Real-Life Effectiveness of Benralizumab, Mepolizumab and Omalizumab in Severe Allergic Asthma Associated with Nasal Polyps.

Biological therapies are available for the treatment of the severe allergic asthma (SAA) with blood eosinophil count ≥ 0.3 × 109/L. Several of them also showed benefits on nasal polyps (NP), one of the most frequent comorbidities of the severe asthma, but comparative studies on their effectiveness in the association SAA-NP are currently lacking. The aim of this study is to compare the effectiveness of benralizumab, mepolizumab and omalizumab in patients with SAA-NP in real-life settings. A retrospective, observational, multicenter real-life study was realized including patients with SAA-NP treated by benralizumab, mepolizumab or omalizumab for 6 months. We analysed the nasal and respiratory symptoms, the number of asthma attacks and salbutamol use/week, acute sinusitis and severe exacerbation rates, the asthma control score, the lung function parameters, the NP endoscopic score, the sinus imaging and the blood eosinophil count 6 months before and after treatment. Seventy-two patients with SAA-NP were included: 16 treated by benralizumab, 21 by mepolizumab and 35 by omalizumab. After 6 months of treatment, almost all studied parameters were improved (except sinus imaging) with a greater effect of omalizumab on the nasal pruritus (p = 0.001) and more benefits of benralizumab on exacerbations rate, asthma attacks per week and lung function (all p < 0.05). Benralizumab and mepolizumab were more effective to improve the NP endoscopic score and the blood eosinophil count (both p < 0.001). All three biological therapies showed effectiveness by improving asthma and nasal outcomes in patients with SAA-NP. Several differences have been found that should be confirmed by larger comparative studies.

Prevalence of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis and Spatial Association With Quarries in a Region of Northeastern France: A Capture-Recapture and Geospatial Analysis.

OBJECTIVE: Silica is an environmental substance strongly linked with autoimmunity. The aim of this study was to assess the prevalence of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and renal limited vasculitis, in a northeastern region of France and to evaluate whether there was a geospatial association between the localization of quarries in the region and the prevalence of these AAVs. METHODS: Potential AAV patients were identified using 3 sources: hospital records, immunology laboratories, and the French National Health Insurance System. Patients who resided in the Alsace region of France as of January 1, 2016 and who fulfilled the American College of Rheumatology criteria for GPA or the 2012 Chapel Hill Consensus Conference definitions for GPA or MPA were included. Incomplete case ascertainment was corrected using a capture-recapture analysis. The spatial association between the number of cases and the presence of quarries in each administrative entity was assessed using regression analyses weighted for geographic region. RESULTS: Among 910 potential AAV patients, we identified 185 patients fulfilling inclusion criteria: 120 patients with GPA, 35 patients with MPA, and 30 patients with renal limited vasculitis. The number of cases missed by any source as estimated by capture-recapture analysis was 6.4 (95% confidence interval [95% CI] 3.6-11.5). Accordingly, the estimated prevalence in Alsace in 2016 was 65.5 GPA cases per million inhabitants (95% CI 47.3-93.0), 19.1 MPA cases per million inhabitants (95% CI 11.3-34.3), and 16.8 renal limited vasculitis cases per million inhabitants (95% CI 8.7-35.2). The risk of AAV was significantly increased in communities with quarries (odds ratio 2.51 [95% CI 1.66-3.80]), and geographic-weighted regression analyses revealed a significant spatial association between the proximity to quarries and the number of GPA cases (P = 0.039). In analyses stratifying the AAV patients by ANCA serotype, a significant association between the presence of quarries and positivity for both proteinase 3 ANCAs (P = 0.04) and myeloperoxidase ANCAs (P = 0.03) was observed. CONCLUSION: In a region with a high density of quarries, the spatial association between the presence of and proximity to quarries and the prevalence of AAVs supports the idea that silica may have a role as a specific environmental factor in this disease.

Validation of Strasbourg environmental exposure chamber (EEC) ALYATEC® in mite allergic subjects with asthma.

