Genetic and T2 biomarkers linked to the efficacy of HDM sublingual immunotherapy in asthma.

BACKGROUND: Hypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT). OBJECTIVE: To investigate whether genetic and type 2 (T2) inflammatory biomarkers correlate with disease severity in subjects with allergic asthma, and whether this can be modified by AIT. METHODS: MITRA (NCT01433523) was a phase III, randomised, double-blind, placebo-controlled trial of HDM sublingual immunotherapy (SLIT)-tablets in adults with HDM allergic asthma. Post hoc analyses of the study population (N=742) evaluated associations between T2 inflammatory (blood eosinophils, eosinophil cationic protein (ECP), total IgE and tryptase) and genetic (single-nucleotide polymorphisms, SNP) biomarkers (n=582) for the primary study endpoint (time to first moderate/severe asthma exacerbation). SNP associations were verified in HDM-positive subgroup from an independent 3-year Severe Asthma Research Programme (SARP3) subject cohort. RESULTS: An increased asthma exacerbation risk in subjects homozygous for SNP rs7216389 (chromosomal locus 17q12-21) was reduced (p=0.037) by treatment with HDM SLIT (HR=0.37 (95% CI 0.22 to 0.64), p<0.001). The associations between exacerbation risk and 17q12-21 SNPs were replicated in the SARP3 HDM-positive subgroup. High levels of T2 biomarkers were associated with increased risk of asthma exacerbations in the placebo group. HDM SLIT-tablet treatment reduced this risk (blood eosinophils: HR=0.50 (95% CI 0.30 to 0.85); ECP: HR=0.45 (95% CI 0.29 to 0.87); tryptase: HR=0.45 (95% CI 0.25 to 0.80)). The treatment effect was higher (p=0.006) for subjects with a higher number of elevated T2 biomarkers. CONCLUSIONS: HDM SLIT-tablet AIT is efficacious in HDM-sensitised asthma subjects with a genetic asthma predisposition and/or an underlying T2 endotype. TRIAL REGISTRATION NUMBER: NCT01433523.

Short-term and long-term efficacy of sublingual immunotherapy in different courses for house dust mite-induced allergic rhinitis.

PURPOSE: Sublingual immunotherapy (SLIT) has been proven to be an effective and safe treatment for patients with house dust mite (HDM)-induced allergic rhinitis (AR) to achieve short-term and long-term efficacy. This study aimed to investigate the relationship between SLIT duration and long-term efficacy. MATERIALS AND METHODS: This study involved 134 patients who underwent SLIT between 2019 and 2021 (in the 2-year group), between 2018 and 2021(in the 3-year group), or between 2017 and 2021 (in the 4-year group). The total nasal symptoms score (TNSS), total medication score (TMS), visual analogue scale (VAS), the Mini Rhinoconjunctivitis Quality of Life Questionnaire (MiniRQLQ) and adverse events (AEs) were assessed at baseline, after treatment (2021) and one year after the treatment completion (2022). The correlation between MiniRQLQ and other indicators was also analyzed. RESULTS: After SLIT, patients in all three groups showed significant improvements in TNSS, TMS, VAS and MiniRQLQ scores (all p < 0.001). These improvements were sustained even one year after SLIT. Patients who received 3-4 years of SLIT showed significant improvement compared with those who received 2 years of SLIT in all clinical outcomes (all p < 0.01). The analysis showed positive correlations between the MiniRQLQ and TNSS, TMS, and VAS (all p < 0.001). No significant difference was observed in the AE rate in all three groups (p > 0.05). CONCLUSION: Different duration of HDM SLIT could generate various short-term and long-term clinical efficacy. The MiniRQLQ could be applied to evaluate SLIT efficacy in clinical practice.

Recombinant T-cell epitope conjugation: A new approach for Dermatophagoides hypoallergen design.

BACKGROUND: Allergen-specific immunotherapy (AIT) is the only clinical approach that can potentially cure some allergic diseases by inducing immunological tolerance. Dermatophagoides pteronyssinus is considered as the most important source of mite allergens worldwide, with high sensitization rates for the major allergens Der p 1, Der p 2 and Der p 23. The aim of this work is to generate a hypoallergenic hybrid molecule containing T-cell epitopes from these three major allergens. METHODS: The hybrid protein termed Der p 2231 containing T-cell epitopes was purified by affinity chromatography. The human IgE reactivity was verified by comparing those with the parental allergens. The hybrid was also characterized immunologically through an in vivo mice model. RESULTS: The hybrid rDer p 2231 stimulated in peripheral blood mononuclear cells (PBMCs) isolated from allergic patients with higher levels of IL- 2, IL-10, IL-15 and IFN-γ, as well as lower levels of IL-4, IL-5, IL-13, TNF-α and GM-CSF. The use of hybrid molecules as a therapeutic model in D. pteronyssinus allergic mice led to the reduction of IgE production and lower eosinophilic peroxidase activity in the airways. We found increased levels of IgG antibodies that blocked the IgE binding to the parental allergens in the serum of allergic patients. Furthermore, the stimulation of splenocytes from mice treated with rDer p 2231 induced higher levels of IL-10 and IFN-γ and decreased the secretion of IL-4 and IL-5, when compared with parental allergens and D. pteronyssinus extract. CONCLUSIONS: rDer p 2231 has the potential to be used in AIT in patients co-sensitized with D. pteronyssinus major allergens, once it was able to reduce IgE production, inducing allergen-specific blocking antibodies, restoring and balancing Th1/Th2 immune responses, and inducing regulatory T-cells.

