Standardization of clinical outcomes used in allergen immunotherapy in allergic asthma: An EAACI position paper.

INTRODUCTION: In allergic asthma patients, one of the more common phenotypes might benefit from allergen immunotherapy (AIT) as add-on intervention to pharmacological treatment. AIT is a treatment with disease-modifying modalities, the evidence for efficacy is based on controlled clinical trials following standardized endpoint measures. However, so far there is a lack of a consensus for asthma endpoints in AIT trials. The aim of a task force (TF) of the European Academy of Allergy and Clinical Immunology (EAACI) is evaluating several outcome measures for AIT in allergic asthma. METHODS: The following domains of outcome measures in asthmatic patients have been evaluated for this position paper (PP): (i) exacerbation rate, (ii) lung function, (iii) ICS withdrawal, (iv) symptoms and rescue medication use, (v) questionnaires (PROMS), (vi) bronchial/nasal provocation, (vii) allergen exposure chambers (AEC) and (viii) biomarkers. RESULTS: Exacerbation rate can be used as a reliable objective primary outcome; however, there is limited evidence due to different definitions of exacerbation. The time after ICS withdrawal to first exacerbation is considered a primary outcome measure. Besides, the advantages and disadvantages and clinical implications of further domains of asthma endpoints in AIT trials are elaborated in this PP. CONCLUSION: This EAACI-PP aims to highlight important aspects of current asthma measures by critically evaluating their applicability for controlled trials of AIT.

IgE recognition of the house dust mite allergen Der p 37 is associated with asthma.

BACKGROUND: House dust mite (HDM) allergens are major elicitors of allergic reactions worldwide. OBJECTIVE: Identification, characterization, and evaluation of diagnostic utility of a new important HDM allergen was performed. METHODS: A cDNA coding for a new Dermatophagoides pteronyssinus (Dp) allergen, Der p 37, was isolated from a Dp expression library with allergic patients' IgE antibodies. Recombinant Der p 37 (rDer p 37) expressed in Escherichia coli was purified, then characterized by mass spectrometry, circular dichroism, and IgE reactivity by ImmunoCAP ISAC technology with sera from 111 clinically defined HDM-allergic patients. The allergenic activity of rDer p 37 was studied by basophil activation and CD4+ T-cell responses by carboxyfluorescein diacetate succinimidyl ester dilution assays. Specific antibodies raised against rDer p 37 were used for the ultrastructural localization of Der p 37 in mites by immunogold transmission electron microscopy. RESULTS: Der p 37, a 26 kDa allergen with homology to chitin-binding proteins, is immunologically distinct from Der p 15, 18, and 23. It is located in the peritrophic membrane of fecal pellets. Der p 37 reacted with IgE antibodies from a third of HDM-allergic patients and induced specific basophil- and CD4+ T-cell activation. Der p 37 IgE-positive patients had significantly higher IgE levels to major HDM allergens, reacted with more HDM allergens, and had a higher risk (odds ratio = 3.1) of asthma compared to Der p 37-negative patients. CONCLUSIONS: Der p 37, a new Dp allergen recognized by a third of HDM-allergic patients, may serve as a surrogate marker for severe HDM sensitization and asthma.

[Allergy Diagnostics 2021]. / Allergologische Diagnostik 2021.

Allergic diseases are among the most common diseases worldwide. For appropriate management knowledge of the allergy trigger is crucial. The clinical picture of allergic diseases is diverse and correct diagnosis is often a challenge. The allergist needs to distinguish intolerances from allergies and infectious diseases from non-infectious triggers. Test results have to be interpreted accordingly to differentiate sensitizations from allergies. In this review current state of the art diagnostic measures to diagnose type I and type IV allergies are described and discussed.Immediate type allergies such as allergic rhinoconjunctivitis, asthma and anaphylaxis are mediated by allergen-specific IgE antibodies detectable both in serum and tissue. Typical triggers are pollen, mites, animal epithelia, food, insect toxins and pharmaceuticals. In everyday practice, diagnostics are based on three complementary pillars: the allergy-specific anamnesis as a prerequisite of correct interpretation of subsequent diagnostic tests like skin testing and serological immunoglobulin detection. These can be supplemented as required and available by provocation tests to prove clinical reactivity and cellular assays to demonstrate the cellular immune response.Type IV allergic reactions are mediated by T cells causing contact allergy with a local eczematous reaction with a latency of several hours to days. Some 3,500 triggers, often from occupational environment, are known; e. g., nickel, chromium, cobalt, fragrances, rubber, plastics, preservatives, dyes, neomycin, benzocaine, sulfonamides, quinidine, wool wax, perubalsam, eye therapeutics, light filter substances, disinfectants, pesticides, technical oils or plants. Diagnosis of contact allergy combines the history of cutaneous exposure with associated symptoms and patch testing, with detection of a late phase clinical reaction after 6 to 48, up to a maximum of 96 hours after antigen contact.

