Rhinoconjunctivitis severity induced by cat exposure influences early and late asthmatic responses: Evidence from an environmental exposure chamber.

BACKGROUND: The impact of allergic rhinoconjunctivitis on the early (EAR) and late asthmatic response (LAR) has yet to be assessed during optimal allergen exposure conditions. OBJECTIVE: We aimed to assess predictive factors of the EAR and LAR and to evaluate the relation between rhinitis, conjunctivitis and asthma induced by cat allergen exposure in an environmental exposure chamber (EEC). METHODS: Data from two cohort studies involving asthmatic patients with cat allergy who performed a cat allergen exposure challenge in ALYATEC EEC were analysed. Spirometry, visual analogue scale (VAS) for asthma, VAS for rhinitis, Total Nasal Symptoms Score, Total Ocular Symptoms Score (TOSS), Rhinoconjunctivitis Total Symptoms Score and Abelson score were used to assess asthma, rhinitis and conjunctivitis during and after exposure. RESULTS: An EAR occurred in 65.1% of patients, 32.1% of whom had a LAR. The diameter of the prick test to cat allergens and non-specific bronchial hypersensitivity level were independent risk factors for EAR (p < .05). No independent risk factors for LAR were identified. Rhinoconjunctivitis severity during exposure correlated with the asthma VAS during EAR and LAR (p < .05). Allergen exposure time needed to trigger an EAR correlated with the Abelson score during exposure (p < .05). The asthma VAS and TOSS during exposure correlated with faster LAR occurrence (p < .05). CONCLUSION: Prick test size and non-specific bronchial hypersensitivity level were confirmed as independent predictive factors of EAR during allergen exposure in an EEC. This study demonstrated the relation between the severity of rhinitis, conjunctivitis and asthma induced by allergen exposure for both EAR and LAR.

Birch-induced allergic rhinitis: Results of exposure during nasal allergen challenge, environmental chamber, and pollen season.

Background: Pollen variation can affect field study data quality. Nasal allergen challenge (NAC) is considered the gold standard for evaluating allergic rhinitis, while environmental exposure chambers (EECs) are mainly used in phase 2 drug development studies. We aimed to study birch-induced allergic rhinitis under 3 different conditions. Methods: This study included 30 participants allergic to birch pollen, based on birch skin prick test, specific immunoglobulin E (IgE), and positive NAC. Participants were exposed to placebo twice, followed by 2 consecutive 4-h birch airborne exposures, repeated on 2 occasions to evaluate reproducibility and priming effect. Nasal response was defined as total corrected nasal symptom score (ΔTNSS) ≥ 5 during NAC and EEC. The primary end-point was to measure TNSS during the last 2 h of first allergen exposure. TNSS was also analyzed during natural exposure. Results: The dose most commonly yielding positive TNSS during NAC was 175.2 ng/200 µL. Eighteen participants experienced ΔTNSS ≥5 during the last 2 h of the first exposure, whereas 21 had positive responses at all 4 exposures. Mean ΔTNSS was 1 with placebo versus 6 with birch. Exposures were reproducible, with no observed priming effect. Airborne Bet v 1 was 25 ng/m3, while the pollen measurement was 279/m3 during pollen season. TNSS reached 5 in 67.9% of participants during peak pollen season. Conclusion: EEC outcomes were similar to those obtained with NAC and natural exposure, suggesting the usefulness of EEC in allergic rhinitis studies. The primary end-point was reached, as 60% of participants experienced nasal responses.

REGN1908/1909 prevented cat allergen-induced early asthmatic responses in an environmental exposure unit.

