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Here we extensively describe a FACS-based protocol for isolating intact non-stained human eosinophils from peripheral blood; a stop forward from our recently published initial study. This method of purification could be accomplished in <3 h with only small volumes of whole blood necessary, even in healthy subjects generally exhibiting low levels of circulating eosinophils. Eosinophil activation during the isolation steps appeared to be minimal and this purification procedure yielded high quality RNA. Moreover, these FACS-isolated eosinophils had prolonged viability in culture and were suitable for further activation assays., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Exacerbations are a key outcome in clinical research, providing patient-relevant information about symptomatic control, health state and disease progression. Generally considered as an episode of (sub)acute deterioration of respiratory symptoms, a precise, clinically useful definition is needed for use in clinical trials., Aim and Methods: Focussing on moderate exacerbations, this opinion piece reviews landmark trials and current guidelines to provide a practical definition of a moderate exacerbation. Specifically, we adapt the ATS/ERS consensus statement of terminology Reddel et al. (2009) [1] which provides a conceptual (or 'theoretical') definition for moderate exacerbations, to an operational (or 'practical') criterion suitable for use in clinical research., Results: The proposed definition for a moderate exacerbation requires ≥1 of the following criteria combined with a change in treatment: a) nocturnal awakening(s) due to asthma requiring SABA for 2 consecutive nights or an increase of ≥0.75 from baseline in daily symptom scores on 2 consecutive days; b) increase from baseline in occasions of SABA use on 2 consecutive days (minimum increase: 4 puffs/day); c) ≥20% decrease in PEF from baseline on at least 2 consecutive mornings/evenings or ≥20% decrease in FEV1 from baseline and/or d) visit to the emergency room/trial site for asthma treatment not requiring systemic corticosteroids., Conclusion: A clinically and patient-relevant, operational definition of moderate exacerbations is needed. The proposed definition has been endorsed by the EMA Scientific Advice Working Party in 2011and needs to be trialled in forthcoming clinical studies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: In a double-blind, placebo-controlled trial (EudraCT identifier: 2006-001795-20), the standardised quality (SQ) house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet (ALK, Denmark) was investigated., Method: The trial included 604 subjects, ≥14 years, with mild-moderate HDM allergic asthma. Subjects were randomised 1:1:1:1 to 1, 3 or 6 SQ-HDM or placebo once daily. The primary endpoint was reduction in inhaled corticosteroid (ICS) after one year. ICS reduction, asthma quality of life questionnaire (AQLQ) and asthma control questionnaire (ACQ) score was analysed post hoc in a subgroup with daily ICS use of 400-800 μg and ACQ score of 1-1.5, corresponding to partly controlled asthma (N = 108)., Results: The trial met its primary endpoint. In the subgroup, the difference between placebo and 6 SQ-HDM in change from baseline in daily ICS use was 327 μg (p < 0.0001), while it was 0.52 (p = 0.010) for AQLQ. The treatment effect on ICS reduction and AQLQ was increased for the subgroup versus the residual population (ICS reduction: p < 0.001); AQLQ: p = 0.044)., Conclusion: In this subgroup, including only patients with partly controlled asthma, the benefit of 1 year of treatment with SQ HDM SLIT-tablet was significantly higher than for the less severe full population, both in terms of increased asthma control and improved quality of life., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study examined the hypothesis that emotion and conduct problems (ECPs) may modify the relationships between ambient air pollutants and childhood asthma and eczema., Methods: In the cross-sectional study, 4209 French schoolchildren (aged 10e12 years) were investigated between March 1999 and October 2000. Ambient air pollutants exposures were estimated with dispersion modeling. Health outcomes and ECPs were evaluated by validated questionnaires, completed by the parents. Marginal models were used to analyze the relationships of exposures to ambient air pollutants and/or ECPs to asthma phenotypes and current eczema, adjusting for potential confounders., Results: In our population, interactions were found between ECPs and exposures to ambient air pollutants (benzene, carbon monoxide, nitrogen dioxide, nitrogen oxides, particulate matter with an aerodynamic diameter below 10 mm, volatile organic compounds) (P < .20). In addition, ECPs were related to current wheezing (adjusted prevalence odds ratio [aOR], 2.35; 95% confidence interval [CI], 1.59e3.47), current doctor-diagnosed asthma (aOR, 1.82; 95% CI, 1.25e2.66), and current eczema (aOR, 2.21; 95% CI, 1.61e3.02). Children with ECPs had 1.17e1.51 times higher aORs for the associations between ambient air pollutants and asthma phenotypes and current eczema than those without ECPs., Conclusions: ECPs may modify the relationships between ambient air pollutants and childhood asthma and eczema., (2013 Elsevier Inc. All rights reserved.)