Circulating MMP-12 as Potential Biomarker in Evaluating Disease Severity and Efficacy of Sublingual Immunotherapy in Allergic Rhinitis.

Background: Allergic rhinitis (AR) is a highly heterogeneous disease, and allergen-specific immunotherapy (AIT) is an effective treatment. This study aims to evaluate the circulating mas-related G protein-coupled receptor-X2 (MRGPRX2) and matrix metalloproteinase-12 (MMP-12) levels in evaluating disease severity and predicting efficacy of SLIT in AR patients. Methods: We enrolled 110 moderate-severe persist AR patients (AR group) and 40 healthy controls (HC group). Circulating levels of MRGPRX2 and MMP-12 were measured, and their associations with disease severity were evaluated. All AR patients were assigned to receive sublingual immunotherapy (SLIT), and the efficacy was evaluated, and serum samples were collected at 1 year and 3 years after treatment. The correlations between serum MRGPRX2 and MMP-12 and clinical efficacy were assessed. Results: The serum concentrations of MRGPRX2 and MMP-12 were significantly higher in the AR group than the HC group, and the elevated MMP-12 levels were correlated with VAS and TNSS, and serum MRGPRX2 levels were correlated with VAS. Finally, 100 and 80 patients completed 1-year and 3-year follow-up and were classified into effective and ineffective groups. Serum MRGPRX2 and MMP-12 levels were lower in the effective group than the ineffective group. Although serum MRGPRX2 and MMP-12 levels did not significantly change after 1 year SLIT, serum MMP-12 levels were decreased 3 years post-SLIT than baseline and 1 year post-SLIT levels. Receiver operating characteristic (ROC) showed that serum MMP-12 was a potential biomarker for predicting the efficacy of SLIT. Conclusion: Serum MRGPRX2 and MMP-12 appeared to be promising biological indicators in reflecting disease severity in AR patients. Moreover, circulating MMP-12 might serve as a reliable predictor for clinical responsiveness of SLIT.

The Effectiveness of Allergen Immunotherapy in Adult Patients with Atopic Dermatitis Allergic to House Dust Mites.

Background and objectives: Allergen immunotherapy (AIT) is not a first-line therapy in atopic dermatitis (AD) and its effectiveness has been criticised. Objectives: The efficacy and safety of AIT in adult patients with AD and monosensitisation to house dust mites (HDMs) were investigated. Materials and Methods: A total of 37 patients were included in this double-blind, placebo-controlled study. Patients were eligible if they were diagnosed with AD; had moderate-to-severe AD according to the Eczema Area and Severity Index (EASI) with at least 7.1 points, the % BSA (body surface area) scale with at least 16 points, and the IsGA (investigator global assessment) scale with 3 points; had positive skin prick tests (SPTs); and were positive for the specific immunoglobulin E (sIgE) response to D. pteronyssinus and D. farinae extracts, as well as Der p 1 and Der f1. The patients received Purethal mites (20,000 AUeq/mL, HAL Allergy, Leiden, The Netherlands) with the extract allergens D. pteronyssinus and D. farinae (50/50%) or a placebo for 12 months. The primary outcomes included changes in EASI, % BSA, and IsGA due to SCIT between the start and after 12 months of therapy. Results: In the study group, significant improvement was observed in terms of the EASI score from 43 ± 8.2 to 21 ± 5.9 points, % BSA from 72 ± 18 to 28 ± 11 points, and IsGA from 4.5 ± 0.5 to 1.5 ± 0.5 points in comparison with the placebo after 1 year of AIT. Additionally, the proportion of patients who achieved success in the IsGA (IsGA < 2) was significantly better in comparison to the placebo with 13/20 (65%) vs. 4/14 (29%), respectively (p < 0.05). Conclusions: HDM-AIT effectively improved atopic dermatitis in patients that strictly qualified for desensitisation with a confirmed monovalent mite allergy.

[Efficacy comparison and safety analysis of subcutaneous specific immunotherapy with standardized house dust mite allergen in patients with single and multiple allergic rhinitis].