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.

Personalized medicine for allergy treatment: Allergen immunotherapy still a unique and unmatched model.

The introduction of personalized medicine (PM) has been a milestone in the history of medical therapy, because it has revolutionized the previous approach of treating the disease with that of treating the patient. It is known today that diseases can occur in different genetic variants, making specific treatments of proven efficacy necessary for a given endotype. Allergic diseases are particularly suitable for PM, because they meet the therapeutic success requirements, including a known molecular mechanism of the disease, a diagnostic tool for such disease, and a treatment blocking the mechanism. The stakes of PM in allergic patients are molecular diagnostics, to detect specific IgE to single-allergen molecules and to distinguish the causative molecules from those merely cross-reactive, pursuit of patient's treatable traits addressing genetic, phenotypic, and psychosocial features, and omics, such as proteomics, epi-genomics, metabolomics, and breathomics, to forecast patient's responsiveness to therapies, to detect biomarker and mediators, and to verify the disease control. This new approach has already improved the precision of allergy diagnosis and is likely to significantly increase, through the higher performance achieved with the personalized treatment, the effectiveness of allergen immunotherapy by enhancing its already known and unique characteristics of treatment that acts on the causes.

Fast effectiveness of a solubilized low-dose budesonide nasal spray in allergic rhinitis.

BACKGROUND: Budesonide, a poorly water-soluble corticosteroid, is currently marketed as a suspension. Budesolv is a novel aqueous formulation containing dissolved budesonide showing increased local availability in preclinical models. Budesolv contains ~85% less corticosteroid than the marketed comparator. OBJECTIVE: The study (EudraCT:2018-001324-19) was designed to assess non-inferiority of Budesolv compared to Rhinocort® Aqua 64 (RA) and early onset of action. METHODS: In a three-way cross-over double-blinded randomized trial, Budesolv 10 was compared to RA and placebo in grass pollen allergic rhinoconjunctivitis volunteers (n = 83 (ITT); n = 75 (PP)). On day 1, participants entered the Vienna Challenge Chamber (VCC) for 6 hours; first treatment took place at 1:45 hours after entry. Participants treated themselves for further 6 days; on day 8, the last treatment was applied before entering the VCC. Subjective symptom scores, nasal airflow and nasal secretion were measured regularly during allergen challenge. RESULTS: Budesolv 10 was equally effective compared to RA with respect to TNSS and nasal airflow after eight days of treatment with a strongly reduced dose (more than 80% reduction). After first dose, only Budesolv 10 showed a significant reduction of nasal and respiratory symptoms starting 90 minutes (P < .05) and 15 minutes (P < .05) after application onwards, respectively, demonstrating an early onset of efficacy. A clinically significant 1 point reduction in nasal symptom score was reached at 195 minutes (P < .05) after application. CONCLUSIONS AND CLINICAL RELEVANCE: The novel preservative-free, aqueous low-dose budesonide formulation is highly efficacious even after an initial single treatment. Thus, Budesolv 10 appears to be an effective acute treatment for allergic rhinitis as well as for AR comorbidities like mild asthma and conjunctivitis.

The Role of Der p 23 Sensitization: An Analysis of 474 Patients Sensitized to Mite.

INTRODUCTION: House dust mite contains several allergen components and causes perennial allergy. Lately, a new major allergen, Der p 23, was described with relatively high sensitization rates in different European Countries. In addition, Der p 23 is supposed to cause asthmatic disease. OBJECTIVE: We would like to question the prevalence and clinical impact of specific immunoglobulin E to Der p 23 in a large patient sample in southern Bavaria, Germany. METHODS: 474 patients from southern Bavaria, who visited the allergy department within the Department of Oto-Rhino-Laryngology of a university hospital, with sensitization to Dermatophagoides pteronyssinus were retrospectively compared regarding their sensitization profile to Der p 1, Der p 2, and Der p 23 and their clinical characteristics. RESULTS: Among D. pteronyssinus-sensitized patients, the overall sensitization rate to Der p 23 was 42% in southern Bavaria. Most likely, patients were simultaneously sensitized to Der p 1, Der p 2, and Der p 23. Der p 23-sensitized patients reported more frequently asthma and showed higher prevalence of poly-sensitization towards 3 additional allergen groups and higher prevalence of double-sensitization to Der p 1 and Der p 2 compared to patients with missing sensitization to Der p 23. Considering the results of allergen provocation tests, neither IgE sensitization against Der p 23 nor levels of specific immunoglobulin E to Der p 23 allow a clear prediction of the clinical relevance of the sensitization. CONCLUSION: With a sensitization rate of 42%, Der p 23 closely misses the criterion of a major allergen in our southern Bavarian patient collective. A higher prevalence of polysensitization and self-reported asthma was the only clinical feature found in Der p 23-sensitized patients.

