Technical standards in allergen exposure chambers worldwide - an EAACI Task Force Report.

Allergen exposure chambers (AECs) can be used for controlled exposure to allergenic and non-allergenic airborne particles in an enclosed environment, in order to (i) characterize the pathological features of respiratory diseases and (ii) contribute to and accelerate the clinical development of pharmacological treatments and allergen immunotherapy for allergic disease of the respiratory tract (such as allergic rhinitis, allergic rhinoconjunctivitis, and allergic asthma). In the guidelines of the European Medicines Agency for the clinical development of products for allergen immunotherapy (AIT), the role of AECs in determining primary endpoints in dose-finding Phase II trials is emphasized. Although methodologically insulated from the variability of natural pollen exposure, chamber models remain confined to supporting secondary, rather than primary, endpoints in Phase III registration trials. The need for further validation in comparison with field exposure is clearly mandated. On this basis, the European Academy of Allergy and Clinical Immunology (EAACI) initiated a Task Force in 2015 charged to gain a better understanding of how AECs can generate knowledge about respiratory allergies and can contribute to the clinical development of treatments. Researchers working with AECs worldwide were asked to provide technical information in eight sections: (i) dimensions and structure of the AEC, (ii) AEC staff, (iii) airflow, air processing, and operating conditions, (iv) particle dispersal, (v) pollen/particle counting, (vi) safety and non-contamination measures, (vii) procedures for symptom assessments, (viii) tested allergens/substances and validation procedures. On this basis, a minimal set of technical requirements for AECs applied to the field of allergology is proposed.

Google Trends and pollen concentrations in allergy and airway diseases in France.

BACKGROUND: Google Trends (GTs) is a web-based surveillance tool that explores the searching trends of specific queries via Google. This tool proposes to reflect the real-life epidemiology of allergic rhinitis and asthma. However, the validation of GTs against pollen concentrations is missing at the country level. OBJECTIVES: In the present study, we used GTs (a) to compare the terms related to allergy in France, (b) to assess seasonal variations across the country for 5 years and (c) to compare GTs and pollen concentrations for 2016. METHODS: Google Trends queries were initially searched to investigate the terms reflecting pollen and allergic diseases. 13- and 5-year GTs were used in France. Then, 5-year GTs were assessed in all metropolitan French regions to assess the seasonality of GTs. Finally, GTs were compared with pollen concentrations (Réseau National de Surveillance en Aerobiology) for 2016 in seven regions (GTs) and corresponding cities (pollen concentrations). RESULTS: The combination of searches for "allergy" as a disease, "pollen" as a disease cause and "ragweed" as a plant was needed to fully assess the pollen season in France. "Asthma" did not show any seasonality. Using the 5-year GTs, an annual and clear seasonality of queries was found in all regions depending on the predicted pollen exposure for spring and a summer peak but not for winter peaks. The agreement between GT queries and pollen concentrations is usually poor except for spring trees and grasses. Moreover, cypress pollens are insufficiently reported by GTs. CONCLUSIONS: Google Trends cannot predict the pollen season in France.

Immunotherapy with grass pollen tablets reduces medication dispensing for allergic rhinitis and asthma: A retrospective database study in France.

BACKGROUND: Moderate-to-severe allergic rhinitis (AR) may increase the risk of developing or worsening asthma, whereas treatment of AR with subcutaneously or sublingual allergen immunotherapy (SLIT) may slow this progression. METHODS: In a retrospective real-world analysis, prescription fulfilment data were gathered from French retail pharmacies between 1 March 2012 and 31 December 2016. Using linear regression analyses, patients having received at least two prescriptions of grass pollen SLIT tablets over at least 2 successive years were compared with control patients having received symptomatic medications only. RESULTS: A total of 1099 SLIT patients and 27 475 control patients were included in the main analysis. With regard to symptomatic AR medication dispensing, we observed a 50% decrease in the pre-index/follow-up ratio in the SLIT group, a 30% increase in the control group without age matching (P < 0.0001 vs SLIT) and a 20% increase in the control group with age matching (P < 0.0001 vs SLIT). During the follow-up, 11 (1.8%) and 782 (5.3%) patients initiated asthma treatment in the SLIT and control groups, respectively. The relative risk of medication dispensing for new asthma was lower in the SLIT group (by 62.5% [29.1%-80.1%] without age matching (P = 0.0025) and by 63.7% [31.5%-80.7%] with age matching; P = 0.0018). SLIT was also associated with slower progression of asthma medication dispensing during the follow-up period, relative to the control group (regression coefficient: -0.58 [-0.74 to 0.42] without age matching (P < 0.0001) and -0.61 [-0.76 to -0.46] with age matching; P < 0.0001). CONCLUSION: Prescription of grass pollen SLIT tablets reduced the dispensing of AR and asthma medications in real life.