Objective: To investigate the efficacy and safety of house dust mite (HDM) allergen subcutaneous specific immunotherapy (SCIT) in patients with allergic rhinitis (AR) with single dust mite allergy and multiple allergen allergy. Methods: A retrospective study was conducted. A total of 372 patients with allergic rhinitis induced by house dust mite were diagnosed in the allergy clinic of General Hospital of North Theater Command from January 2013 to January 2018.They were treated with house dust mite allergen preparation for standardized SCIT for 3 years or more, and had complete follow-up data. The age ranged from 5 to 55 years, the median age was 13 years, and the average age was (19.4±14.7) years; 216 males and 156 females. According to their age, they were divided into the older group (age >14 years) and younger group (age ≤ 14 years). According to the number of allergens, they were divided into single group (only HDM group allergic to house dust mites) and multi recombination (including 2 or more allergens including house dust mites). The multi recombination was further divided into HDM+1 group, HDM+2 group, HDM+3 group, HDM+4 and above group. Before treatment (T0), 1 year (T1) and 3 years (T2) after SCIT treatment, the patients in each group established files, analyzed and compared the average total nasal symptoms score (TNSS), total non nasal symptoms score (TNNSS), visual analogue scale (VAS), total medicine score (TMS) and rhinoconjunctivitis quality of life questionnaire (RQLQ), and evaluated the clinical efficacy of the treatment and the comparison of various scores in the efficacy of SCIT with different allergens and ages. Record the occurrence of local and systemic adverse reactions of all patients during treatment, and evaluate the safety of SCIT. All scores are measurement data that do not conform to normal distribution. Mann-Whitney U and Kruskai-Wallis test of independent samples are used for inter group comparison, and Bonferroni correction is used for further pairwise comparison; Chi square test and continuity correction method were used for the comparison between count data groups such as the incidence of adverse reactions and the effective rate of TNSS, and a-division method was used for further pairwise comparison. Results: After SCIT treatment, the scores of TNSS, TNNSS, TMS, VAS and RQLQ in T1 and T2 were significantly lower than those in T0, and the scores in T2 were significantly lower than those in T1 (Z=-11.168, -4.786, -6.639, -13.012, -10.652 in T0 vs T1; Z=-13.527, -8.746, -13.397, -14.477, -11.833 in T0 vs T2; Z=-4.721, -4.607, -10.020, -7.180, -5.721 in T1 vs T2; P<0.05). In T1 and T2, compared with the older group, the scores of TNSS, TNNSS, TMS, VAS and RQLQ in younger group were lower, and the differences of various indexes were statistically significant(the median scores of T1: Myounger=3.0, 1.0, 2.0, 4.0, 2.6, Molder=5.0, 2.0, 3.0, 5.0, 3.2; the median scores of T2: Myounger=3.0, 1.0, 0, 2.0, 1.3, Molder=4.0, 1.0, 1.5, 3.0, 2.3; ZT1=-4.525, -5.830, -4.061, -3.608, -2.785; ZT2=-3.847, -4.055, -2.820, -2.998, -3.418; P<0.05). In T1 and T2, the scores of TNSS, VAS and RQLQ in a single group after SCIT treatment were lower than those in multiple recombination(the median scores of T1:Msingle=4.0, 4.0, 2.6, Mmultiple=5.0, 5.0, 3.2; the median scores of T2: Msingle=3.0, 2.0, 1.4, Mmultiple=4.0, 3.0, 2.1), and the difference was statistically significant (ZT1=-3.002, -2.092, -1.977; ZT2=-3.354, -2.469, -2.116; P<0.05). There was no significant difference in TMS (the median score during T1 period: Msingle=2.0, Mmultiple=3.0, ZT1=-1.130; the median score during T2 period: Msingle=1.0, Mmultiple=1.0, ZT2=-1.544; P>0.05). Further comparison within the group showed that there was no significant difference in the improvement rate of TNSS during T2 period among HDM group, HDM+1 group, HDM+2 group and HDM+3 group (HDM vs HDM+1 group χ2=0.277, HDM vs HDM+2 group χ2=0.78, HDM vs HDM+3 group χ2=0.075, HDM+1 vs HDM+2 group χ2=0.057, HDM+1 vs HDM+3 group χ2=0.019, HDM+2 vs HDM+3 group χ2=0.003; P>0.005), the improvement rates were 92.5%, 90.3%, 89.1% and 89.5%. Respectively in HDM group,HDM+1 group, HDM+2 group, HDM+3 group, compared with HDM+4 and above group, the difference was statistically significant (χ2=26.144, 13.254, 15.144, 8.808; P<0.005). The improvement rate of TNSS in HDM+4 and above group was 60.9%. 122 patients had local adverse reactions during the treatment of SCIT, accounting for 32.8%. The local adverse reactions were 759 injections (15 336 injections in total), accounting for 4.95%. Most of them were swelling, dizziness, induration and pruritus at the injection site, which could be relieved by oral antihistamines or within 2 hours. There were 2 cases of local urticaria, once for each case. The symptoms were relieved within 1 week after oral antihistamine. No serious systemic adverse reactions occurred. Conclusion: Standardized SCIT may be a safe and effective treatment for AR patients, and the type of allergen may be one of the important factors affecting the efficacy of SCIT. The efficacy of SCIT was significant in AR patients with three or less allergens other than house dust mite.

