asthma, Cochrane review and UK commissioning guidance. A panel of 5 European BT experts, individually scored the statements and following a day of discussion, rescored a revised final list independently. Results An initial list of 132 statements, were independently scored. These were modified to 108 following group discussion. Consensus/total agreement was reached for 68 (63%) of the statements; 8 (7.4%) statements achieving total disagreement. For only 17 statements, could some form of consensus not be achieved. Conclusions The consensus document could be applied to guide BT clinical practice and used to serve as a minimum acceptable level of assessment for BT, drive the development of clinical practice protocols and help define quality indicators

Objective To describe a new entity characterized by airway-centered fibroelastosis. Methods We identified cases with prominent airway-centered elastosis in lung samples, and little or no pleural involvement identified through a pathologic database at a single institution over an 8-year period. Results Airway-centered fibroelastosis was characterized by (1) extensive airway-centered fibroelastosis of the upper lobes on histopathology and (2) marked bronchial abnormalities with bronchial wall thickening, bronchial wall deformation, and bronchiectasis, along with progressive parenchymal retraction and predominantly subpleural upper-lobe consolidations on high-resolution CT. Pateints were five nonsmoking women aged between 38 and 56 years old. They experienced chronic dyspnea with acute attacks of wheezing and dyspnea. Moderate to severe physiological abnormalities were observed, with an obstructive pattern in three cases and a restriction in two. Despite inhaled and oral corticosteroids, the disease was progressive in all patients and evolved to chronic respiratory failure, requiring lung transplantation in two patients. Four patients had chronic asthma. Conclusions We consider airway-centered fibroelastosis to be a unique and distinct pathological entity in women that needs to be individualized, with a specific clinical, imaging, and pathological presentation. We hypothesize that airway-centered fibroelastosis may be idiopathic or asthma-associated.

Resume Introduction L’omalizumab, un anticorps monoclonal bloquant les immunoglobulines E, a depuis maintenant dix ans une autorisation de mise sur le marche dans l’asthme severe atopique de l’adulte, en cas de mauvais controle malgre de fortes doses de corticoides inhales associes a des bronchodilatateurs de longue duree d’action. Il s’agit de la premiere biotherapie utilisee a large echelle dans l’asthme severe. Etat des connaissances L’omalizumab a prouve un benefice, notamment dans la prevention des exacerbations severes d’asthme et ce, avec un profil de tolerance tres satisfaisant. Il s’agit d’une alternative interessante a considerer, malgre son cout, face aux complications a long terme de la corticotherapie orale continue. Perspectives Ces dix ans d’utilisation sont l’occasion de faire le point sur le mecanisme d’action de l’omalizumab, le benefice a en attendre, les effets secondaires ainsi que le rapport cout–efficacite de cette molecule. On rappelle egalement les modalites pratiques d’utilisation de l’omalizumab, notamment l’importance d’une evaluation rigoureuse de son efficacite a 16 semaines de traitement. Les futures indications de cette therapeutique sont egalement abordees. Conclusion L’omalizumab a prouve aussi bien dans des etudes randomisees de grande ampleur que dans des etudes de « vraie vie » son interet dans l’asthme severe allergique.

Objective To describe the clinical and economic burden of severe asthma in France over 12 months. Methods Data were retrieved from the observational, prospective “Cohorte Obstruction Bronchique et Asthme” (COBRA) cohort, which has enrolled nearly 1000 asthma patients since 2007 from throughout France. Patients undergoing treatment with GINA step-4 or 5 medications uninterruptedly for 12 months (thus defining “severe asthma”) were identified and their clinical data used to describe the clinical burden of asthma (exacerbations, symptoms outside exacerbations, and level of asthma control). Patients’ utilization of healthcare resources was described and used to estimate the direct medical costs incurred to treat severe asthma. Results 155 patients were included in the present study. Over the 12-month period of interest, 128 (83%) patients experienced at least one asthma exacerbation, 22 (14%) patients were hospitalized for asthma, 133 (86%) patients experienced continuous symptoms outside exacerbations, and 77 (50%) patients experienced important limitations in daily life activities. The median number of asthma-related drugs used was 4. The mean estimated annual asthma-related cost was 8,222 euros (standard deviation, SD = 11,886), including 7,229 euros (SD = 11,703) for controller medications. Conclusion Symptoms outside exacerbation periods are highly prevalent in severe asthma patients, for whom the main driver of medical costs is controller medication.