Objective: Environmental Exposure Chamber (EEC) should have standardized and controlled allergenic and non-allergenic exposures to perform reproducible clinical studies. The aim was to demonstrate that mite exposure in the Alyatec® EEC could induce early (EAR) and/or late asthmatic reactions (LAR) in at least 60% of subjects allergic to mite.Methods: The EEC has a volume of 147-m3 with 20 seats. The nebulized particle number, airborne Der p1, endotoxins, and volatile organic compound (VOC) concentrations were measured. Twenty-four asthmatics allergic to mite were randomly exposed to 15, 25, and 46 ng/m3 Der p1. Specificity was assessed in not mite-sensitized asthmatics.Results: No significant endotoxin or VOC contamination was measured. The mean inter-assay CVs were 12.5% for the airborne particle number and 28.7% for airborne Der p1 concentrations. For the three Der p1 concentrations, at least 88% of the subjects developed EAR and/or LAR, and at least 46% developed a dual response. No reaction occurred with placebo or in the control group. No severe bronchial reaction occurred.Conclusions: The Alyatec® EEC demonstrated a tight control of allergenic and non-allergenic exposures. The EEC was clinically validated, with airborne Der p1 levels close to levels found in natural settings.

Cluster analysis of indoor environmental factors associated with symptoms of mite allergy.

BACKGROUND: The clinical efficacy of controlling environmental allergens as a component of allergic asthma treatment remains controversial. Multifaceted allergen reductions appeared to be the most efficient methods. However, they require home visits with indoor technicians. OBJECTIVE: To examine the characteristics of indoor environments that might be related to symptoms of children and adult patients with mite allergic rhinitis and/or asthma. METHODS: We included 315 patients allergic to house dust mites with rhinitis and/or asthma who had been visited at home by 2 medical indoor environment counselors (MIECs) from the Strasbourg University Hospital between January 2007 and June 2015. In a cluster analysis, we analyzed 42 characteristics of respiratory symptoms, dwelling characteristics, and indoor pollutants in this population. RESULTS: Three clusters were defined among the patients. Cluster 1 included 55 patients, all with rhinitis, 32% with asthma, and all living in an urban area. Clusters 2 and 3 included 86 and 174 patients, respectively. The important factors in these 2 clusters were asthma incidence and exposure to different indoor pollutants, such as indoor perfumes, cleaning products, and tobacco smoke. CONCLUSION: Our results underlined the variability of indoor environments and the importance of MIEC home visits to investigate individual patient environments and propose an appropriate avoidance management plan. Our results showed that sensitization to mite and exposure to indoor chemical pollutants were associated with severe asthma.

Diagnostic procedure after an immediate hypersensitivity reaction in the operating room.

The diagnosis of a perioperative allergic reaction is based on clinical features associated with a suggestive timeline, the exclusion of other diagnoses, elevated concentrations of degranulation markers (histamine, tryptase), and positive allergy assessments (skin tests, specific IgE). After initiating appropriate treatment, the anesthesiologist should take blood samples to measure histamine and tryptase concentrations just after the reaction and repeat them 1-2hours later to validate the diagnosis of immediate hypersensitivity. A delayed measurement of basal tryptase is useful to rule out mastocytosis and to interpret moderate tryptase levels. The anesthesiologist must inform the patient of the reaction to obtain adhesion and consent to subsequent investigations and must record the timing of the reaction and of the blood sampling, the possible causal agents, and the treatment administered. These data must be shared with the laboratory and the allergist. An adverse drug reaction report must be filed. The gold standard for allergy assessment is skin testing. These tests should be done in an appropriate facility, with experienced staff and in compliance with current guidelines. Specific IgE assays and cellular assays can help when clinical features and skin tests are discordant. Provocation tests are sometimes required. After allergy assessment, the safest protocol for subsequent anesthesia is determined in collaboration with the anesthesiologist. The patient must be informed and carry an allergy alert card.

Efficacy of 2 months of allergen-specific immunotherapy with Bet v 1-derived contiguous overlapping peptides in patients with allergic rhinoconjunctivitis: Results of a phase IIb study.