Background: While up to 50% of patients with severe asthma have no evidence of allergy, IgE has been linked to asthma, irrespective of atopic status. Omalizumab, an anti-IgE monoclonal antibody, is reported to significantly benefit a subset of patients with severe, persistent, allergic asthma. Therefore, we investigated whether omalizumab has biologic and clinical effects in patients with refractory nonatopic asthma., Methods: Forty-one adult patients who, despite daily treatment with or without maintenance oral corticosteroids, had severe, nonatopic, refractory asthma according to GINA (Global Initiative for Asthma) step 4, were randomized to receive omalizumab or placebo in a 1:1 ratio. The primary end point was the change in expression of high-affinity IgE receptor (FcεRI) on blood basophils and plasmacytoid dendritic cells (pDC2) after 16 weeks. The impact of omalizumab on lung function and clinical variables was also examined., Results: Compared with placebo, omalizumab resulted in a statistically significant reduction in FcεRI expression on basophils and pDC2 (P &lt; .001). The omalizumab group also showed an overall increase in FEV1 compared with baseline (+250 mL, P = .032; +9.9%, P = .029). A trend toward improvement in global evaluation of treatment effectiveness and asthma exacerbation rate was also observed., Conclusions: Omalizumab negatively regulates FcεRI expression in patients with severe nonatopic asthma, as it does in severe atopic asthma. Omalizumab may have a therapeutic role in severe nonatopic asthma. Nonetheless, our preliminary findings support further investigation to better assess the clinical efficacy of omalizumab., Trial Registry: ClinicalTrials.gov; No.: NCT01007149; URL: www.clinicaltrials.gov and European Clinical Trials Database, EudraCT; No.: 2009-010937-38; URL: https://www.clinicaltrialsregister.eu.

In the present study, we investigated the immunomodulatory activity of multi-walled carbon nanotubes (MWCNTs) in peripheral blood mononuclear cells (PBMCs) from healthy donors and mite-allergic subjects. Freshly prepared PBMCs, stimulated or not with Toll-like receptor (TLR)1-9 agonists, a T cell mitogen (phytohemagglutinin A) or mite allergen extract were cultured in the presence or absence of MWCNTs. Secretion of TNF-α, IL-2, IL-5, IL-6, IL-12/23p40 or IFN-γ was quantified in the culture supernatants by ELISA. Basal secretion of all the cytokines was not altered by MWCNTs in PBMCs from both healthy donors and allergic subjects. In PBMCs from healthy donors, TNF-α, IL-6 and IL-12/23p40 secretion in response to the TLR4 agonist, lipopolysaccharide was however increased in a dose-dependent manner by MWCNTs. Significant increases in the release of these cytokines were also observed in PBMCs stimulated with a TLR2 or TLR3 agonist. MWCNTs also increased the release of IL-2 and IFN-γ by PBMCs stimulated with a T cell mitogen. In contrast, MWCNTs inhibited allergen-induced IL-5 secretion by PBMCs from mite-allergic subjects. As well, MWCNTs altered the capacity of PBMC-derived monocytes to differentiate into functional dendritic cells. All together, our data suggest that according to its immune cell target, MWCNTs may either promote or suppress immune responses in humans. Further investigations are necessary to fully understand the complexity behind interactions of engineered nanoparticles with the immune system., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: It is documented that omalizumab treatment reduces the cell surface expression of immunoglobulin E high-affinity receptor (FcɛRI) on several cell types. This has not been investigated in patients with uncontrolled severe persistent allergic asthma., Methods: In a double-blind, randomized, placebo-controlled study, patients with severe allergic asthma uncontrolled by high dose inhaled corticosteroids and long-acting β(2)-agonist received either omalizumab (n = 20) or placebo (n = 11) over 16 weeks at appropriate doses and frequencies. Baseline and end of study (week 16) FcɛRI expression on basophils and plasmacytoid dendritic cells was determined by flow cytometry for the primary endpoint. Secondary efficacy endpoints included asthma control and lung function as part of an initial investigation into the use of FcɛRI expression as a marker of response., Results: In the omalizumab group, and with respect to placebo, FcɛRI expression was significantly reduced at end of study on basophils (-82.6%, p < 0.01) and plasmacytoid dendritic cells (-44.2%, p = 0.029). FcɛRI expression reduction was not found to be correlated with clinical response., Conclusions: Long-term omalizumab treatment induced reduction of FcɛRI expression on circulating basophils and plasmacytoid dendritic cells. These changes were not associated with those of clinical features related to severe asthma, which does not support further investigation into its use as a predictive marker of response., Trial Registration: The study was registered with ClinicalTrials.gov (identifier: NCT00454051) and the European Clinical Trials Database, EudraCT (identifier: 2006-003591-35)., (Copyright © 2010. Published by Elsevier Ltd.)

