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.

Safety and effect on reported symptoms of depigmented polymerized allergen immunotherapy: a retrospective study of 2927 paediatric patients.

BACKGROUND: Allergen immunotherapy (AIT) is effective treatment for allergic diseases, and subcutaneous use of depigmented polymerized extracts may allow rapid up-dosing and safe therapy. To date, there is little information on their safety and clinical effects for children and adolescents with allergic disease. METHODS: We performed a retrospective survey of patient notes of 2927 children and adolescents across 136 centres who had received subcutaneous AIT (SCIT) with depigmented polymerized extracts to pollen or mite allergens for at least 1 yr to collect documentation on safety and clinical symptoms. RESULTS: 16.3% percent of patients had local reactions, of these 148 were larger than 12 cm in diameter. Systemic reactions were documented in 1.6% of children and in 0.8% of adolescents. There were no documented cases of anaphylactic shock. There were significant reductions in the frequency of patients with recorded nasal symptoms over time of treatment. Moreover, the prescribing rate of rescue medication was reduced over the course of SCIT. CONCLUSION: These 'real-life' data from a large retrospective analysis including 2927 children and adolescents with pollen- and/or mite-induced allergic rhinoconjunctivitis with/or without allergic asthma indicate that AIT with depigmented polymerized extracts is well tolerated, and they are compatible with clinical response.

Efficacy and safety of subcutaneous allergen-specific immunotherapy with depigmented polymerized mite extract in atopic dermatitis.

BACKGROUND: Exposure to house dust mites (HDMs) aggravates the course of atopic dermatitis (AD) in patients sensitized to HDMs. OBJECTIVES: This study investigated the efficacy and safety of subcutaneous allergen-specific immunotherapy with the use of depigmented polymerized mite extract as an add-on therapy to basic (ie, topical and, as necessary, systemic) medication. METHODS: Patients (n = 168) were recruited in a randomized, double-blind, placebo-controlled parallel group phase III study conducted in Germany (21 sites), in adult patients with AD aggravated by HDMs. The primary end points of the study were the assessments of the area under the curves of the total Severity Scoring Atopic Dermatitis (SCORAD) score and of the use of basic medication during the 18-month treatment period. Post hoc subgroup analyses were also performed. RESULTS: Overall efficacy analysis of the intention-to-treat and per-protocol study populations showed no statistically significant differences between the active treatment and placebo groups. However, the subgroup of patients with severe AD (SCORAD > 50) showed a statistically significant reduction of the median total SCORAD by 18% (P = .02) compared with placebo. The frequency of adverse reactions was similar in both groups, suggesting the safety of the active treatment. CONCLUSION: Although subcutaneous allergen-specific immunotherapy showed no statistically significant difference in the overall population of patients with AD, statistically significant reduction of the total SCORAD could be achieved in a subgroup of patients with severe AD.

A high-dose, depigmented polymerized birch pollen extract for subcutaneous allergen immunotherapy has a favourable efficacy/safety ratio.

BACKGROUND: Subcutaneous allergen immunotherapy (SCIT) with depigmented, polymerized (DPP) birch pollen extract has been marketed at doses of up to 1000 DPP units/mL since 2001. We sought to determine the dose-dependent efficacy of a DPP birch pollen extract formulation in patients suffering from birch-pollen-induced allergic rhinitis or rhinoconjunctivitis with or without intermittent asthma. METHODS: A titrated conjunctival provocation test (CPT) was applied as a surrogate marker. This Phase II randomized, double-blind, parallel-group, dose-ranging clinical trial was performed at 39 centres in Germany, Lithuania and Poland. After randomization to four dose-level groups (100, 1000, 5000 and 10,000 DPP units/mL) and up-dosing, participants received maintenance SCIT with five monthly subcutaneous injections. The primary endpoint was the proportion of patients in whom a higher concentration of birch pollen (vs. baseline) was needed to elicit a positive CPT. RESULTS: Three hundred forty-three patients were included (mean (range) age: 42.6 (19-70)). The highest CPT responder rates were seen in the higher dose-level groups. In the intention-to-treat analysis, the difference between the 100 and 10,000 groups was statistically significant (p = 0.0118). Although the proportion of patients with ≥1 treatment-emergent adverse events increased with the dose, almost all these events were mild (65.6%) or moderate (18.5%). CONCLUSION: Judging by the results of a CPT, the efficacy/safety ratio in SCIT appears to be favourable for a high-dose-level preparation of a DPP birch pollen extract.

Persistence in allergen immunotherapy: A longitudinal, prescription data-based real-world analysis.