Perspectives in allergen immunotherapy: 2019 and beyond.

The seventh "Future of the Allergists and Specific Immunotherapy (FASIT)" workshop held in 2019 provided a platform for global experts from academia, allergy clinics, regulatory authorities and industry to review current developments in the field of allergen immunotherapy (AIT). Key domains of the meeting included the following: (a) Biomarkers for AIT and allergic asthma; (b) visions for the future of AIT; (c) progress and data for AIT in asthma and the updates of GINA and EAACI Asthma Guidelines (separated for house dust mite SCIT, SLIT tablets and SLIT drops; patient populations) including a review of clinically relevant endpoints in AIT studies in asthma; (d) regulatory prerequisites such as the "Therapy Allergen Ordinance" in Germany; (e) optimization of trial design in AIT clinical research; (f) challenges planning and conducting phase III (field) studies and the future role of Allergen Exposure Chambers (AEC) in AIT product development from the regulatory point of view. We report a summary of panel discussions of all six domains and highlight unmet needs and possible solutions for the future.

Structural and Functional Characterization of the Major Allergen Amb a 11 from Short Ragweed Pollen.

Allergy to the short ragweed (Ambrosia artemisiifolia) pollen is a major health problem. The ragweed allergen repertoire has been recently expanded with the identification of Amb a 11, a new major allergen belonging to the cysteine protease family. To better characterize Amb a 11, a recombinant proform of the molecule with a preserved active site was produced in Escherichia coli, refolded, and processed in vitro into a mature enzyme. The enzymatic activity is revealed by maturation following an autocatalytic processing resulting in the cleavage of both N- and C-terminal propeptides. The 2.05-Å resolution crystal structure of pro-Amb a 11 shows an overall typical C1A cysteine protease fold with a network of molecular interactions between the N-terminal propeptide and the catalytic triad of the enzyme. The allergenicity of Amb a 11 was confirmed in a murine sensitization model, resulting in airway inflammation, production of serum IgEs, and induction of Th2 immune responses. Of note, inflammatory responses were higher with the mature form, demonstrating that the cysteine protease activity critically contributes to the allergenicity of the molecule. Collectively, our results clearly demonstrate that Amb a 11 is a bona fide cysteine protease exhibiting a strong allergenicity. As such, it should be considered as an important molecule for diagnosis and immunotherapy of ragweed pollen allergy.

Randomized phase 1 study of the phosphatidylinositol 3-kinase δ inhibitor idelalisib in patients with allergic rhinitis.

BACKGROUND: Phosphatidylinositol 3-kinase p110δ isoform (PI3K p110δ) activity is essential for mast cell activation, suggesting that inhibition of PI3K p110δ might be useful in treating allergic diseases. OBJECTIVE: We sought to determine the effect of the PI3K p110δ-selective inhibitor idelalisib on allergic responses. METHODS: This phase 1 randomized, double-blind, placebo-controlled, 2-period crossover study was conducted with the Vienna Challenge Chamber. Grass pollen-induced allergic symptoms were documented during screening. Eligible subjects received idelalisib (100 mg twice daily) or placebo for 7 days, with allergen challenge on day 7. After a 2-week washout period, subjects received the alternate treatment and repeated allergen challenge. Study measures included safety, nasal and nonnasal symptoms, nasal airflow, nasal secretions, basophil activation, and plasma cytokine levels. RESULTS: Forty-one patients with allergic rhinitis received idelalisib/placebo (n = 21) or placebo/idelalisib (n = 20). Idelalisib treatment was well tolerated. Mean total nasal symptom scores were lower during the combined idelalisib treatment periods compared with placebo (treatment difference [idelalisib - placebo], -1.78; 95% CI, -2.53 to -1.03; P < .001). Statistically significant differences were also observed for the combined treatment periods for total symptom scores, nasal airflow, nasal secretion weight, and nasal congestion scores. The percentage of ex vivo-activated basophils (CD63(+)/CCR3(+) cells; after stimulation with grass pollen) was substantially lower for idelalisib-treated compared with placebo-treated subjects. Plasma CCL17 and CCL22 levels were reduced after idelalisib treatment. CONCLUSION: Idelalisib treatment was well tolerated in patients with allergic rhinitis and appears to reduce allergic responses clinically and immunologically after an environmental allergen challenge.