Efficacy of house dust mite sublingual tablet in the treatment of allergic rhinoconjunctivitis: A randomized trial in a pediatric population.

BACKGROUND: The efficacy and safety of 300 index of reactivity (IR) tablets of house dust mite (HDM) allergen extracts in Japanese pediatric (5-16 years old) patients with allergic rhinitis (AR) were assessed in a double-blind, randomized, placebo-controlled study (JAPIC CTI-152981). METHODS: Patients were randomized 1:1 to HDM sublingual tablets or placebo once daily for 52 weeks. The primary end-point was average adjusted symptom score (AASS; average of daily Rhinitis Total Symptom Scores, comprising sneezing, rhinorrhea, nasal congestion, and nasal pruritus, adjusted for rescue medication use), analyzed during Weeks 48-52 (mixed-effects model for repeated measures). RESULTS: Of 438 patients randomized, 403 (92%; 193 active, 210 placebo) completed the study. AASS (least-squares [LS] mean [SE]) during Weeks 48-52 was significantly (P = 0.0005) lower in the active group compared with placebo (6.32 [0.20] vs 7.27 [0.19]; relative LS mean difference, -13%). Immunological responses (IgE and IgG4 antibodies specific to antigens of two HDM species) were significantly greater in the active group compared with placebo (P < 0.0001). Almost all patients experienced mild or moderate adverse events (AEs). The most common treatment-related AEs were oral pruritus, mouth edema, throat irritation, and ear pruritus. One patient experienced serious pseudocroup (subglottic laryngitis) that recovered. There were no deaths or anaphylaxis requiring the use of injectable adrenaline. CONCLUSIONS: The HDM tablet significantly improved symptoms of HDM-induced perennial AR and was associated with a significant immunological response. The safety profile in pediatric patients was consistent with that in adults, with no new safety concerns.

An Engineered Hybrid Protein from Dermatophagoides pteronyssinus Allergens Shows Hypoallergenicity.

The house dust mite (HDM) Dermatophagoides pteronyssinus is an important risk factor for asthma and rhinitis. Allergen specific immunotherapy that is based on recombinant proteins has been proposed for the safer and more efficient treatment of allergic diseases. The aim of this study was to design and obtain a hybrid protein (DPx4) containing antigenic regions of allergens Der p 1, Der p 2, Der p 7, and Der p 10 from this mite. DPx4 was produced in Escherichia coli and its folding was determined by circular dichroism. Non-denaturing dot-blot, ELISA, basophil activation test, dot blot with monoclonal antibodies, ELISA inhibition, and cysteine protease activity assays were performed. Mice that were immunized with DPx4 were also analyzed. We found that DPx4 had no cysteine protease activity and it showed significantly lower IgE reactivity than Der p 1, Der p 2, and D. pteronyssinus extract. DPx4 induced lower basophil activation than Der p 2 and the allergen extract. Immunized mice produced IgG antibodies that inhibited the binding of allergic patient's IgE to the allergen extract and induced comparatively higher levels of IL-10 than the extract in peripheral blood mononuclear cells (PBMC) culture. These results suggest that DPx4 has immunological properties that are useful for the development of a mite allergy vaccine.

Efficacy and safety of sublingual immunotherapy with Dermatophagoides farinae drops in pre-school and school-age children with allergic rhinitis.

BACKGROUND: The safety and efficacy of sublingual immunotherapy (SLIT) have been confirmed by many studies. However, in China, the research on efficacy and safety in young and older children with allergic rhinitis (AR) is still rare. OBJECTIVE: The aim of this retrospective study is to evaluate the efficacy and safety of SLIT with Dermatophagoides farinae drops in pre-school and school-age children with AR. METHODS: A total of 282 subjects aged 2-13 years with AR received a two-year course of sublingual immunotherapy along with pharmacotherapy. According to the age, patients were defined as the pre-school group (2-6 years old, n=116) and school-age group (7-13 years old, n=166). Total nasal rhinitis symptom scores (TNSS), visual analogue score (VAS) and total medication scores (TMS) were evaluated at four time points: baseline, after SLIT for half a year, one year and two years. The adverse events (AEs) were evaluated at each visit. RESULTS: After two-year SLIT, the four rhinitis symptom scores, TNSS, VAS and TMS scores were significantly lower than baseline (all P<0.05). The comparison of efficacy between one and two-year duration showed no significant difference in global clinical outcomes (all P>0.05). In addition, there were no significant differences between the pre-school and school-age group in TNSS (all P>0.05), VAS (all P>0.05) and TMS scores (P>0.05) after SLIT for half a year, one year and two years. No severe systemic AEs were reported. CONCLUSION: SLIT with D. farinae drops is clinically effective and safe in pre-school and school-age patients with house dust mites (HDMs)-induced AR.