Grass pollen sublingual immunotherapy tablets provide long-term relief of grass pollen-associated allergic rhinitis and reduce the risk of asthma: findings from a retrospective, real-world database subanalysis.

BACKGROUND: We assessed real-world, long-term effectiveness of two marketed sublingual immunotherapy (SLIT) tablets for allergic rhinitis (AR), and their impact on allergic asthma (AA) onset/progression. METHODS: Retrospective, longitudinal German prescription database subanalysis of AR patients receiving 5- or 1-grass pollen SLIT tablets (n = 1,466/1,385), versus patients not using allergy immunotherapy (AIT) (n = 71,275). Primary endpoint: change over time in AR symptomatic medication prescriptions after treatment cessation; secondary endpoints: new asthma onset, and change over time in asthma medication prescriptions during treatment/follow-up periods. RESULTS: Mean number of AR medication prescriptions was significantly decreased during follow-up (of up to 6 years) with both SLIT tablets versus the non-AIT group (p < 0.001). Over the full-analysis period, proportions of patients with new-onset asthma were 8.8% (odds ratio: 0.676, p = 0.011), 10.3% (odds ratio: 0.720, p = 0.060) and 11.6% in the 5- and 1-grass pollen SLIT tablet and non-AIT groups, respectively. For all treatment-analysis periods, both SLIT tablet groups were associated with fewer asthma medication prescriptions versus non-AIT controls. CONCLUSIONS: These findings confirm the real-world benefits of 5- and 1-grass-pollen SLIT tablets in slower AR progression, reduced risk of new asthma onset in the non-asthmatic population, and slower asthma progression in the asthmatic population.

Sialylated Fetuin-A as a candidate predictive biomarker for successful grass pollen allergen immunotherapy.

BACKGROUND: Eligibility to immunotherapy is based on the determination of IgE reactivity to a specific allergen by means of skin prick or in vitro testing. Biomarkers predicting the likelihood of clinical improvement during immunotherapy would significantly improve patient selection. METHODS: Proteins were differentially assessed by using 2-dimensional differential gel electrophoresis and label-free mass spectrometry in pretreatment sera obtained from clinical responders and nonresponders within a cohort of 82 patients with grass pollen allergy receiving sublingual immunotherapy or placebo. Functional studies of Fetuin-A (FetA) were conducted by using gene silencing in a mouse asthma model, human dendritic cell in vitro stimulation assays, and surface plasmon resonance. RESULTS: Analysis by using quantitative proteomics of pretreatment sera from patients with grass pollen allergy reveals that high levels of O-glycosylated sialylated FetA isoforms are found in patients exhibiting a strong decrease in rhinoconjunctivitis symptoms after sublingual immunotherapy. Although FetA is involved in numerous inflammatory conditions, its potential role in allergy is unknown. In vivo silencing of the FETUA gene in BALB/c mice results in a dramatic upregulation of airway hyperresponsiveness, lung resistance, and TH2 responses after allergic sensitization to ovalbumin. Both sialylated and nonsialytated FetA bind to LPS, but only the former synergizes with LPS and grass pollen or mite allergens to enhance the Toll-like receptor 4-mediated proallergic properties of human dendritic cells. CONCLUSIONS: As a reflection of the patient's inflammatory status, pretreatment levels of sialylated FetA in the blood are indicative of the likelihood of clinical responses during grass pollen immunotherapy.

Comparison of outcome measures in allergic rhinitis in children, adolescents and adults.

BACKGROUND: Grass pollen-induced allergic rhinoconjunctivitis (AR) is very common worldwide. However, its symptoms may vary with the patient's age. The present study compared symptom profiles and quality of life (QoL) in children, adolescents and adults with grass pollen-induced AR. METHODS: This was a four-week, multicentre, observational study of children (aged 6-11), adolescents (12-17) and adults (18-65) consulting specialist physicians in France. The management of AR was at the physicians' discretion. Participants regularly rated their symptoms (the rhinoconjunctivitis total symptom score (RTSS) and a visual analogue scale (VAS)) and QoL (the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). RESULTS: A total of 806 patients (253 children, 250 adolescents and 303 adults, of whom 83.5% suffered from moderate-to-severe, persistent AR) provided data for at least the first 2 weeks of the study. Ocular pruritus (the most bothersome symptom in children (35%), adolescents (22%) and adults (16%)) was associated with poor QoL in all groups, whereas nasal obstruction and pruritus were associated with poor QoL in adolescents and children. Over 4 weeks, the weekly mean RTSS and VAS scores fell by around half. This change was associated with an improvement in the RQLQ scores. In all age groups, the VAS score was well correlated with the weekly mean RTSS score (Pearson's r: 0.79-0.88) and moderately correlated with the weekly mean RQLQ score (Pearson's r: 0.64-0.80). CONCLUSIONS: In moderate-to-severe grass pollen-induced AR, symptom perception differs in children vs. older patients. However, the assessments of treatment outcomes (using the RTSS, VAS and RQLQ) were similar in all age groups.