We previously showed that patients with severe allergic asthma have high numbers of circulating ILC2s expressing CCR10.Herein, CCR10When compared to healthy controls, CCR10Frequencies of circulating CCR10

Many inflammatory conditions, such as asthma, show circadian symptoms that are worse at night. Delayed-release prednisone was developed for bedtime administration to optimize inhibition of nocturnally elevated pro-inflammatory cytokines. A proof-of-concept study was undertaken to examine the impact of delayed-release prednisone on nocturnal awakenings in patients with asthma requiring treatment with oral steroids. In this single-center, open-label study, patients receiving long-term treatment with conventional prednisone administered at 08:00 h were switched to 4 weeks of treatment with the same dose of delayed-release prednisone given at 22:00 h. The primary efficacy endpoint was the change in number of nocturnal awakenings during the final 2 weeks of each treatment phase. Seven patients received treatment with delayed-release prednisone. Mean nocturnal awakenings because of asthma decreased from 10.0 ± 5.45 with conventional prednisone to 2.1 ± 4.41 with delayed-release prednisone, a mean reduction of −7.9 ± 6.07 (82.7% reduction). Delayed-release prednisone was generally well tolerated, and there were no unexpected safety findings. Although the size of the efficacy population was too small to detect any statistically significant changes in nocturnal asthma control, this proof-of-concept study suggests that nighttime administration of delayed-release prednisone provides better asthma symptom control compared with morning administration of conventional prednisone. Horizon Pharma, Inc (formerly Nitec Pharma GmbH).

Epicardial fat necrosis is a rare cause of benign chest pain. Its physiopathological mechanism is unknown. Diagnosis is easily performed through radiological investigations that show a round opacity of fat density limited by a dense pseudo-capsule in the anterior mediastinum, close to the heart.

Bronchial thermoplasty is a recent endoscopic technique for the treatment of severe asthma. It is an innovative treatment whose clinical efficacy and safety are beginning to be better understood. Since this is a device-based treatment, the evaluation procedure of risks and benefits is different that for pharmaceutical products; safety aspects, regulatory requirements, study design and the assessment of the magnitude of effects may all be different. The mechanism of action and optimal patient selection need to be assessed further in rigorous clinical and scientific studies. This technique is in harmony with the development of personalised medicine in the 21st century. It should be developed further in response to the numerous challenges and needs not yet met in the management of severe asthma.

Major risks associated with asbestos exposure (mesothelioma, lung cancer and asbestosis) have been knownfor a long time. Various clinical and epidemiological studies, which include assessment of risk of developing cancer after discovering atypical computer-tomography (CT) images or pleural plaques in persons who had been exposed to asbestos, are still ongoing, however. This short report updates the risk of occupational exposure in 2014, the consequences of the former occupational exposures, the scale of compensation and recent legal dispositions intended to reduce the risk of occupational and non-professional exposure in France.

Bronchial thermoplasty is a young yet promising treatment for severe asthma whose benefit for long-term asthma control outweighs the short-term risk of deterioration and hospitalisation in the days following the treatment. It is an innovative treatment whose clinical efficacy and safety are beginning to be better understood. Since this is a device-based therapy, the overall evaluation of risk–benefit is unlike that of pharmaceutical products; safety aspects, regulatory requirements, study design and effect size assessment may be unfamiliar. The mechanisms of action and optimal patient selection need to be addressed in further rigorous clinical and scientific studies. Bronchial thermoplasty fits in perfectly with the movement to expand personalised medicine in the field of chronic airway disorders. This is a device-based complimentary asthma treatment that must be supported and developed in order to meet the unmet needs of modern severe asthma management. The mechanisms of action and the type of patients that benefit from bronchial thermoplasty are the most important challenges for bronchial thermoplasty in the future.