BACKGROUND: An immunotherapy formulation consisting of 3 contiguous overlapping peptides (COPs) derived from Bet v 1, the major birch pollen allergen, showed good clinical tolerability in a previous phase I/IIa clinical trial. OBJECTIVES: We sought to evaluate the efficacy and safety of allergen-specific immunotherapy using 2 dose regimens of Bet v 1 COPs versus placebo in subjects with birch pollen-induced allergic rhinoconjunctivitis. METHODS: A randomized, double-blind, placebo-controlled phase IIb clinical trial was performed to assess the efficacy of Bet v 1 COP immunotherapy during the 2013 birch pollen season. Before the season, Bet v 1 COPs (50 and 100 µg in aluminum hydroxide) or placebo (saline and aluminum hydroxide) were administered as 5 subcutaneous injections to 239 adults with allergic rhinoconjunctivitis to birch pollen. Bet v 1 COPs at 25 or 50 µg were administered on day 1, and 50 or 100 µg was administered on days 8, 15, 29, and 57, respectively. Patients were monitored for adverse events during the treatment period and assessed for combined rhinoconjunctivitis symptom and medication scores, as well as quality of life. RESULTS: Rhinoconjunctivitis symptom and medication scores improved in both Bet v 1 COP-treated groups, reaching statistical significance over placebo in the 50-µg group (least squares mean, -0.23; 26% improvement; P = .015). Both active groups showed significant improvement in quality of life and nighttime nasal symptom scores, supporting the primary end point findings. Bet v 1 COP injections were well tolerated, with a higher frequency of systemic adverse events in the 100-µg group. CONCLUSION: Two months of preseasonal immunotherapy with 3 COPs derived from Bet v 1 at a 50-µg dose showed promising efficacy, small risk for systemic reactions, and immunomodulatory changes in this single-season, dose-finding, phase IIb trial in patients allergic to birch pollen.

Circulating Human Eosinophils Share a Similar Transcriptional Profile in Asthma and Other Hypereosinophilic Disorders.

Eosinophils are leukocytes that are released into the peripheral blood in a phenotypically mature state and are capable of being recruited into tissues in response to appropriate stimuli. Eosinophils, traditionally considered cytotoxic effector cells, are leukocytes recruited into the airways of asthma patients where they are believed to contribute to the development of many features of the disease. This perception, however, has been challenged by recent findings suggesting that eosinophils have also immunomodulatory functions and may be involved in tissue homeostasis and wound healing. Here we describe a transcriptome-based approach-in a limited number of patients and controls-to investigate the activation state of circulating human eosinophils isolated by flow cytometry. We provide an overview of the global expression pattern in eosinophils in various relevant conditions, e.g., eosinophilic asthma, hypereosinophilic dermatological diseases, parasitosis and pulmonary aspergillosis. Compared to healthy subjects, circulating eosinophils isolated from asthma patients differed in their gene expression profile which is marked by downregulation of transcripts involved in antigen presentation, pathogen recognition and mucosal innate immunity, whereas up-regulated genes were involved in response to non-specific stimulation, wounding and maintenance of homeostasis. Eosinophils from other hypereosinophilic disorders displayed a very similar transcriptional profile. Taken together, these observations seem to indicate that eosinophils exhibit non-specific immunomodulatory functions important for tissue repair and homeostasis and suggest new roles for these cells in asthma immunobiology.

Correction: Postnatal Environmental Tobacco Smoke Exposure Related to Behavioral Problems in Children.

[This corrects the article DOI: 10.1371/journal.pone.0133604.].

Postnatal Environmental Tobacco Smoke Exposure Related to Behavioral Problems in Children.

