Development of an air flow calorimeter prototype for the measurement of thermal power released by large radioactive waste packages.

The estimation and control of the thermal power released by the radioactive waste packages are a key parameter in the management of radioactive waste geological repository sites. In the framework of the European project "Metrology for decommissioning nuclear facilities," the French National Agency of Radioactive Waste Management (ANDRA) collaborates with Laboratoire National de Métrologie et D'essais in order to measure the thermal power up to 500 W of typical real size radioactive waste packages (of at least 0.175 m3) with an uncertainty better than 5% by using a measurement method traceable to the international system of units. One of the selected metrological approaches is based on the principles of air flow calorimetry. This paper describes in detail the development of the air flow calorimeter prototype as well as the design of a radioactive waste package simulator used for its calibration. Results obtained from the calibration of the calorimeter and from the determination of thermal powers are presented here with an investigation of the measurement uncertainties.

In allergic rhinitis, work, classroom and activity impairments are weakly related to other outcome measures.

BACKGROUND: The impact of grass pollen-induced allergic rhinitis (AR) on classroom/work productivity and activities can be assessed with a specific instrument: the Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment Questions: Allergy Specific (WPAI-AS). This study evaluated the relationships between the WPAI-AS and other outcome measures in AR. METHODS: Adolescents (aged 12-17) and adults (aged 18-65) consulting specialists for AR were enrolled in a four-week, multicentre, observational study. The management of AR was left to the physicians' discretion. Participants regularly rated the WPAI-AS, their symptoms (using the Rhinoconjunctivitis Total Symptom Score (RTSS) and a 0- to 100-mm visual analogue scale (VAS)) and quality of life (according to the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ)). RESULTS: A total of 247 adolescents and 292 adults showed similar baseline impairments in classroom/work productivity and activities other than work. In both age groups, the WPAI-AS scores were moderately correlated with the RQLQ score and, to a lesser extent, with the VAS score and the RTSS. A multiple regression analysis indicated that the RQLQ score was a weak but statistically significant predictor of both impaired work/classroom productivity and daily activities. A 50-mm VAS cut-off categorized patients in whom AR had the greatest impact on productivity. CONCLUSIONS: Grass pollen-induced AR impairs work/classroom and daily activity to a similar extent in adults and adolescents. The weak-to-moderate correlations with AR symptom scores and quality-of-life scores suggest that a specific tool (such as the WPAI-AS) should be used to assess AR's impact on word/classroom productivity and daily activities.

House dust mite sublingual immunotherapy is safe in patients with mild-to-moderate, persistent asthma: a clinical trial.

BACKGROUND: The safety of allergen immunotherapy (AIT) in asthma has not always been sufficiently documented; accordingly, fear of asthma exacerbations has made physicians somewhat reluctant to prescribe AIT in this context. In a double-blind, placebo-controlled, randomized clinical trial, house dust mite (HDM) sublingual AIT was found to be efficacious in moderate, persistent asthma. The trial's safety results are now reported in detail. METHODS: Asthmatic adults were randomized 2 : 1 to twelve months of daily treatment with a sublingual solution of Dermatophagoides pteronyssinus and Dermatophagoides farinae extracts or a placebo. Adverse events (AEs) at least possibly related to the investigational product were classified by the investigators as adverse drug reactions (ADRs). RESULTS: Overall, the patients in the safety analysis set (n = 484; active treatment: n = 322; placebo: n = 162) had mostly well-controlled, persistent asthma [mild in 290 patients (59.9%), moderate in 183 (37.8%) and severe in 11 (2.3%)]. No treatment-related serious AEs were reported. A total of 87.0% and 75.9% of the patients in the active and placebo groups, respectively, experienced at least one AE (mostly mild), and 78.9% and 48.1% experienced an ADR (mostly mild or moderate oral reactions). The incidence of asthma exacerbations (symptoms requiring a short course of oral corticosteroids) during the study was similar in the active treatment group (3.7%) and the placebo group (4.3%). There were no significant intergroup differences or intragroup changes over time in respiratory AEs, lung function or asthma-related quality of life. CONCLUSIONS: HDM sublingual AIT was safe and well tolerated in adult patients with mild-to-moderate, persistent asthma (ClinicalTrials.gov: NCT00660452).

Allergen Immunotherapy (AIT): a prototype of Precision Medicine.

