Efficacy of a Non-Pharmacological Intervention in Seasonal Allergic Rhinitis Symptoms.

BACKGROUND: Patients suffering from allergic rhinitis seek for several therapeutic symptomatic options, including nonconventional treatments, to control their symptoms. OBJECTIVES: Through the present proof-of-concept study, we prospectively investigated the potential role of Puressentiel® nasal protection spray (SNPA) in patients suffering from cypress pollen allergic rhinitis. METHODS: In 15 adults, we performed two nasal provocation tests, with a cypress pollen extract, with a 15-day interval, with and without previous randomized administration of SNPA, and evaluated a nasal symptom score, the nasal inspiratory peak flow, and the concentration of inflammatory cytokines in the nasal lavage after the procedures. RESULTS: Comparing results in patients challenged with and without the SNPA spray before the nasal challenge, we found a 57% mean decrease in symptoms, and a 62% average difference in inspiratory peak flow, after the use of the spray. CONCLUSIONS: Puressentiel® SNPA is effective in reducing nasal symptoms, as assessed by nasal symptoms score and nasal inspiratory peak flow, and could be a valid natural non-pharmacological option in patients suffering from allergic rhinitis.

Proteomic profiling of serum identifies a molecular signature that correlates with clinical outcomes in COPD.

OBJECTIVE: Novel biomarkers related to main clinical hallmarks of Chronic obstructive pulmonary disease (COPD), a heterogeneous disorder with pulmonary and extra-pulmonary manifestations, were investigated by profiling the serum levels of 1305 proteins using Slow Off-rate Modified Aptamers (SOMA)scan technology. METHODS: Serum samples were collected from 241 COPD subjects in the multicenter French Cohort of Bronchial obstruction and Asthma to measure the expression of 1305 proteins using SOMAscan proteomic platform. Clustering of the proteomics was applied to identify disease subtypes and their functional annotation and association with key clinical parameters were examined. Cluster findings were revalidated during a follow-up visit, and compared to those obtained in a group of 47 COPD patients included in the Melbourne Longitudinal COPD Cohort. RESULTS: Unsupervised clustering identified two clusters within COPD subjects at inclusion. Cluster 1 showed elevated levels of factors contributing to tissue injury, whereas Cluster 2 had higher expression of proteins associated with enhanced immunity and host defense, cell fate, remodeling and repair and altered metabolism/mitochondrial functions. Patients in Cluster 2 had a lower incidence of exacerbations, unscheduled medical visits and prevalence of emphysema and diabetes. These protein expression patterns were conserved during a follow-up second visit, and substanciated, by a large part, in a limited series of COPD patients. Further analyses identified a signature of 15 proteins that accurately differentiated the two COPD clusters at the 2 visits. CONCLUSIONS: This study provides insights into COPD heterogeneity and suggests that overexpression of factors involved in lung immunity/host defense, cell fate/repair/ remodelling and mitochondrial/metabolic activities contribute to better clinical outcomes. Hence, high throughput proteomic assay offers a powerful tool for identifying COPD endotypes and facilitating targeted therapies.

Contribution of rapid lateral flow assays from capillary blood specimens to the diagnosis of COVID-19 in symptomatic healthcare workers: a pilot study in a university hospital, Paris, France.

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.

Clinical and histopathologic predictors of therapeutic response to bronchial thermoplasty in severe refractory asthma.

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/ß 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/ß 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.

IL-33-ST2 axis regulates myeloid cell differentiation and activation enabling effective club cell regeneration.

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.

Focal bronchial dilatations after thermoplasty for severe asthma.

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.

Prospective, Single-Arm, Longitudinal Study of Biomarkers in Real-World Patients with Severe Asthma.

BACKGROUND: ARIETTA was a prospective, single-arm, noninterventional, multicenter study in patients with severe asthma. OBJECTIVE: To examine the predictive and prognostic abilities of type 2 biomarkers for severe asthma outcomes. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

An IgG-induced neutrophil activation pathway contributes to human drug-induced anaphylaxis.

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.

European consensus meeting/statement on Bronchial Thermoplasty Who? Where? How?

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.

CCR10+ ILC2s with ILC1-like properties exhibit a protective function in severe allergic asthma.

BACKGROUND: 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.

Clinical and economic burden of severe asthma: A French cohort study.

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.

Characteristics of patients with severe, uncontrolled, eosinophilic asthma enrolled in a French cohort.

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 ß2-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 ß2-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 1 second 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.

Anti-parietal cell autoimmunity is associated with an accelerated decline of lung function in IPF patients.

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.

Clinical and biological characteristics of the French COBRA cohort of adult subjects with asthma.

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.

Effector and regulatory dendritic cells display distinct patterns of miRNA expression.

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 TH 1, TH 2 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.

[18F]FDG PET/CT predicts progression-free survival in patients with idiopathic pulmonary fibrosis.

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 <0.00001). For patients with IPF, SUV mean, SUV max, MLV and TLG were correlated with severity of lung involvement as measured by a decline in forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) and increased GAP score. In a univariate and in a multivariate Cox proportional-hazards model, risk of death was increased although not significantly with high SUV mean. On univariate analysis, risk of death was significantly associated with high TLG and MLV, which disappeared after adjustment functional variables or GAP index. Increased MLV and TLG were independent predictors of death or disease progression during the 12 months after PET scan completion (for every 100-point increase in TLG, hazard ratio [HR]: 1.11 (95% CI 1.06; 1.36), p = 0.003; for every 100-point increase in MLV, HR: 1.20 (1.04; 1.19), p = 0.002). On multivariable analysis including TLG or MLV with age, FVC, and DLCO or GAP index, TLG and MLV remained associated with progression-free survival (HR: 1.1 [1.03; 1.22], p = 0.01; and 1.13 [1.0; 1.2], p = 0.005). CONCLUSION: FDG lung uptake may be a marker of IPF severity and predict progression-free survival for patients with IPF.

Early computed tomography modifications following bronchial thermoplasty in patients with severe asthma.

Bronchial thermoplasty (BT) is a recent, promising and well-tolerated technique for the treatment of severe asthma. By delivering thermal energy to the airway wall, this procedure can induce early pulmonary opacities seen on computed tomography (CT). We aimed to examine early CT modifications induced by BT and to determine their association with respiratory symptoms.Unenhanced chest CT was performed the day after each BT session in 13 patients with severe asthma, leading to the examination of 38 treated lobes. A total of 15 BT-treated lobes were evaluated in 11 patients at 1 month. The first two patients also underwent CT at 1 week.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 on day 1, with three lower lobes showing complete collapse. Mild involvement of an adjacent untreated lobe was observed in 12 out of 38 (32%) cases. Opacities had decreased in 5 out of 15 (33%) and disappeared in 10 out of 15 (67%) at 1 month.BT induced early pulmonary peribronchial hyperdensities in all treated lobes. These alterations were unrelated to clinical symptoms and spontaneously decreased or disappeared after 1 month.