A pilot study of immunotherapy in dogs with atopic dermatitis using a mannan-Dermatophagoides farinae allergoid targeting dendritic cells.

BACKGROUND: Polymerized allergoids coupled to nonoxidized mannan (PM-allergoids) are novel allergen preparations used for immunotherapy. OBJECTIVE: To evaluate PM-allergoids as an alternative immunotherapy for dogs with canine atopic dermatitis (cAD) associated with serological responses to Dermatophagoides farinae allergens. ANIMALS: Sixteen dogs with history and clinical signs of cAD; positive on serum allergen specific IgE testing to D. farinae. Twelve dogs were, in addition, positive to Acarus siro and/or Lepidoglyphus destructor. METHODS AND MATERIALS: A prospective pilot study with no control group. PM-allergoids were administered by subcutaneous injection over a 10 month period. A pruritus Visual Analog Scale (pVAS) and medication scores were evaluated. Adverse reactions were recorded. RESULTS: The median value of the pVAS of the dogs decreased from 0.6 to 0.2 with a median of 67% improvement over the first three months (P < 0.0001). The individual improvement for each dog was greater than 60%. No major adverse effects were observed. CONCLUSIONS AND CLINICAL IMPORTANCE: Allergen-specific immunotherapy using an allergoid coupled to nonoxidized mannan may be an effective alternative for the management of cAD.

The European Survey on Adverse Systemic Reactions in Allergen Immunotherapy (EASSI): A paediatric assessment.

BACKGROUND: Safety data on 'real-life' allergen immunotherapy (AIT) in children and adolescents is usually extrapolated from studies in adults. METHODS: Patients aged 18 or under initiating aeroallergen AIT were evaluated in a prospective European survey. Patient profiles and systemic reactions (SRs) were recorded. Descriptive, univariate and multivariate analyses were used to identify risk factors for SRs. RESULTS: A total of 1563 patients (mean ± SD age: 11.7 ± 3.9 years; rhinitis: 93.7%; asthma: 61.5%; polysensitization: 62.5%) and 1578 courses of AIT were assessed. Single-allergen AIT was administered in 89.5% of cases (n = 1412; mites: 49%; grass pollen: 25.8%; tree pollen: 8.7%; Alternaria: 4.6%; dander: 0.8%; weed pollen: 0.6%). Subcutaneous AIT (SCIT) was used in 71.4% (n = 1127) of the treatments, including 574 (50.9%) with natural extracts. Sublingual AIT (SLIT) was used for the remaining 451 treatments (drops: 73.8%; tablets: 26.2%). The mean ± SD follow-up period was 12.9 ± 3.3 months. The estimated total number of doses was 19,669 for SCIT and 131,550 for SLIT. Twenty-four patients (1.53%) experienced 29 SRs. Respiratory (55.7%) and skin symptoms (37.9%) were most frequent. Anaphylaxis was diagnosed in 3 SRs (10.3%), and adrenaline was administered in 2 of these cases. In a univariate analysis, the risk of SRs was lower in mite-sensitized patients and higher in cases of pollen polysensitization (>3), grass pollen extracts and the use of natural extracts (vs. allergoids). CONCLUSIONS: In a real-life paediatric setting, AIT is safe. SRs are infrequent and generally not severe. Pollen polysensitization, grass pollen extracts and natural extracts (vs. allergoids) were risk factors for AIT-associated SRs.

Tablet-based sublingual immunotherapy for respiratory allergy.

Allergic respiratory disease represents a significant and expanding health problem worldwide. The gold standard of therapeutic intervention is still grucocorticosteroids, although they are not effective in all patients and may cause side effects. Allergen Immunotherapy has been administrated as subcutaneous injections for treatment of allergic rhinoconjunctivitis and asthma and has been practiced for the past century. Sublingual immunotherapy (SLIT) tablets are now available for grass- or ragweed-induced rhinoconjunctivitis and will be available in Spain for house dust mite (HDM)-induced rhinoconjunctivitis and asthma in the next months. In this review, new developments in the field of tablet-based SLIT for respiratory allergy are summarized, with special emphasis on HDM-induced allergic rhinitis and asthma. SLIT tablets are the best-documented immunotherapy products on the market and represent a more patient-friendly concept because they can be self-administrated at home.

The efficacy and safety of sublingual immunotherapy in children and adult patients with allergic rhinitis.