INTRODUCTION: Allergic rhinitis (AR) is a widespread disease with increasing prevalence in developed countries. The only treatment that tackles the underlying causes is allergen immunotherapy (AIT). This treatment is performed through two application routes, the subcutaneous immunotherapy (SCIT) or the sublingual immunotherapy (SLIT). However, persistence during the long course of treatment over 3 years is key for the efficacy of this treatment option. The impaired adherence significantly impacts public health resources. The aim of this study was to assess the persistence of AIT for both application routes. METHODS: IQVIATM LRx was used to identify patients starting AIT between 2009 and 2018 with grass pollen (GP), early flowering tree pollen (EFTP) and house dust mite (HDM) allergens. Patients were classified within each allergen category by AIT groups (subcutaneous depigmented polymerised allergen AIT [dSCIT], other subcutaneous AIT [oSCIT] and SLIT) and age (5-11 years, 12-17 years, 18+ years). Furthermore, they were followed up for up to 3 years until the cessation of treatment. Patients, who were still on treatment after 3 years were deemed to be censored. Kaplan-Meier curves of persistence were generated and compared by log-rank tests. RESULTS: The number of patients included in the three allergen categories was 38,717 GP, 23,183 EFTP, and 41,728 HDM AIT. In all allergen categories and for any product group, patient persistence decreased with increasing age class with the difference between 5-11 years and 12-17 years greater than between the latter and 18+ years. The percentage of patients completing the first year of AIT was low, particularly for SLIT where 22.2%-27.1% of patients remained persistent after 12 months. The equivalent figures for dSCIT were 52.0%-64.1% and for oSCIT 38.3%-50.3%. CONCLUSION: Persistence in AIT in AR was low in this retrospective prescription-based database and was clearly linked to patient age and application route.

Subcutaneous birch pollen allergen immunotherapy with a depigmented polymerized extract shows only sustained and long-term efficacy in a subgroup of monosensitized adults and adolescents with allergic rhinitis.

Background: Allergen immunotherapy (AIT) is an approved treatment for seasonal respiratory allergic diseases. A depigmented polymerized birch pollen extract for subcutaneous allergen immunotherapy (SCIT) has been demonstrated to be efficacious and safe in patients allergic to birch pollen and its homologous group. Objective: To determine whether SCIT with a birch pollen formulation (5000 depigmented polymerized (DPP) units/mL) shows sustained and long-term efficacy in adults and adolescents with birch-pollen induced allergic rhinitis with or without intermittent asthma. Methods: A multicentre (n = 66), double-blind, placebo-controlled Phase III clinical trial was performed in the Czech Republic, Finland, Germany, Latvia, Lithuania, Poland and Russia. Participants were randomized 2:1 to active treatment (birch 5000 DPP/ml) or placebo for three years of SCIT and followed up for two treatment-free years. The primary efficacy endpoint was the EAACI's combined symptom and medication score for rhinoconjunctivitis (CSMSEAACI). Results: A total of 973 participants were screened and 649 were randomized (active treatment: n = 434; placebo: n = 215). The intention-to-treat analysis of the CSMSEAACI in the overall study population did not demonstrate statistically significant differences in years 1, 2 and 3. In a post-hoc analysis, among the subgroup of patients monosensitized to birch pollen allergen only (n = 200), we observed a statistically significant difference (active treatment vs. placebo) in the CSMSEAACI in year 2, 3 and 5. The AIT's safety profile was good. Conclusions: SCIT with a depigmented polymerized birch pollen extract was safe. Sustained and long-term efficacy in years 2, 3 and 5 in monosensitized patients, but not in polysensitized patients was demonstrated.(EudraCT 2012-000414-11).

Correlation of the combined symptom and medication score with quality of life, symptom severity and symptom control in allergic rhinoconjunctivitis.

Background: The European Academy of Allergy and Clinical Immunology recommended the Combined Symptom and Medication Score (CSMS) as primary endpoint in clinical trials on allergen-specific immunotherapy (AIT) in allergic rhinoconjunctivitis. Here, the correlation between the CSMS and the validated standardised Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ(S)), Rhinitis Control Assessment Test (RCAT) and Visual Analogue Scale (VAS) was analysed. Methods: Two prospective, multicentre, non-interventional studies on tree pollen, grass pollen and house dust mite allergic patients were performed. The first study comprised 167 patients receiving AIT (AIT population), and the second included 56 patients treated with symptomatic medication only (control population). For up to two seasons (pollen)/exposure periods (house dust mites), participants documented their symptoms and medication intake in a CSMS diary, including VAS. In addition, the standardised RQLQ(S) and the RCAT were completed during study visits. Results: Comparison between CSMS and RQLQ(S) revealed a positive correlation in the AIT population (r = 0.426) and in the control population (r = 0.569). For CSMS and RCAT, a negative correlation with r = -0.409 (AIT) and r = -0.547 (control) was shown. Positive correlation between CSMS and VAS was also demonstrated with r = 0.585 (AIT) and r = 0.563 (control). Conclusion: These results support the assumption that the CSMS correlates with quality of life, symptom severity and symptom control on the one hand, while the moderate strength of correlations on the other hand mirrors distinctions of the CSMS compared to the assessments used here.