OBJECTIVE: The purpose of this study was to examine the association between pre and post environmental tobacco smoke (ETS) exposure and behavioral problems in schoolchildren. METHODS: In the cross-sectional 6 cities Study conducted in France, 5221 primary school children were investigated. Pre- and postnatal exposure to secondhand tobacco smoke at home was assessed using a parent questionnaire. Child's behavioral outcomes (emotional symptoms and conduct problems) were evaluated by the Strengths and Difficulties Questionnaire (SDQ) completed by the parents. RESULTS: ETS exposure during the postnatal period and during both pre- and postnatal periods was associated with behavioral problems in children. Abnormal emotional symptoms (internalizing problems) were related to ETS exposure in children who were exposed during the pre- and postnatal periods with an OR of 1.72 (95% Confidence Interval (CI)= 1.36-2.17), whereas the OR was estimated to be 1.38 (95% CI= 1.12-1.69) in the case of postnatal exposure only. Abnormal conduct problems (externalizing problems) were related to ETS exposure in children who were exposed during the pre- and postnatal periods with an OR of 1.94 (95% CI= 1.51-2.50), whereas the OR was estimated to be 1.47 (95% CI=1.17-1.84) in the case of postnatal exposure only. Effect estimates were adjusted for gender, study center, ethnic origin, child age, low parental education, current physician diagnosed asthma, siblings, preterm birth and single parenthood. CONCLUSION: Postnatal ETS exposure, alone or in association with prenatal exposure, increases the risk of behavioral problems in school-age children.

Skeletal muscle mitochondrial dysfunction during chronic obstructive pulmonary disease: central actor and therapeutic target.

Muscle dysfunction is a common complication and an important prognostic factor in chronic obstructive pulmonary disease (COPD). As therapeutic strategies are still needed to treat this complication, gaining more insight into the process that leads to skeletal muscle decline in COPD appears to be an important issue. This review focuses on mitochondrial involvement in limb skeletal muscle alterations (decreased muscle mass, strength, endurance and power and increased fatigue) in COPD. Mitochondria are the main source of energy for the cells; they are involved in production of reactive oxygen species and activate an important pathway that leads to apoptosis. In COPD patients, skeletal muscles are characterized by decreased mitochondrial density and biogenesis, impaired activity and coupling of mitochondrial respiratory chain complexes, increased mitochondrial production of reactive oxygen species and, possibly, increased apoptosis. Of particular interest, a sedentary lifestyle, hypoxia, hypercapnia, tobacco smoking, corticosteroid therapy and, possibly, inflammation participate in this mitochondrial dysfunction, which is accessible to conventional therapies, such as exercise and tobacco cessation, as well as, potentially, to more innovative approaches, such as antioxidant treatment and supplementation with polyunsaturated fatty acids.

Factors related to under-diagnosis and under-treatment of childhood asthma in metropolitan France.

BACKGROUND: Under-diagnosis and under-treatment of childhood asthma were investigated in France using data collected during the 6 Cities Study, the French contribution to the International Study of Asthma and Allergies in Childhood. METHODS: 7,781 schoolchildren aged between 9 and 10 years underwent a medical visit including skin prick tests to common allergens and exercise test for Exercise-Induced Asthma (EIA) and their parents filled in a standardized questionnaire on asthma, management, treatment and potential risk factors. RESULTS: 903 children reported asthma (11.6%), 377 without a doctor's diagnosis. Of the 526 participants with a diagnosis of asthma confirmed by a doctor (58.2%), 353 were treated and 76 were not treated during the year preceding the investigation despite their diagnosis. The information on the treatment was missing for the rest of individuals diagnosed with asthma (n = 97). Having a treatment was significantly associated with severe asthma and with the presence of other respiratory and allergic stigmata (atopic eczema, rhinitis, positive skin allergy tests, and EIA). In addition, having a treatment did not correspond to a good control of the disease. Similarly, children with asthma-like symptoms but without doctor-diagnosed asthma had asthma less well controlled than children with diagnosed asthma. They were also more exposed to passive smoking and traffic but had fewer pets. In contrast, diagnosed children reported more frequently a small weight at birth and a preterm birth. CONCLUSIONS: In France, childhood asthma is still under-diagnosed and under-treated and environmental factors play a role in these phenomena.

Varying allergen composition and content affects the in vivo allergenic activity of commercial Dermatophagoides pteronyssinus extracts.