More than one mechanism may cause early and transient opacities in non-BT-treated lung zones http://ow.ly/3nfB30gzEpS

Introduction and Aim: As recognition of asthma heterogeneity increases and targeted treatment options are introduced, the future role of biomarkers (BM) in patient (pt) selection, monitoring and risk prediction will be important. We report baseline demographic and clinical characteristics from ARIETTA, an ongoing, prospective, longitudinal study assessing the relationship between BM and disease-related health outcomes in the real world. Methods: Pts with severe asthma (GINA steps 4-5) receiving daily inhaled corticosteroids (CS; fluticasone propionate ≥500 μg or equivalent) and ≥1 second controller medication were enrolled. Study enrollment is now complete. BM, clinical characteristics and safety data will be collected over 52 weeks of the study. The primary endpoint is asthma exacerbation rate from baseline to week 52 in pts with high periostin (≥50 ng/mL) vs low periostin ( Results: 463 pts from 84 sites in 13 countries were enrolled and are included in the analyses; 306 (66.1%) were female. LABA, LTRA and LAMA were the most frequent second controllers, with 12.3% of pts receiving oral CS. 42.5% of pts had ≥1 exacerbation in the previous year. 51.8% had periostin ≥50 ng/mL, 33.9% had eosinophils ≥300 109/L and 42.1% had FeNO ≥25 ppb. Conclusions: This study design is capturing BM phenotypes and treatment patterns in real-world pts with severe asthma who may be considered for new targeted therapies.

The COhort of BRonchial obstruction and Asthma (COBRA) is a longitudinal cohort that involves 12 French academic institutions. DNA, serum samples and clinical data are collected at entry and every 6 months thereafter. Of 1080 patients with asthma recruited between 2007 and 2015, 401 had mild/moderate and 613 had severe asthma. In cross-sectional analyses, compared with patients with milder disease, patients with severe asthma had more symptoms, exacerbations, hospitalisations and visits to the emergency department during the preceding 12 months, higher numbers of blood eosinophils, and more comorbidities. More than 60% of patients with severe asthma were therapy-uncontrolled at entry, and 152 of them were being treated with omalizumab. In addition, patients with asthma who had the highest eosinophilia levels (>300/mm3) had shorter asthma duration, lower lung function, and higher rates of severe exacerbations and unacceptable asthma control than patients with lower eosinophil counts. Longitudinal analyses performed in 427 patients with asthma with at least three differential blood cell counts demonstrated that both eosinophil numbers and eosinophil increase over time were associated with the number of exacerbations occurring until the next visit and with Juniper score. Studies with the COBRA cohort will help to improve knowledge concerning the risk and biological factors associated with asthma severity and to better understand their influence on the disease trajectory., The COBRA cohort will be a useful tool to characterise asthma phenotypes and to identify associated biomarkers http://ow.ly/10HX30d71vG

Background Autoantibodies against lung epithelial antigens are often detected in patients with Idiopathic Pulmonary Fibrosis (IPF). Anti-Parietal Cell Antibodies (APCA) target the H+/K+ATPase (proton pump). APCA prevalence and lung H+/K+ATPase expression was never studied in IPF patients. Methods We retrospectively collected clinical, lung function and imaging data from APCA positive patients (APCA+IPF) and compared them with APCA negative IPF patients matched on the date of diagnostic assessment. H+/K+ATPase expression was assessed with immunohistochemistry and PCR. Results Among 138 IPF patients diagnosed between 2007 and 2014 and tested for APCA, 19 (13.7%) APCA+ patients were identified. APCA+IPF patients were 16 men and 3 women, mean age 71 years. The median titer of APCA was 1:160. A pernicious anemia was present in 5 patients and preceded the fibrosis in 3 cases. With a mean follow up of 31 months, 2 patients had an exacerbation and 7 patients died. As compared with 19 APCA- IPF patients, APCA+IPF patients had a less severe disease with better DLCO (57% vs 43% predicted), preserved PaO2 (85 ± 8 mmHg vs 74 ± 11 mmHg), a lower rate of honeycombing on HRCT (58% vs 89%), but they experienced an accelerated decline of FVC (difference 61.4 ml/year; p = .0002). The H+/K+ATPase was strongly expressed by hyperplastic alveolar epithelial cells in the fibrotic lung. Conclusion Anti-parietal cell autoimmunity is detected in some IPF patients and is associated with an accelerated decline of lung function. Anti-parietal cell autoimmunity may promote lung fibrosis progression.