BACKGROUND: The dominant allergen in cat dander, Felis domesticus allergen 1 (Fel d 1), is a persistent trigger for allergic rhinitis and asthma symptoms. OBJECTIVE: We evaluated the efficacy of Fel d 1 monoclonal antibodies (REGN1908/1909) in preventing cat allergen-induced early asthmatic responses (EARs) in cat-allergic patients with mild asthma. METHODS: Patients were randomized to single-dose REGN1908/1909 600 mg (n = 29) or placebo (n = 27). The FEV1 was measured for up to 4 hours in a cat allergen environmental exposure unit up to 85 days after dosing. Assessments included between-group differences in change from baseline in FEV1 area under the curve (AUC; 0-2 hours) and incidence of EAR (FEV1 reduction ≥20%). TRIAL REGISTRATION: NCT03838731. RESULTS: Single-dose REGN1908/1909 significantly prevented reductions in FEV1 on days 8, 29, 57, and 85. Most REGN1908/1909 patients did not have an EAR by 4 hours (the last time point tested). In contrast, placebo-treated patients experienced a ≥20% mean FEV1 reduction on days 8, 29, 57, and 85 after dosing, with most experiencing an EAR within 1 hour. REGN1908/1909-treated patients tolerated 3-fold higher allergen quantities (P < .05 at all time points) versus placebo. REGN1908/1909 substantially reduced skin test reactivity to cat allergen versus placebo at all time points tested (nominal P < .001). REGN1908/1909 was generally well tolerated; no serious adverse events or deaths were reported. CONCLUSION: Single-dose REGN1908/1909 significantly prevented reductions in FEV1 in cat-allergic patients with mild asthma on cat allergen environmental exposure unit exposure at 8 days and up to 85 days after dose.

Efficacy of N-acetyl aspartyl glutamic acid versus fluorometholone for treating allergic conjunctivitis in an environmental exposure chamber.

BACKGROUND: Topical mast cell stabilizers were previously shown to treat the signs and symptoms of seasonal and perennial allergic conjunctivitis safely and effectively in active and placebo-controlled trials. However, mast cell stabilizers have not been compared to topical corticosteroids for efficacy. We tested the non-inferiority of a topical mast cell stabilizer, N-acetyl aspartyl glutamic acid (4.9%, NAAGA), compared to fluorometholone (0.1%, FM) during controlled exposures to the airborne birch pollen allergen, Bet v 1, in an environmental exposure chamber (EEC). METHODS: This randomized, cross-over, investigator-blinded study included 24 patients with a history of birch pollen allergic conjunctivitis. Patients were randomized to 5 days of treatment with NAAGA, then FM (n = 12) or FM, then NAAGA (n = 12). After each treatment, patients were exposed to a fixed airborne concentration of Bet v 1 in ALYATEC EEC. The primary endpoint was the amount of allergen required to trigger a conjunctival response (Abelson score ≥5). Groups were compared with a linear model for cross-over studies. Non-inferiority was assumed, when the lower bound of the risk ratio confidence interval (CI) was >0.5. RESULTS: At screening, the mean time-to-conjunctival response was 72.5 ± 35.9 min. NAAGA and FM extended the response time to 114.8 ± 55.0 and 116.6 ± 51.5 min respectively. The mean amounts of allergen required to trigger a conjunctival response were 1.165 ng after NAAGA and 1.193 ng after FM treatment. The risk ratio for the conjunctival response was 0.977 (95% CI: 0.812; 1.174), which indicated non-inferiority. Adverse events occurred less frequently with NAAGA (29.2%) than with FM (58.3%). CONCLUSION: In patients with allergic conjunctivitis to birch pollen, NAAGA was non-inferior to FM in exposures to airborne Bet v 1. The EEC was a good model for simulating real-life airborne allergen exposure and for demonstrating the efficacy and safety of eye drops for treating allergic conjunctivitis. TRIAL REGISTRATION: Not registered.

Birch allergen challenges in allergic conjunctivitis using standard conjunctival allergen challenge and environmental exposure chamber.