Precision medicine is a medical model aiming to deliver customised healthcare - with medical decisions, practices, and/or products tailored to the individual patient informed but not directed by guidelines. Allergen immunotherapy has unique immunological rationale, since the approach is tailored to the specific IgE spectrum of an individual and modifies the natural course of the disease as it has a persistent efficacy after completion of treatment. In this perspective Allergen Immunotherapy - AIT has to be presently considered a prototype of Precision Medicine. Precise information and biomarkers provided by systems medicine and network medicine will address the discovery of Allergen immunotherapy biomarkers for (i) identification of the causes, (ii) stratification of eligible patients for AIT and (iii) the assessment of AIT efficacy. This area of medical technology is evolving rapidly and, compelemented by e-health, will change the way we practice medicine. It will help to monitor patients' disease control and data for (i) patient stratification, (ii) clinical trials, (iii) monitoring the efficacy and safety of targeted therapies which are critical for reaching an appropriate reimbursement. Biomarkers associated with e-health combined with a clinical decision support system (CDSS) will change the scope of Allergen immunotherapy. The cost/effectiveness of Allergen immunotherapy is a key issue for successful implementation. It should include the long-term benefits in the pharmaco-economic evaluation, since no other allergy treatment has this specific characteristic. AIT is the prototype of current and future precision medicine.

Development and evaluation of a sublingual tablet based on recombinant Bet v 1 in birch pollen-allergic patients.

BACKGROUND: Sublingual immunotherapy (SLIT) applied to type I respiratory allergies is commonly performed with natural allergen extracts. Herein, we developed a sublingual tablet made of pharmaceutical-grade recombinant Bet v 1.0101 (rBet v 1) and investigated its clinical safety and efficacy in birch pollen (BP)-allergic patients. METHODS: Following expression in Escherichia coli and purification, rBet v 1 was characterized using chromatography, capillary electrophoresis, circular dichroism, mass spectrometry and crystallography. Safety and efficacy of rBet v 1 formulated as a sublingual tablet were assessed in a multicentre, double-blind, placebo-controlled study conducted in 483 patients with BP-induced rhinoconjunctivitis. RESULTS: In-depth characterization confirmed the intact product structure and high purity of GMP-grade rBet v 1. The crystal structure resolved at 1.2 Å documented the natural conformation of the molecule. Native or oxidized forms of rBet v 1 did not induce the production of any proinflammatory cytokine by blood dendritic cells or mononuclear cells. Bet v 1 tablets were well tolerated by patients, consistent with the known safety profile of SLIT. The average adjusted symptom scores were significantly decreased relative to placebo in patients receiving once daily for 5 months rBet v 1 tablets, with a mean difference of 17.0-17.7% relative to the group treated with placebo (P < 0.025), without any influence of the dose in the range (12.5-50 µg) tested. CONCLUSION: Recombinant Bet v 1 has been produced as a well-characterized pharmaceutical-grade biological drug. Sublingual administration of rBet v 1 tablets is safe and efficacious in patients with BP allergic rhinoconjunctivitis.

The minimally important difference in the Rhinoconjunctivitis Total Symptom Score in grass-pollen-induced allergic rhinoconjunctivitis.

BACKGROUND: The minimally important difference (MID) has been defined as the smallest improvement considered worthwhile by a patient. The MID has not been estimated for the Rhinoconjunctivitis Total Symptom Score (RTSS). METHODS: In a prospective multicentre study, patients consulting for grass-pollen-induced allergic rhinitis (AR) recorded a 15-point global rating of change scale (GRCS) score and the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score on a weekly basis and the individual symptom scores comprising the RTSS on a daily basis over two consecutive weeks. The MID in the RTSS was determined with anchor-based methods (using the GRCS and the RQLQ) and a distribution-based method [based on the RTSS' standard deviation (SD)]. RESULTS: The study population comprised 806 patients (253 children, 250 adolescents and 303 adults). During the first week of the study, the mean ± SD RTSSs for these age groups were 6.5 ± 3.3, 6.8 ± 3.4 and 7.0 ± 3.4, respectively. For an improvement of 2 points in the GRCS or 0.5 points in the RQLQ score, the regression analysis yielded MIDs in the RTSS of 1.24 ± 0.17 and 1.12 ± 0.14 in children, 1.33 ± 0.14 and 1.20 ± 0.13 in adolescents and 1.13 ± 0.14 and 0.89 ± 0.12 in adults, respectively. When applying distribution-based methods, the MID ranged from 1.09 to 1.13 (based on 0.33 SDs of the first-week RTSS) and from 1.22 to 1.40 (based on 0.5 SDs of the difference in RTSSs between the first and second weeks). CONCLUSION: The MID in the RTSS was consistently estimated as 1.1-1.3 (and could conceivably be rounded to 1) in patients with grass-pollen-induced AR.

House dust mite sublingual immunotherapy is safe and appears to be effective in moderate, persistent asthma.