Background: Nitrogen dioxide (NO2), a ubiquitous atmospheric pollutant, may enhance the asthmatic response to allergens through eosinophilic activation in the airways. However, the effect of NO2 on inflammation without allergen exposure is poorly studied. Objectives: We investigated whether repeated peaks of NO2, at various realistic concentrations, induce changes in airway inflammation in asthmatics. Methods: Nineteen nonsmokers with asthma were exposed at rest in a double-blind, crossover study, in randomized order, to 200 ppb NO2, 600 ppb NO2, or clean air once for 30 min on day 1 and twice for 30 min on day 2. The three series of exposures were separated by 2 weeks. The inflammatory response in sputum was measured 6 hr (day 1), 32 hr (day 2), and 48 hr (day 3) after the first exposure, and compared with baseline values measured twice 10–30 days before the first exposure. Results: Compared with baseline measurements, the percentage of eosinophils in sputum increased by 57% after exposure to 600 ppb NO2 (p = 0.003) but did not change significantly after exposure to 200 ppb. The slope of the association between the percentage of eosinophils and NO2 exposure level was significant (p = 0.04). Eosinophil cationic protein in sputum was highly correlated with eosinophil count and increased significantly after exposure to 600 ppb NO2 (p = 0.001). Lung function, which was assessed daily, was not affected by NO2 exposure. Conclusions: We observed that repeated peak exposures of NO2 performed without allergen exposure were associated with airway eosinophilic inflammation in asthmatics in a dose-related manner. Citation: Ezratty V, Guillossou G, Neukirch C, Dehoux M, Koscielny S, Bonay M, Cabanes PA, Samet JM, Mure P, Ropert L, Tokarek S, Lambrozo J, Aubier M. 2014. Repeated nitrogen dioxide exposures and eosinophilic airway inflammation in asthmatics: a randomized crossover study. Environ Health Perspect 122:850–855; http://dx.doi.org/10.1289/ehp.1307240

Asthma is a chronic inflammatory airway disorder that leads to symptoms such as coughing, wheezing and chest tightness. Typical features of asthma are chronic airway inflammation and remodeling, leading to airway obstruction. The airway epithelium is considered as an essential controller of inflammatory, immunological and regenerative responses to allergens. Abnormal molecular crosstalk between bronchial epithelial and immune cells plays an important role in driving chronic inflammation and airway remodeling. Drugs that selectively inhibit crucial aspects of epithelial-immune or epithelial-mesenchymal interactions could potentially prevent these processes.

Introduction Dans la population adulte francaise, la prevalence de l’asthme est estimee approximativement a 7 % ; environ 10 % des asthmatiques ont un asthme severe, avec une morbidite plus elevee et un besoin plus important de recours aux soins. Le benralizumab est un anticorps monoclonal, humanise, non fucosyle, ciblant le recepteur α de l’interleukine 5. Dans les etudes de phase III, le benralizumab a conduit a une diminution significative des exacerbations d’asthme, une augmentation du fonction pulmonaire et une amelioration du controle de l’asthme chez les patients avec un asthme severe a eosinophiles, non controle. L’objectif de cette etude etait d’evaluer la prevalence des patients susceptibles d’etre traites par benralizumab et de definir leurs caracteristiques cliniques. Methodes La cohorte obstruction bronchique et asthme (COBRA) est une cohorte francaise de patients suivis tous les 6 mois pendant 10 ans. Les patients inclus dans cette analyse etaient des adultes avec un asthme severe (GINA 4/5), un dosage d’eosinophiles sanguins documente et des donnees disponibles sur 24 mois (12 mois avant et apres l’inclusion). L’extraction des donnees a eu lieu le 9 decembre 2015. Les patients susceptibles de recevoir du benralizumab etaient definis par ≥ 2 exacerbations dans les 12 mois precedents, un taux d’eosinophiles sanguins ≥ 300/μL et un traitement par forte dose de corticoides inhales/β-2-agoniste de longue duree d’action a l’entree dans la cohorte. Resultats La base de donnees COBRA incluait 1081 patients. Parmi les 441 patients remplissant les criteres d’inclusion de cette analyse, 85 (19,3 %) repondaient aux criteres d’eligibilite du benralizumab. A l’inclusion dans l’etude, les patients eligibles au benralizumab comparativement a ceux ne remplissant pas les criteres d’eligibilite avaient un VEMS moins eleve (69,8 % de la valeur predite [deviation standard (DS) 18,3] vs 74,4 % [DS 22,9]) et un moins bon controle de l’asthme (optimal dans 4,7 % vs 19,5 %). Pendant la periode de suivi de 12 mois, la population eligible au benralizumab vs la non-eligible presentait une frequence plus elevee d’exacerbations d’asthme (3,9 [DS 8,6] vs 2,5 [DS 6,3]) et d’hospitalisations (0,19 [DS 0,66] vs 0,11 [DS 0,48]). Conclusion Environ 20 % des asthmatiques severes etaient eligibles au benralizumab et se caracterisaient par une obstruction bronchique plus importante, un plus mauvais controle de l’asthme et une frequence plus elevee d’exacerbations et d’hospitalisations pendant la periode de suivi.