BACKGROUND: Environmental exposure chambers (EECs) have been used extensively to study allergic rhinoconjunctivitis. Few studies have been published using EECs in conjunctivitis only, and none have used conjunctival allergen challenge as a selection criterion. The present study validated ALYATEC EEC in allergic conjunctivitis to birch pollen. METHODS: Sixteen patients with a positive conjunctival allergen challenge (CAC) were exposed to 60 ng/m3 of Bet v 1 in an EEC on two consecutive days for a maximum of 4 h to validate EEC exposure to birch. Reproducibility was tested among seven of the patients. A conjunctival positive scoring during the CAC and the EEC exposure was defined as a Total Ocular Symptom Score (TOSS) ≥ 5. RESULTS: Fifty percent of patients had a conjunctival positive scoring during first exposure and 75% during second exposure. The mean time to a conjunctival response was 81.2 ± 33.9 min and 101.6 ± 57 (P > 0.05) during first and second exposure, respectively. No difference in TOSS occurred between the two exposures. The time necessary to obtain a positive response during the CAC was significantly shorter than with the EEC. The estimated quantity of Bet v 1 inducing a positive response was 0.07 ± 0.03 ng (exposure 1), 0.07 ± 0.07 ng (exposure 2), 980 ± 784 ng (CAC). Conjunctival positive scoring and quantity of Bet v 1 was reproducible in all six EEC exposures. CONCLUSIONS: Early conjunctival responses induced by birch allergen exposures in EEC were different than from those identified with direct instillation during CAC. EEC appears to be closer to natural exposure than CAC.

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.

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.

Efficacy of air cleaners in asthmatics allergic to cat in ALYATEC® environmental exposure chamber.

BACKGROUND: Air cleaners have been promoted for respiratory allergic disease prevention, but there is no clear clinical proof of their efficacy in allergic asthma. OBJECTIVE: To examine the efficacy of a new air cleaner on early and late asthmatic responses in cat-allergic patients. METHODS: This randomized, cross-over, double-blind placebo-controlled study enrolled 24 cat-asthmatic patients with GINA 1 asthma. At baseline, participants were exposed to 40 ng/m3 of airborne cat allergen for a maximum of 2 hours in ALYATEC® environmental exposure chamber (EEC). All participants were subsequently randomized into two groups that were exposed to cat allergen, either with active then placebo air cleaners or with placebo then active air cleaners with a 3-week interval in the EEC. This study was registered under number (NCT03928561). RESULTS: Fewer patients experienced an EAR with active air cleaners (seven patients; 29.17%) than placebo (21 patients; 87.50%). The response incidence was lower with active than with placebo air cleaners. A Cox model demonstrated a significant treatment effect (hazard ratio, 0.10; P = .002). Active air cleaners also prevented late asthmatic response: four patients (16.67%) had a late asthmatic response with active air cleaners compared to 11 patients (45.83%) with placebo (Prescott test P = .002). Active air cleaners also decreased the maximal severity of bronchial response (FEV1 decrease of 17.24% with active vs 25.62% with placebo air cleaners; P = .001). CONCLUSIONS: Our present results demonstrated that Intense Pure Air XL® air cleaners significantly prevented early and late asthmatic responses among cat-allergic asthmatics during cat allergen exposure in the ALYATEC® EEC.

Insomnia treatment assessment based on physiological data analysis.

For the purposes of insomnia treatment, pharmacotherapy is widely used, despite the possibility for the use of behavioural treatment of insomnia. Thus, the assessment and treatment of patients with insomnia needs further investigation. This work addresses insomnia treatment evaluation and medication side-effect assessment based on continuous physiological signals such as EEG and ECG monitoring and analysis. EEG and ECG measurements regarding drug medication (verum/placebo cases) have been used in a series of experiments, where spectral and non-linear features have been calculated, for assessing a possible distinct behaviour between the verum/placebo condition and furthermore the relation of features to a physiological conditions. Results show that a combination of EEG and ECG based characteristics, both spectral and non-linear, can be used to reveal the differences introduced with insomnia medication treatment, either being improvement in the hyperarousal state, or undesired side effects.