BACKGROUND: Diagnosis and immunotherapy of house-dust mite (HDM) allergy is still based on natural allergen extracts. The aim of this study was to analyze commercially available Dermatophagoides pteronyssinus extracts from different manufacturers regarding allergen composition and content and whether variations may affect their allergenic activity. METHODS: Antibodies specific for several D. pteronyssinus allergens (Der p 1, 2, 5, 7, 10 and 21) were used to analyze extracts from 10 different manufacturers by immunoblotting. Sandwich ELISAs were used to quantify Der p 1 and Der p 2 in the extracts. Mite-allergic patients (n = 45) were skin-tested with the extracts and tested for immunoglobulin E (IgE) reactivity to a panel of 10 mite allergens (Der p 1, 2, 4, 5, 7, 8, 10, 14, 20 and 21) by dot blot. RESULTS: Only Der p 1 and Der p 2 were detected in all extracts but their concentrations and ratios showed high variability (Der p 1: 6.0-40.8 µg ml(-1); Der p 2: 1.7-45.0 µg ml(-1)). At least 1 out of 4 allergens (i.e. Der p 5, 7, 10 and 21) was not detected in 8 of the studied extracts. Mite-allergic subjects showed different IgE reactivity profiles to the individual mite allergens, the extracts showed different allergenic activity in skin-prick tests and false-negative results. CONCLUSIONS: Commercially available D. pteronyssinus extracts lack important allergens, show great variability regarding allergen composition and content and some gave false-negative diagnostic test results in certain patients.

Allergic fungal sinusitis associated with allergic bronchopulmonary aspergillosis: an uncommon sinobronchial allergic mycosis.

BACKGROUND: The identification of allergic fungal sinusitis (AFS) is still controversial and much more recent than that of allergic bronchopulmonary aspergillosis (ABPA). Their association has been reported very rarely in the literature. METHODS: The aim of this study was to present a review of 6 cases of AFS associated with ABPA from a series of 12 cases of AFS and to compare AFS associated with ABPA and isolated AFS. RESULTS: All cases of AFS presented with chronic rhinosinusitis. The six cases with AFS and ABPA were atopic, asthmatic, with pulmonary infiltrates (five cases), central bronchiectasis (four cases), and both (three cases). The mycological and immunoallergological features of isolated AFS and AFS associated with ABPA were similar: eosinophilic allergic mucin with noninvasive fungi hyphae, high levels of blood eosinophils, total IgE, specific IgE, IgG, and positive skin tests to Aspergillus. The association of AFS and ABPA was concomitant (two cases) or remote in time (four cases). The treatment with oral corticosteroids and sinus surgery (six cases) associated with antifungal drugs (four cases) led to resolution in three cases, considerable improvement in one case, and therapeutic failure in two cases (follow-up longer than 5 years in all cases). CONCLUSION: Independently of the signs linked to the organs involved (sinuses and bronchi) the mycological and immunoallergological features were similar for AFS and AFS associated with ABPA. AFS and ABPA can be isolated or associated in a sinobronchial allergic

Marked stem cell factor expression in the airways of lung transplant recipients.

BACKGROUND: Airways repair is critical to lung function following transplantation. We hypothesised that the stem cell factor (SCF) could play a role in this setting. METHODS: We studied 9 lung transplant recipients (LTx recipients) during their first year postgraft, and evaluated SCF mRNA expression in bronchial biopsy specimens using on-line fluorescent PCR and SCF protein levels in bronchoalveolar lavage (BAL) and serum using ELISA. The expression of SCF receptor Kit was assessed using immunostaining of paraffin-embedded bronchial sections. RESULTS: SCF mRNA was highly expressed during the early postgraft period [Month (M)1-M3] (300% increase vs controls: 356 vs 1.2 pg SCF/microg GAPDH cDNA, p < 0.001) and decreased thereafter (M4-M12: 187 pg/microg), although remaining at all times 10-100 times higher than in controls. While SCF protein levels in BAL were similar in LTx recipients and in controls, the SCF serum levels were at all times higher in LTx recipients than in controls (p < 0.05), with no relationship between these levels and the acute complications of the graft. Finally, Kit was strongly expressed by the mast cells as well as by the bronchial epithelium of LTx recipients. CONCLUSION: SCF and Kit are expressed in bronchial biopsies from lung transplant recipients irrespective of the clinical status of the graft. A role for these factors in tissue repair following lung transplantation is hypothesised.