Subcutaneous immunotherapy with a depigmented polymerized birch pollen extract--a new therapeutic option for patients with atopic dermatitis.

BACKGROUND: Birch pollen is an important outdoor allergen able to aggravate symptoms in atopic dermatitis (AD). Specific immunotherapy (SIT), an established procedure for allergic airway diseases, might also represent an attractive therapeutic option for the causal treatment of allergen-triggered cutaneous symptoms in these patients. Studies with house dust mite SIT have already shown beneficial effects in AD patients, whereas the safety and efficacy of SIT with birch pollen extract in AD patients have not been studied so far. The aim of this study was to evaluate for the first time the safety and efficacy of SIT with a depigmented polymerized birch pollen extract in AD patients. METHODS: Fifty-five adult patients with moderate-to-severe AD and clinically relevant sensitization to birch pollen received SIT for 12 weeks. SIT was continued during birch pollen season. The assessment of safety, the total SCORAD value, and the Dermatology Life Quality Index (DLQI) were evaluated. RESULTS: The median total SCORAD value was reduced by 34% (p < 0.001) during the course of treatment and the mean DLQI improved by 49% (p < 0.001) despite strong simultaneous birch pollen exposure. Eight patients (14.5%) developed systemic reactions and 19 patients (34.5%) developed local reactions which were of mild intensity in most cases. No patient discontinued the study prematurely due to adverse drug reactions. Coseasonal treatment was well tolerated. CONCLUSION: SIT with a depigmented polymerized birch pollen extract leads to significant improvement of the SCORAD value and the DLQI in patients suffering from moderate-to-severe AD sensitized to birch pollen.

Efficacy and safety results of micellar water, cream and serum for rosacea in comparison to a control group.

BACKGROUND: Rosacea is a common inflammatory skin disorder with centrofacial erythema, flushing, telangiectasia, papules/pustules, and possible ocular or phymatous manifestation. Patients' skin is particularly sensitive to chemical and physical stimuli leading to burning, stinging, dryness, and skin tightness. OBJECTIVE: Dermatological evaluation of the efficacy and safety of skin care products designed for centrofacial erythema in rosacea patients, in comparison with a control group using objective measurements. Rosacea symptoms (itching, tension, warmth, burning, dryness) and quality of life were examined. METHODS: Sixty Caucasians with centrofacial erythema were enrolled in an 8-week prospective study, fifty of them exclusively using the study products (micellar water, cream, and serum) with ten participants randomly assigned to a control group. Patients were evaluated at baseline (V0), at 4 weeks (V1), and at 8 weeks (V2). Three-dimensional objective measurements (VECTRA® ) as well as standardized questionnaires were used. RESULTS: Results were compared with the control group. A significant reduction of 16% in skin redness as indicated by VECTRA® analysis was seen in the intervention group comparing V0-V2. Furthermore, rosacea-associated symptoms diminished by 57.1%, while life quality of affected patients within the intervention group improved by 54.5% comparing V0-V2, respectively. CONCLUSIONS: A skin care regime suitable for sensitive and redness-prone skin led to an enhanced clinical appearance, to a decrease of associated symptoms in rosacea patients, and to an improved life quality.

Subcutaneous immunotherapy with depigmented-polymerized allergen extracts: a systematic review and meta-analysis.