Background Omalizumab has been shown to decrease the risk of hospitalization or ED visits in patients with uncontrolled severe allergic asthma compared with placebo. This longitudinal study observed the conditions under which omalizumab is prescribed in real-life settings and assessed whether its use as an add-on therapy alongside standard treatments decreases the risk of severe asthmatic exacerbations. Methods A cohort of adult patients with uncontrolled severe asthma despite optimal treatment with inhaled and oral corticosteroids and a long-acting β 2 -agonist but no treatment with omalizumab upon entry was assembled. Risk of hospitalization or ED visits for asthma exacerbation was assessed using the Andersen-Gill extension of the Cox model for repeated events, controlling for age, sex, smoking history, BMI, gastroesophageal reflux, allergic status, allergic rhinitis, treatment, and hospitalization or ED visits for asthma in the 2 months prior to omalizumab treatment. Results Overall, 163 physicians recruited 767 patients, of whom 374 took omalizumab at least once (mean observation period, 20.4 months). Omalizumab use was associated with an adjusted relative risk of 0.57 (95% CI, 0.43-0.78) for hospitalization or ED visits for asthma. In users of omalizumab, the adjusted relative risk of hospitalization or ED visits for asthma during omalizumab treatment vs nontreatment periods was 0.40 (95% CI, 0.28-0.58). Conclusions Add-on omalizumab is associated with a significantly decreased risk of hospitalization or ED visits in patients with uncontrolled severe asthma in real-life practice.

Introduction: Bronchial thermoplasty (BT) is a recent promising and well tolerated technique for the treatment of severe asthma. It acts by delivering thermal energy to airway walls and may induce pulmonary opacities on CT in the immediate post procedural time as previously reported (Pretolani M et al. AJRCCM 2014;190:1452-4). Aims and objectives: To examine early CT modifications following BT and to determine their association with respiratory symptoms. Background: Unenhanced chest CT was systematically performed the day after each BT session (ALAIR® device, Boston Scientific, Natick, MA, USA) in 13 severe asthmatics, leading to 38 treated lobes evaluated on day 1. In 11 patients, 15 BT-treated lobes were evaluated at 1 month. The first 2 patients had also a follow-up CT performed at 1 week. Background: No symptoms suggestive of pulmonary infection were noted following BT in any patient. Peribronchial consolidations and ground-glass opacities were observed in all treated lobes the day after BT, with 3 lower lobes showing complete collapse. Mild involvement of an adjacent untreated lobe was observed in 12/38 (32%) cases. Opacities had decreased in 5/15 (33%) and disappeared in 10/15 (67%) treated lobes at 1 month. Conclusion: BT induced early (24 h) pulmonary peribronchial hyperdensities in all treated lobes. These alterations were unrelated to clinical symptoms and they spontaneously decreased or disappeared after 1 month. These findings suggest that BT can promote lung inflammation or edema and that this effect extends to an adjacent untreated lobe, in approximately one third of cases.