Objective: To describe omalizumab (Xolair) effectiveness in the first patients treated on compassionate grounds before its commercialisation in France., Methods: In a historic-prospective study, data were obtained by questionnaire from the physicians whose patients had received a nominative temporary use authorisation (ATU) for omalizumab from July 2003 to January 2006. Anonymised patient data regarding demographics, asthma-related treatments and events in the year previous to the start of omalizumab treatment as well as the details of omalizumab treatment itself were obtained at inclusion. Follow-up data at more than 3 months following inclusion were also obtained and regarded asthma-related treatment (including omalizumab), events and undesirable effects suspected to be linked to omalizumab treatment., Results: Data were obtained for 147 of the 154 patients treated via ATU. 31.3% received inappropriate monthly doses of omalizumab. Of the 28 patients (19%) who discontinued for unsatisfactory therapeutic effect, 7 were treated for less than the 16 weeks recommended to evaluate efficacy and 9 who were treated for a longer period of time were underdosed. During the treatment period and compared to the previous year, patients with follow-up data at 5 months or more had experienced 62% fewer exacerbations requiring oral corticosteroids, 65% fewer emergency department visits and 29% fewer hospitalisations per year. The nature of adverse effects reported was similar to that reported in omalizumab clinical trials., Conclusion: Results strongly suggest that omalizumab in the first patients treated in real-life setting provided a similar benefit to that observed in clinical trials. Underdosing of patients may limit this therapeutic effect.

A 41-yr-old patient experienced an anaphylactic shock reaction caused by formaldehyde in a root canal sealant during endodontic treatment. The clinical events, positive skin tests, and a high level of immunoglobin E to formalin RAST (class 4) suggest the involvement of immunoglobin E-dependent mechanisms toward formaldehyde. This very infrequent observation in endodontic therapy focuses attention on the different pathological manifestations related to formalin, their mechanisms, and the prevention possibilities in dentistry.

The present case report describes a case of invasive pulmonary aspergillosis with cerebromeningeal invasion in an asthmatic non-immunocompromised patient. This fatal complication occurred despite early anti-fungal antibiotherapy after a 2-week course of intravenous corticosteroid therapy for treatment of an exacerbated asthma. Diagnostic and therapeutic procedures are discussed.

The present case report describes a 27-year-old patient who presented with post-traumatic pleural effusion. Analysis of the pleural fluid showed hypereosinophilia (990 mm-3), a decreased level of total complement, and decreased levels of C3 and C4 fractions (less than 50% of normal serum levels), indicating a local consumption mechanism for complement. Complement serum levels (CH50, C3, C4) were normal. All other aetiologic possibilities were eliminated. This case suggests that the immunopathological mechanism of post-traumatic pleural effusion may involve activation of the classical pathway of complement and a recruitment of inflammatory cells such as eosinophils.