BACKGROUND: Double-blind, placebo-controlled trials (DBPCTs) have confirmed the efficacy of allergen-specific immunotherapy (AIT) with depigmented-polymerized allergen extracts (DPAEs). This systematic review evaluates the efficacy of AIT using different allergens in different severity stages of rhinoconjunctivitis with or without asthma in the pollen studies and asthma and rhinitis in the house dust mite studies in comparison to placebo. METHODS: We used MEDLINE, Embase, CENTRAL and LILACS databases to review DBPCTs published until July 2016. The combined symptom and medication score (cSMS) served as primary endpoint. The total rhinoconjunctivitis symptom score (RCSS) and total score in Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) were secondary efficacy endpoints. Solicited local and systemic adverse events were secondary safety endpoints. We assumed a random effects model with standardized mean differences (SMDs) or mean differences as summary statistics. In a subgroup analysis, we classified the studies following the GINA (Global Initiative for Asthma) and ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines for rhinoconjunctivitis and asthma severity. RESULTS: Six DBPCTs in pollen and 2 trials in house dust mites (HDM) were selected. Patients (N = 915) with intermittent or mild persistent asthma were included in 3 (37.5%) and 5 (62.5%) trials, respectively. Two (25%) HDM studies included patients with moderate persistent asthma, 4 trials patients with moderate-to-severe rhinoconjunctivitis. Treatment periods ranged from 12 to 24 months. AIT with DPAEs yielded significantly lower cSMS (SMD: 1.9, 95% CI: 0.9-2.8) and RQLQ (SMD: 0.3, 95% CI: 0.1-0.5) values than did placebo. An exploratory analysis of cSMS and RCSS suggested that the efficacy of AIT treatment with DPAEs was higher in trials including patients with more severe rhinoconjunctivitis and asthma. A publication bias was not detected. Heterogeneity between individual studies was explained by differences in severity. Patients receiving DPAEs did not experience a significantly higher risk of local (OR: 1.55, 95% CI: 0.86-2.79) or systemic reactions (OR: 1.94, 95% CI: 0.98-3.84). CONCLUSIONS: Compared to placebo, AIT with DPAEs is effective in patients with pollen- or HDM-induced rhinoconjunctivitis with or without allergic asthma and improves health-related quality of life. It does not differ significantly in safety and tolerability.

House dust mite-specific immunotherapy with two licensed vaccines: Outcome under clinical routine conditions.

INTRODUCTION: House dust mite (HDM) allergens are major causes for the development of allergic diseases. A disease modifying effect and clinical benefit of allergen immunotherapy (AIT) has been demonstrated in a number of clinical trials. Clinical trials, however, are carried out in selected populations under specific conditions based on inclusion and exclusion criteria and may not represent the entire patient population from medical practice. Objective of this study conducted in patients with HDM allergy was to systematically collect information about the benefit of AIT under clinical routine conditions. METHODS: In this prospective, multi-center non-interventional study, 220 patients (117 adults, 103 children) with HDM allergy receiving subcutaneous AIT with Depigoid® were monitored for 2 years. Organ-specific key symptoms, health-related quality of life (QoL), and the use of concomitant anti-allergic medication were assessed at baseline and after 12 and 24 months. Effectiveness and tolerability of the AIT was assessed by physicians and patients. Occurrence of adverse events (AEs) was continuously monitored. RESULTS: Two hundred and nineteen patients (116 adults, 103 children) were evaluated. A major improvement of the total symptom-score was observed after 24 (12) months in 76% (72%) and 80% (79%) of adults and children, respectively, accompanied by a reduction in concomitant anti-allergic medication and a pronounced improvement in QoL. The effectiveness and tolerability of the AIT was estimated as very good/good by 80-90% of physicians and patients. AEs were observed in 4/117 adults (3.4%) and in 7/103 children (6.8%). Serious AEs were reported in three adults and one child: A grade-II anaphylactic reaction (one adult) controlled by oral antihistamines (no hospitalization) classified as "definitely," three others as not (2) or possibly (1) drug-related. CONCLUSIONS: The data collected from 220 patients confirm the efficacy, tolerability/safety, and acceptance of AIT with Depigoid® in adults and children with HDM allergy under routine clinical conditions.

Safety of a depigmented, polymerized vaccine for the treatment of allergic rhinoconjunctivitis and allergic asthma.

BACKGROUND: Clinical efficacy of specific immunotherapy (SIT) with depigmented, polymerized allergen extracts is well documented in placebo-controlled trials, and safety data are encouraging although further data are required. METHODS: We enrolled 768 patients (51% men; mean age, 31 years) in this prospective multicenter study on safety and clinical effects of Depigoid (Laboratorios LETI, S.L., Madrid, Spain). Immunotherapy consisted of four injections of increasing doses of Depigoid at weekly intervals followed by monthly maintenance injections. All adverse events were documented. Moreover, nose, eye, and lung symptoms were assessed at baseline after 3 and 6 months. Results were compared with the scores of the preceding season. RESULTS: Rates for local and systemic reactions that might possibly be related to the study medication were 2.36 and 4.56/1000 injections, respectively. With 5923 injections given, 14 local reactions were reported (5 patients), and 27 systemic reactions were reported, including 20 of grade 1 (6 patients) and 7 of grade 2 (4 patients). The best safety profile was seen for patients vaccinated against house-dust mites. Reductions in nose, eye, and lung symptoms as well as in concomitant medication compared with either the preceding season (pollen-sensitized patients) or the baseline (house-dust mite-sensitized patients) were observed at the end of study. CONCLUSION: In this large multicenter study on 768 patients with allergic rhinoconjunctivitis and allergic asthma under daily practice conditions SIT with Depigoid was well tolerated with low rates of local and systemic reactions. Furthermore, SIT resulted in considerable reductions in symptoms and concomitant medication.