BACKGROUND: Clinical research has shown that sublingual immunotherapy (SLIT) is effective and safe in moderate-severe allergic rhinitis (AR) induced by house dust mite (HDM). However, the sample size in many studies is small. Meanwhile, the controversy on the efficacy and safety in the very young children younger than four years old still existed. OBJECTIVE: The aim of this retrospective study is to evaluate the efficacy and safety of SLIT with Dermatophagoides farinae (Der.f) extracts in children and adult patients with allergic rhinitis, particularly in the very young children. METHOD: A total of 573 subjects aged 3-69 with AR received a three-year course of sublingual immunotherapy with Der.f extracts along with pharmacotherapy. The total nasal symptoms score (TNSS), total medication score (TMS), visual analogue score (VAS) and adverse events (AEs) were evaluated at each visit. RESULT: TNSS, TMS, VAS were significantly improved during the three-year course of treatment in comparison to the baseline values (P<0.01). Besides, significant improvement in nasal symptoms and reduction of medication use were also observed in young children aged 3-6 years (P<0.01). No severe systemic adverse events (AEs) were reported. CONCLUSION: SLIT with Der.f drops is clinically effective and safe in children and adult patients with HDM-induced AR, including the very young children less than four years old.

Safety of immunotherapy with glutaraldehyde modified allergen extracts in children and adults.

BACKGROUND: Glutaraldehyde-modified natural allergen extracts show significant reduction in the IgE-binding capacity and proteolytic activity. This allows the administration of higher doses in a shorter period of time, and to mix different allergen extracts. OBJECTIVE: Evaluate the safety of different concentrations and mixtures of glutaraldehyde-modified allergen extracts in a large group of paediatric and adult patients undergoing specific immunotherapy treatment. MATERIALS AND METHODS: 1855 patients (1156 adults and 699 children), suffering from rhinoconjunctivitis and/or asthma, participated in an observational multicentre cohort study, to evaluate the safety of immunotherapy using vaccines containing modified allergen extracts. Patients were monosensitised, or polysensitised, and received a therapeutic vaccine containing polymerised allergen extracts adsorbed onto aluminium hydroxide. Safety was assessed by recording all side reactions related to immunotherapy. RESULTS: The clinically relevant local reactions totalled 120, (90 immediate and 30 delayed) (1.02% of injections). Of them, 31 (0.26% of injections) occurred in children (26 immediate and 5 delayed) and 89 (0.76% of injections) in adults (64 immediate and 25 delayed). There were 38 systemic reactions. Eleven reactions were immediate (9 of grade 1 and 2 of grade 2) and 27 delayed (22 of grade 1 and 5 of grade 2). There were seven grade 2 systemic reactions (0.06% of the injections). No differences (P>0.05) in the number of reactions were observed between adults and children and between treatments were found in systemic reactions. All systemic reactions were mild and resolved spontaneously without the need of medication. CONCLUSION: Specific immunotherapy using natural modified allergen vaccines is safe to treat allergic patients, even at higher doses and in mixtures of unrelated allergen extracts. The percentage of adverse reactions detected is lower than those reported in the literature with native unmodified allergen extracts.

Efficacy of house dust mite sublingual immunotherapy tablet in North American adolescents and adults in a randomized, placebo-controlled trial.

BACKGROUND: The house dust mite (HDM) sublingual immunotherapy (SLIT) tablet (MK-8237; Merck & Co, Kenilworth, NJ/ALK-Abelló, Hørsholm, Denmark) has demonstrated beneficial effects on allergic rhinoconjunctivitis and asthma outcomes in European trials. OBJECTIVE: This is the first trial to assess the efficacy/safety of HDM SLIT-tablets in North American subjects with HDM-induced allergic rhinitis with or without conjunctivitis (AR/C). METHODS: In this double-blind, multicenter trial (NCT01700192) 1482 subjects (aged ≥12 years) with HDM-induced AR/C with or without asthma were randomized to a daily SQ HDM SLIT-tablet (12 SQ-HDM dose) or placebo for up to approximately 52 weeks. A rhinitis daily symptom score (DSS; 4 nasal symptoms, maximum score = 12) of 6 or greater, or 5 or greater with 1 symptom being severe, on 5 of 7 consecutive days before randomization was required. The primary end point was the average total combined rhinitis score, which was defined as the rhinitis DSS plus rhinitis daily medication score (DMS), during the last 8 treatment weeks. RESULTS: Treatment with 12 SQ-HDM improved the total combined rhinitis score by 17% (95% CI, 10% to 25%) versus placebo. Improvements versus placebo in the secondary end points of average rhinitis DSS, rhinitis DMS, total combined rhinoconjunctivitis score, and visual analog scale-assessed AR/C symptoms were 16%, 18%, 17%, and 16%, respectively. All nominal P values were less than .001 versus placebo, except rhinitis DMS (P = 0.15). No treatment-related adverse events meeting the International Council on Harmonization definition of a serious adverse event were reported; 1 nonserious treatment-related systemic allergic reaction occurred (assessed as moderate intensity) at first administration under medical supervision and was treated with epinephrine. CONCLUSIONS: In the first North American trial of use of a SLIT-tablet for HDM allergy, 12 SQ-HDM was well tolerated and improved HDM-induced rhinitis symptoms in adults and adolescents.