BACKGROUND: The efficacy and safety of sublingual immunotherapy in house dust mite-induced asthma have yet to be firmly established. We report the results of a double-blind, placebo-controlled, randomized clinical trial performed in mainland China. METHODS: After a three-month baseline period, 484 asthmatic adults were randomized 2 : 1 to 12 months of daily treatment with either an aqueous, standardized, 300 index of reactivity mixture of Dermatophagoides pteronyssinus and Dermatophagoides farinae extracts or a placebo. The primary efficacy criterion was well-controlled asthma for at least 16 of the last 20 weeks of treatment. RESULTS: In the active (n = 308) and placebo (n = 157) groups, well-controlled asthma was achieved by 85.4% and 81.5% of the patients, respectively (P = 0.244). A subsequent post hoc analysis by asthma severity revealed significant clinical benefits in actively treated subjects with moderate, persistent asthma at baseline [401-800 µg budesonide/day (n = 175)], with greater achievement of well-controlled asthma (80.5% and 66.1% for the active treatment and placebo groups, respectively; P = 0.021) and totally controlled asthma (54.0% and 33.9%, respectively, P = 0.008), a higher percentage of patients with an asthma control questionnaire score < 0.75 (56.6% and 40.0%, respectively; P = 0.039) and a greater mean reduction in inhaled corticosteroid use (218.5 µg and 126.2 µg, respectively; P = 0.004). The active vs placebo differences in disease control and corticosteroid use were not significant for mild, persistent asthma. No treatment-related serious adverse events were reported. CONCLUSIONS: Sublingual mite allergen immunotherapy was well tolerated in adult asthmatics and effectively controlled disease in patients with moderate (but not mild) persistent asthma (ClinicalTrials.gov: NCT00660452).

Comments on :"Allergen immunotherapy as a drug: the new deal of grass allergen tablets from clinical trials to current practice".

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Allergen-specific CD4+ T cell responses in peripheral blood do not predict the early onset of clinical efficacy during grass pollen sublingual immunotherapy.

BACKGROUND: Surrogate biomarkers of efficacy are needed in support of allergen-specific immunotherapy. OBJECTIVE: The aim of this study was to relate changes in peripheral CD4(+) T cell responses to clinical efficacy during sublingual immunotherapy (SLIT). METHODS: Allergen-specific CD4(+) T cell responses were assessed in peripheral blood mononuclear cells (PBMCs) from 89 grass pollen-allergic individuals enrolled in a double-blind placebo-controlled SLIT study conducted in an allergen exposure chamber (ClinicalTrials.gov NCT00619827). Surface phenotype, proliferative responses, cytokine production and gene expression were analysed in coded samples at baseline, and after 2 and 4 months of SLIT, in PBMCs after in vitro allergen stimulation or among MHC class II/peptide (pMHCII)-tetramer-positive CD4(+) T cells. RESULTS: SLIT induced a 29.3% improvement of the average rhinoconjunctivitis total symptom score in the active group, when compared to the placebo group. In parallel, only minor changes in proportions of CD4(+) T cells expressing Th1 (CCR5(+), CXCR3(+)), Th2 (CRTh2(+), CCR4(+)) and Treg (CD25(+), CD127(-), Foxp3(+)) markers were detected. A down-regulation of IL-4 and IL-10 gene expression and IL-10 secretion (P < 0.001) were observed, as well as a decrease in the frequency of potential "pro-allergic" CD27(-) Th2 cells from patients receiving active tablets (P < 0.001), but without any correlation with clinical benefit. pMHCII-tetramer analyses failed to document any major impact in both numbers and polarization of circulating Phl p 1- and Phl p 5-specific CD4(+) T cells, confirming that early clinical improvement during SLIT is not associated with dramatic alterations in T lymphocyte responses. CONCLUSION & CLINICAL RELEVANCE: Changes in patterns of peripheral CD4(+) T cells are not markers for the early onset of efficacy during SLIT.

Absence of IgE neosensitization in house dust mite allergic patients following sublingual immunotherapy.