Introduction: In spite of treatment advances, many asthma patients remain undertreated or with reduced quality of life. A multi-country study was conducted to identify challenges across the asthma patient9s care path, with a focus on severe asthma (SA) Aim & Objectives: To examine SA care in France, Germany, United Kingdom & Canada, in order to identify factors which may interfere with optimal SA diagnosis, treatment & management. Methods: This IRB-approved study included multiple data sources: 1) literature review, 2) input from co-authors & 3) virtual focus groups/interviews with: Specialists (Respirologists/Pneumologists), General Practitioners (GPs), Healthcare Administrators (HC), Policy Influencers (PI) & Patient Advocates (PA). Data sources were integrated to obtain a comprehensive understanding of factors perceived to undermine optimal SA care. Results: 117 participants were enrolled; Specialists (n=55), GPs (n=31), HCs (n=11), PIs (n=16) & PAs (n=4). Four themes were identified across all countries representing challenges in SA care: 1) diagnosis, 2) follow-up/reassessment, 3) referral to specialists & 4) awareness and integration of new treatment options. Underlying causes were identified including gaps in SA knowledge & skills, attitudinal barriers (e.g. patient stigmatisation, patient/provider complacency) & organization of SA healthcare. Conclusions: Common challenges were identified in SA care in all 4 countries, with similar observations made regarding asthma care in general. Findings emphasize the need for discussion of these factors which are common to different healthcare systems & cultures. Targeted awareness, education & policy change may represent solutions.

Major risks associated with asbestos exposure (mesothelioma, lung cancer and asbestosis) have been knownfor a long time. Various clinical and epidemiological studies, which include assessment of risk of developing cancer after discovering atypical computer-tomography (CT) images or pleural plaques in persons who had been exposed to asbestos, are still ongoing, however. This short report updates the risk of occupational exposure in 2014, the consequences of the former occupational exposures, the scale of compensation and recent legal dispositions intended to reduce the risk of occupational and non-professional exposure in France.

The role of autoimmunity targeting epithelial antigens in asthma has been suggested, in particular in non-atopic and severe asthma. Periplakin, a desmosomal component, is involved in epithelial cohesion and intracellular signaling. We detected anti-periplakin IgG antibodies in 47/260 (18 %) patients with asthma, with no association with severity or atopy. In addition, anti-periplakin IgE antibodies were detected in 12 of 138 tested patients (8.7 %) and were more frequently observed in patients with than without nasal polyposis. This study identifies a new autoimmune epithelial target in asthma. Whether periplakin autoimmunity (both IgG and IgE auto-antibodies) is involved in asthma pathogenesis remains to be studied during the disease course of these patients.

Background The effectiveness of bronchial thermoplasty (BT) has been reported in patients with severe asthma, yet its effect on different bronchial structures remains unknown. Objective We sought to examine the effect of BT on bronchial structures and to explore the association with clinical outcome in patients with severe refractory asthma. Methods Bronchial biopsy specimens (n = 300) were collected from 15 patients with severe uncontrolled asthma before and 3 months after BT. Immunostained sections were assessed for airway smooth muscle (ASM) area, subepithelial basement membrane thickness, nerve fibers, and epithelial neuroendocrine cells. Histopathologic findings were correlated with clinical parameters. Results BT significantly improved asthma control and quality of life at both 3 and 12 months and decreased the numbers of severe exacerbations and the dose of oral corticosteroids. At 3 months, this clinical benefit was accompanied by a reduction in ASM area (median values before and after BT, respectively: 19.7% [25th-75th interquartile range (IQR), 15.9% to 22.4%] and 5.3% [25th-75th IQR], 3.5% to 10.1%, P P = 0.02), submucosal nerves (1.0 ‰ [25th-75th IQR, 0.7-1.3 ‰] immunoreactivity and 0.3 ‰ [25th-75th IQR, 0.1-0.5 ‰] immunoreactivity, P 2 and 62.7 [25th-75th IQR, 0.0-230.3] immunoreactive pixels per mm 2 , P = .02), and epithelial neuroendocrine cells (4.9/mm 2 [25th-75th IQR, 0-16.4/mm 2 ] and 0.0/mm 2 [25th-75th IQR, 0-0/mm 2 ], P = .02). Histopathologic parameters were associated based on Asthma Control Test scores, numbers of exacerbations, and visits to the emergency department (all P ≤ .02) 3 and 12 months after BT. Conclusion BT is a treatment option in patients with severe therapy-refractory asthma that downregulates selectively structural abnormalities involved in airway narrowing and bronchial reactivity, particularly ASM, neuroendocrine epithelial cells, and bronchial nerve endings.