V0162 a new long-acting bronchodilator for treatment of chronic obstructive lung diseases: preclinical and clinical results.

BACKGROUND: Long acting bronchodilators are the standard of care in the management of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the efficacy and safety of V0162, a novel anticholinergic agent with bronchodilator properties, in preclinical models and in patients with COPD. METHODS: Guinea pigs were used to evaluate the impact of V0162 on the acetylcholine or histamine-induced bronchoconstriction. V0162 was also investigated in an allergic asthma model on ovalbumin-sensitized guinea pig. For clinical investigations, healthy volunteers were included in a dose-escalation, randomized, placebo-controlled phase I study to determine the maximal tolerated dose, followed by a randomized, placebo-controlled, cross-over phase II study in patients with COPD. V0162 was given via inhalation route. The objectives of the phase I/II study were to assess the safety and efficacy of V0162, in terms of bronchodilation and reduction in hyperinflation. RESULTS: Preclinical results showed that V0162 was able to prevent bronchoconstriction induced either by acetylcholine or histamine. V0162 reversed the bronchoconstriction and airway inflammation caused by ovalbumin challenge in sensitized guinea pigs. In the healthy volunteers study, 88 subjects were enrolled: 66 received V0162 and 22 received placebo. No particular safety concerns were raised. The maximal tolerated dose was not reached and the dose escalation was stopped at 2400 µg. A total of 20 patients with COPD were then enrolled. All patients received a single-dose of V0162 1600 µg and of placebo in two alternating periods. In COPD patients, V0162 demonstrated a significant increase in FEV1 compared with placebo (148 ± 137 ml vs. 36 ± 151 ml, p = 0.003). This bronchodilatory effect was corroborated by a reduction in hyperinflation. There was a trend toward dyspnea relief (change in visual analog scale at 22 h, -15.1 ± 26.0 mm vs.- 5.3 ± 28.8 mm with placebo, p = 0.054). No serious adverse events (AEs) were reported. Most common AEs were productive and non-productive cough, dyspnea and pruritus. CONCLUSIONS: V0162 improved pulmonary function and tended to improve dyspnea in patients with COPD over more than 24 h. The slight plasmatic exposure observed might support the good safety profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01348555.

Is arginase a potential drug target in tobacco-induced pulmonary endothelial dysfunction?

BACKGROUND: Tobacco-induced pulmonary vascular disease is partly driven by endothelial dysfunction. The bioavailability of the potent vasodilator nitric oxide (NO) depends on competition between NO synthase-3 (NOS3) and arginases for their common substrate (L-arginine). We tested the hypothesis whereby tobacco smoking impairs pulmonary endothelial function via upregulation of the arginase pathway. METHODS: Endothelium-dependent vasodilation in response to acetylcholine (Ach) was compared ex vivo for pulmonary vascular rings from 29 smokers and 10 never-smokers. The results were expressed as a percentage of the contraction with phenylephrine. We tested the effects of L-arginine supplementation, arginase inhibition (by N(omega)-hydroxy-nor-l-arginine, NorNOHA) and NOS3 induction (by genistein) on vasodilation. Protein levels of NOS3 and arginases I and II in the pulmonary arteries were quantified by Western blotting. RESULTS: Overall, vasodilation was impaired in smokers (relative to controls; p < 0.01). Eleven of the 29 smokers (the ED(+) subgroup) displayed endothelial dysfunction (defined as the absence of a relaxant response to Ach), whereas 18 (the ED(-) subgroup) had normal vasodilation. The mean responses to 10(-4) M Ach were -23 ± 10% and 31 ± 4% in the ED(+) and ED(-) subgroups, respectively (p < 0.01). Supplementation with L- arginine improved endothelial function in the ED(+) subgroup (-4 ± 10% vs. -32 ± 10% in the presence and absence of L- arginine, respectively; p = 0.006), as did arginase inhibition (18 ± 9% vs. -1 ± 9%, respectively; p = 0.0002). Arginase I protein was overexpressed in ED(+) samples, whereas ED(+) and ED(-) samples did not differ significantly in terms of NOS3 expression. Treatment with genistein did not significantly improve endothelial function in ED(+) samples. CONCLUSION: Overexpression and elevated activity of arginase I are involved in tobacco-induced pulmonary endothelial dysfunction.