A pilot study of the effect of pullulan-conjugated Der f 2 allergen-specific immunotherapy on canine atopic dermatitis.

BACKGROUND: Dermatophagoides farinae is a major and common environmental house dust mite involved in canine atopic dermatitis (CAD). A formulation of recombinant protein Der f 2 is available in Japan for immunotherapy in dogs. HYPOTHESIS/OBJECTIVES: To evaluate the efficacy of a recombinant allergen based on Der f 2-pullulan for the treatment of cAD. METHODS: Dogs (n = 15) with atopic dermatitis were administered Der f 2 conjugated with pullulan (-P). Two dogs were eliminated because of death unrelated to the treatment during the study. The remaining 13 cases were included in the analysis. Clinical signs were evaluated with the Canine Atopic Dermatitis Lesion Index (CADLI) and pruritus levels were evaluated from 0 to 10 with a pruritus Visual Analog Scale (PVAS). RESULTS: The mean ± standard deviation (SD) of CADLI [before allergen-specific immunotherapy (pre-ASIT) 21.9 ± 9.7; 60 days post-ASIT 9.8 ± 8.4 and 120 days post-ASIT 9.7 ± 8.2] and the mean ± SD of PVAS [pre-ASIT 7.2 ± 1.2; post-ASIT (60 days) 2.6 ± 2.2 and post-ASIT (120 days) 3.1 ± 2.5] significantly decreased after treatment (Dunnett's test, P < 0.05). Furthermore, the total doses of oral glucocorticoids in the two months pre-ASIT significantly decreased in comparison with two months post-ASIT (123 ± 72.6 mg vs. 70.0 ± 84.3 mg; Dunnett's test, P < 0.05). CONCLUSIONS AND CLINICAL IMPORTANCE: The results indicate the effectiveness of Der f 2-P recombinant protein in the treatment of dogs with CAD and testing positive to D. farinae.

Randomized controlled trial of primary prevention of atopy using house dust mite allergen oral immunotherapy in early childhood.

BACKGROUND: Children born to atopic parents are at increased risk of sensitization to environmental allergens. OBJECTIVE: We sought to demonstrate proof of concept for oral immunotherapy to high-dose house dust mite (HDM) allergen in infancy in the prevention of allergen sensitization and allergic diseases. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, proof-of-concept study involving 111 infants less than 1 year of age at high risk of atopy (≥ 2 first-degree relatives with allergic disease) but with negative skin prick test responses to common allergens at randomization. HDM extract (active) and appropriate placebo solution were administered orally twice daily for 12 months, and children were assessed every 3 months. Coprimary outcomes were cumulative sensitization to HDM and sensitization to any common allergen during treatment, whereas development of eczema, wheeze, and food allergy were secondary outcomes. All adverse events were recorded. RESULTS: There was a significant (P = .03) reduction in sensitization to any common allergen (16.0%; 95% CI, 1.7% to 30.4%) in the active (5 [9.4%]) compared with placebo (13 [25.5%]) treatment groups. There was no treatment effect on the coprimary outcome of HDM sensitization and the secondary outcomes of eczema, wheeze, and food allergy. The intervention was well tolerated, with no differences between active and placebo treatments in numbers or nature of adverse events. CONCLUSION: Prophylactic HDM oral immunotherapy is well tolerated in children at high heredity risk. The results met the trial's prespecified criteria for proof of concept in reducing sensitization to any allergen; however, no significant preventive effect was observed on HDM sensitization or allergy-related symptoms.

SQ house dust mite sublingually administered immunotherapy tablet (ALK) improves allergic rhinitis in patients with house dust mite allergic asthma and rhinitis symptoms.