BACKGROUND: The impact of sublingual immunotherapy (SLIT) on IgE neosensitization remains to be evaluated in large cohorts of patients. OBJECTIVES: The aim of this study was to assess the dynamics of antibody responses induced in patients with allergic rhinitis during a 12-month treatment with sublingual tablets of house dust mites (HDM) allergen extracts. METHODS: Antibody responses were assessed in relationship with neosensitization and clinical benefit in sera from 509 European house dust mite-allergic patients before and after 1 year of daily sublingual immunotherapy, using tablets containing Dermatophagoides pteronyssinus plus D farinae extracts or placebo (ClinicalTrials.gov NCT00674700). Patients were followed for one additional year after treatment cessation. IgE and IgG4 antibodies specific for mite extracts or purified group 1, 2 and 10 allergens were assessed using Immulite, Immunocap and ISAC assays. RESULTS: After 1 year of SLIT, mite-specific IgE and IgG4 titres increased by 1.5-fold and fourfold, respectively, in the active, but not in the placebo group. A strong IgG4 induction occurred in a subgroup (i.e. 10-15%) of "immunoreactive" patients, without any correlation with improvement in the average adjusted symptom score. Pre-existing IgE levels to purified mite allergens were not impacted during immunotherapy, and no de novo IgE responses to group 1, 2, 10 allergens were induced in patients who were unsensitized prior to immunotherapy. Similarly, no IgE neosensitization to wheat germ or yeast components used in the mite culture medium was observed. CONCLUSIONS AND CLINICAL RELEVANCE: We document in a cohort of 509 patients followed over a 2-year period that SLIT does not induce any IgE neosensitization to allergens contained in the vaccine, such as groups 1, 2 as well as the food-related group 10 allergen. This observation further corroborates the safer safety profile of SLIT over SCIT.

Changes in basophil activation during grass-pollen sublingual immunotherapy do not correlate with clinical efficacy.

BACKGROUND: Biomarkers predicting the safety and efficacy of sublingual immunotherapy (SLIT) remain to be established. METHODS: Eighty-nine patients with allergic rhinoconjunctivitis to grass pollen received either a placebo or five-grass-pollen daily tablet sublingually for 4 months. Following exposure in an allergen challenge chamber, clinical responders and nonresponders were identified individually by evaluating their rhinoconjunctivitis total symptom score (RTSS). Activation of peripheral blood basophils was measured by cytofluorometry before and after 2 or 4 months of immunotherapy, based on CD203c surface expression following allergen stimulation. RESULTS: Patients receiving the grass-pollen tablet had a relative mean improvement of 29.3% vs placebo in the average RTSS after 4 months of SLIT (P < 0.0003). No significant changes in basophil activation were noticed after 2 or 4 months of SLIT despite induction of specific IgGs. Among individual clinical responders, basophil activation was either decreased, increased, or unmodified during SLIT. Levels of basophil activation prior to immunotherapy were not predictive of local adverse reactions associated with immunotherapy. A moderate association was found between basophil activation and allergen-specific IgE levels, skin reactivity, or RTSS, suggesting that the former is, to some extent, indicative of disease severity. As such, patients with the highest level of basophil activation before treatment were more likely to benefit clinically from SLIT. CONCLUSIONS: Allergen reactivity of peripheral blood basophils is not a biomarker for adverse events or early onset of clinical responses to SLIT.

The average Adjusted Symptom Score, a new primary efficacy end-point for specific allergen immunotherapy trials.

BACKGROUND: In clinical trials, the efficacy of immunotherapy for allergic rhinoconjunctivitis symptoms is often evaluated with the average Rhinoconjunctivitis Total Symptom Score (ARTSS). Effective treatment is associated with a lower ARTSS vs. placebo but use of rescue medication to alleviate symptoms reduces the RTSS and decreases the mean difference between active treatment and placebo groups. OBJECTIVE: To develop and describe the average Adjusted Symptom Score (AdSS), a new end-point reflecting symptom severity and rescue medication use in allergic rhinoconjunctivitis trials. METHODS: To calculate the AdSS, the RTSS is adjusted as follows: if a patient takes rescue medication on day d, the day's AdSS (AdSS(d)) is defined as the value of RTSS(d) or AdSS(d-1), whichever is higher. The AdSS on the following day (AdSS(d+1)) is defined as the value of RTSS(d+1) or AdSS(d), whichever is higher. The average of the daily AdSSs (during the season) was calculated post hoc for two trials investigating the efficacy of five-grass pollen sublingual immunotherapy tablets in adult and paediatric patients and compared with the ARTSS and three other outcome measures (the average Rescue Medication Score (ARMS), the ARTSS and the average Combined Score). RESULTS: The average AdSS clearly discriminated between active and placebo treatments and confirmed the original ARTSS results. Adjustment for rescue medication use decreased the observed placebo effect. CONCLUSION AND CLINICAL RELEVANCE: The average AdSS can be a valuable alternative to the ARTSS as a primary efficacy end-point in grass pollen allergic rhinoconjunctivitis trials. By adjusting the RTSS for rescue medication use, the AdSS can estimate symptom severity and the treatment effect more accurately. The AdSS is now being tested prospectively in large clinical trials.