A meta-analysis of sublingual allergen immunotherapy and pharmacotherapy in pollen-induced seasonal allergic rhinoconjunctivitis.

BACKGROUND: The capacity of sublingual allergen immunotherapy (SLIT) to provide effective symptom relief in pollen-induced seasonal allergic rhinitis is often questioned, despite evidence of clinical efficacy from meta-analyses and well-powered, double-blind, placebo-controlled randomized clinical trials. In the absence of direct, head-to-head, comparative trials of SLIT and symptomatic medication, only indirect comparisons are possible. METHODS: We performed a meta-analysis of classes of products (second-generation H1-antihistamines, nasal corticosteroids and grass pollen SLIT tablet formulations) and single products (the azelastine-fluticasone combination MP29-02, and the leukotriene receptor antagonist montelukast) for the treatment of seasonal allergic rhinitis in adults, adolescents and/or children. We searched the literature for large (n >100 in the smallest treatment arm) double-blind, placebo-controlled randomized clinical trials. For each drug or drug class, we performed a meta-analysis of the effect on symptom scores. For each selected trial, we calculated the relative clinical impact (according to a previously published method) on the basis of the reported post-treatment or season-long nasal or total symptom scores: 100 × (scorePlacebo - scoreActive)/scorePlacebo. RESULTS: Twenty-eight publications on symptomatic medication trials and ten on SLIT trials met our selection criteria (total number of patients: n = 21,223). The Hedges' g values from the meta-analyses confirmed the presence of a treatment effect for all drug classes. In an indirect comparison, the weighted mean (range) relative clinical impacts were -29.6% (-23% to -37%) for five-grass pollen SLIT tablets, -19.2% (-6% to -29%) for timothy pollen SLIT tablets, -23.5% (-7% to -54%) for nasal corticosteroids, -17.1% (-15% to -20%) for MP29-02, -15.0% (-3% to -26%) for H1-antihistamines and -6.5% (-3% to -10%) for montelukast. CONCLUSIONS: In an indirect comparison, grass pollen SLIT tablets had a greater mean relative clinical impact than second-generation antihistamines and montelukast and much the same mean relative clinical impact as nasal corticosteroids. This result was obtained despite the presence of methodological factors that mask the clinical efficacy of SLIT for the treatment of seasonal allergic rhinitis.

Early onset of action of a 5-grass-pollen 300-IR sublingual immunotherapy tablet evaluated in an allergen challenge chamber.

BACKGROUND: The efficacy and safety of a 5-grass-pollen sublingual immunotherapy (SLIT) tablet (Stallergènes SA, Antony, France) have been evaluated in clinical studies during the pollen season. The allergen challenge chamber (ACC) has been developed as a pharmacodynamic assessment tool to control the environmental allergens and to avoid all problems associated with unpredictable pollen seasons. OBJECTIVE: We sought to evaluate the onset of action and efficacy of 300-IR (index of reactivity) SLIT tablets by using an ACC. METHODS: Patients with grass pollen-induced rhinoconjunctivitis were randomized into the active or placebo groups. A standardized allergen challenge with grass pollen and symptom evaluation every 15 minutes was performed at baseline, 1 week, and 1, 2, and 4 months of treatment. The primary end point was the average rhinoconjunctivitis total symptom score (ARTSS). Allergen-specific basophil activation, T-cell proliferation, and plasmatic IgE and IgG responses were assessed before and after treatment. RESULTS: In the intention-to-treat population (n = 89) a significant treatment effect was achieved after the first month (P = .0042) and second month (P = .0203) and was maintained through to the fourth month (P = .0007). In the active group the ARTSS (means +/- SDs) decreased at each challenge: week 1, 7.40 +/- 2.682; month 1, 5.89 +/- 2.431; month 2, 5.09 +/- 2.088; and month 4, 4.85 +/- 1.999. An improvement (vs placebo) of 29.3% for the mean ARTSS (median, 33.3%) was observed at end point. Furthermore, the induction of grass pollen allergen-specific IgGs was associated with clinical response. The most frequent adverse reactions were local: oral pruritus, ear pruritus, and throat irritation. CONCLUSIONS: In this ACC study the 300-IR 5-grass-pollen SLIT tablets had a significant effect on rhinoconjunctivitis symptoms (vs placebo) from the first month of treatment onward.