BACKGROUND: House dust mite (HDM) allergy is associated with persistent allergic rhinitis (AR) and allergic asthma. OBJECTIVE: To investigate the efficacy and safety of a SQ HDM sublingually administered immunotherapy tablet (ALK, Hørsholm, Denmark) in adults and adolescents with HDM respiratory allergic disease and report the AR results. METHODS: Six hundred four subjects at least 14 years old with HDM AR and mild to moderate HDM allergic asthma were randomized 1:1:1:1 to double-blinded daily treatment with 1, 3, 6 SQ-HDM or placebo. End-of-treatment rhinoconjunctivitis symptoms and medication score were predefined extrapulmonary end points. A subgroup analysis was conducted post hoc in subjects with a total combined rhinitis score (TCRS) > 0 (ie, with AR symptoms and/or AR medication use during the 4-week baseline period). The subgroup was comprised of 498 subjects (82%). RESULTS: In the subgroup, the absolute difference in end-of-treatment TCRS between 6 SQ-HDM and placebo was -0.78 (95% confidence interval -1.47 to -0.07, relative difference 28.8%, P = .0357). Furthermore, a significant difference was found for the total score of the Rhinitis Quality of Life Questionnaire with Standardized Activities RQLQ(S) and for the individual domains: activities, sleep, non-nose and non-eye symptoms, and nasal symptoms. For the TCRS and Rhinitis Quality of Life Questionnaire score, a dose response was seen, with numerically lower, nonsignificant differences for 1 and 3 SQ-HDM. The predefined analysis for the entire trial population showed no statistically significant difference between the placebo and actively treated groups. No safety concerns were observed. CONCLUSION: Efficacy in mild to severe AR of 6 SQ-HDM compared with placebo was demonstrated by statistically significant improvements in TCRS and Rhinitis Quality of Life Questionnaire score in subjects with AR present at baseline. The treatment was well tolerated. TRIAL REGISTRATION: EudraCT, no 2006-001795-20; ClinicalTrials.gov, identifier NCT00389363.

Clinical and cytokine responses to house dust mite sublingual immunotherapy.

BACKGROUND: Cytokine responses accompanying sublingual immunotherapy (SLIT) responder phenotypes have not previously been reported. OBJECTIVE: To investigate clinical and cytokine responses of house dust mite (HDM) sensitive patients with allergic rhinitis receiving HDM SLIT or placebo for 2 years. METHODS: Sixty adults were randomized to receive SLIT or placebo. Clinical symptoms were measured using the Total 5 Symptom Score (TSS5) and Juniper Rhinitis Quality of Life Questionnaire. HDM specific IgE, IgG, skin prick tests, and HDM-stimulated release of interleukin (IL) 5 and interferon γ (IFN-γ) in peripheral blood mononuclear cells was studied at 0, 6, 12, and 24 months and IL-13, IL-4, and IL-10 at 0 and 24 months. RESULTS: A total of 32 of 39 SLIT and 16 of 21 placebo patients completed the study. There was significant clinical improvement in both the SLIT and placebo groups. Median T5SS decreased from 14.75 to 5.25 in the SLIT group (P < .001) and 12.7 to 6.0 in the placebo group (P = .003). The median quality-of-life score also decreased in the SLIT group (P < .001) and the placebo group (P < .001). A subgroup analysis of patients found a 60% or greater improvement (on the T5SS and the Juniper Rhinitis Quality of Life Questionnaire) in the good responders group and a 30% to 59% improvement or no improvement in the intermediate responders group. This subgroup analysis also found more good responders in the SLIT group (47%) compared with the placebo group (25%; P = .07). Significant decreases in the IL-5/IFN-γ (P < .001), IL-13/IFN-γ (P < .001), and IL-4/IFN-γ (P = .03) ratios were found in the combined good clinical improvement group at 24 months. CONCLUSION: A good clinical response (≥60% improvement in both TSS5 and quality of life) is associated with significant decreases in IL-5, IL-13, and IL-4 relative to IFN-γ during 2 years of SLIT therapy for HDMs.

Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma control: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Investigations meeting current standards are limited for the effect of house dust mite (HDM) allergy immunotherapy in asthmatic patients. OBJECTIVE: This trial investigated the efficacy and safety of a standardized quality (SQ; allergen standardization method proprietary to the trial sponsor) HDM SLIT-tablet (ALK, Hørsholm, Denmark) in adults and adolescents with HDM respiratory allergic disease. This publication reports the results of the endpoints related to asthma. METHODS: Six hundred four subjects 14 years or older with HDM allergic rhinitis and mild-to-moderate asthma were randomized 1:1:1:1 to double-blind daily treatment with one of 3 active doses (1, 3, or 6 SQ-HDM) or placebo. Their use of inhaled corticosteroid (ICS) was standardized and adjusted at baseline and the end of treatment to the lowest dose providing asthma control. The primary end point was a reduction in ICS dose from the individual subject's baseline dose after 1 year of treatment. RESULTS: The primary analysis revealed a mean difference between 6 SQ-HDM and placebo in the reduction in daily ICS dose of 81 µg (P = .004). Relative mean and median reductions were 42% and 50% for 6 SQ-HDM and 15% and 25% for placebo, respectively. No statistically significant differences were observed for the other assessed asthma parameters, reflecting the intended controlled status of the trial subjects. The most common adverse events were local reactions in the mouth. The rate and severity of adverse events were higher for 3 and 6 SQ-HDM than for 1 SQ-HDM and placebo. CONCLUSION: Efficacy in mild-to-moderate asthma of 6 SQ-HDM relative to placebo was demonstrated by a moderate statistically significant reduction in the ICS dose required to maintain asthma control. All active doses were well tolerated.