Long-term effects of a house dust mite sublingual immunotherapy tablet in an environmental exposure chamber trial.

BACKGROUND: Treatment with SQ house dust mite (HDM) sublingual immunotherapy (SLIT) tablet is effective for HDM respiratory allergic disease, but data on long-term effects are lacking. OBJECTIVE: Post hoc analyses were conducted to determine the long-term effect of SQ HDM SLIT-tablet on nasal, ocular, and cough symptoms 1 year after discontinuation of treatment. METHODS: Study participants underwent environmental exposure chamber (EEC) challenges at baseline and week 24 in a randomized, placebo-controlled, double-blind trial (NCT01644617) during which participants received daily 12 SQ-HDM, 6 SQ-HDM, or placebo for 24 weeks. Asthma had to be stable, well controlled, and nonsevere. The mean total asthma symptom score (TASS; sum of 3 symptoms: cough, wheeze, and dyspnea) during baseline and week 24 EEC challenge was analyzed in all participants who completed the trial (n = 106). Approximately 1 year after trial completion, another EEC challenge was conducted in a subset of participants (n = 51). Total nasal symptom score (sum of 4 symptoms), total ocular symptom score (sum of 2 symptoms), and cough were assessed. RESULTS: Compared with baseline and end-of-treatment values, sustained improvement of all symptoms assessed at the 1-year follow-up EEC challenge was evident in participants treated with 12 SQ-HDM. Results with 6 SQ-HDM were less notable. After 24 weeks of 12 SQ-HDM, TASS during EEC challenge was improved 65% vs baseline; at 1-year follow-up, cough was improved 57% vs baseline. CONCLUSION: Persistent improvement of nasal and ocular symptoms was observed up to 1 year after completing 24 weeks of 12 SQ-HDM treatment. Beneficial effects on cough were also observed. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT01644617.

Onset and dose-related efficacy of house dust mite sublingual immunotherapy tablets in an environmental exposure chamber.

BACKGROUND: The magnitude of effect of sublingual immunotherapy for house dust mite (HDM)-induced allergic rhinitis with or without conjunctivitis is uncertain, partly because there are few well-controlled trials with well-defined doses. OBJECTIVE: We sought to determine the dose-related efficacy and onset of action of the HDM sublingual immunotherapy tablet MK-8237 (Merck/ALK-Abelló) using the Vienna Challenge Chamber. METHODS: In this randomized, double-blind, single-site trial, adults with HDM-induced allergic rhinitis with or without conjunctivitis and with or without asthma (n = 124) received 12 developmental units (DU) of MK-8237, 6 DU of MK-8237, or placebo daily for 24 weeks. Subjects underwent 6-hour exposure challenges at screening and weeks 8, 16, and 24. The total nasal symptom score (TNSS) during chamber challenge at week 24 was the primary end point. The TNSS was the sum of 4 nasal symptom scores (maximum = 12). Total ocular symptom scores (TOSSs; 2 symptoms; maximum = 6) and total symptom scores (TSSs; TSS = TNSS plus TOSS; maximum = 18) were secondary end points. RESULTS: Dose- and time-dependent improvements with MK-8237 versus placebo were observed. At week 24, TNSS improvement relative to placebo was 48.6% (95% CI, 35.3% to 60.2%) with 12 DU of MK-8237 and 26.6% (95% CI, 11.2% to 39.6%) with 6 DU of MK-8237. Statistically significant improvements for TNSSs were also observed at weeks 8 (12 DU of MK-8237) and 16 (6 and 12 DU of MK-8237) and for TOSSs and TSSs by both doses at week 24. MK-8237 was well tolerated. No investigator-assessed anaphylactic allergic reactions or reactions requiring epinephrine were observed. CONCLUSIONS: MK-8237, 12 DU, reduced nasal and ocular symptoms and exceeded World Allergy Organization-established clinical efficacy criteria (≥20% improvement vs placebo). The onset of action for 12 DU of MK-8237 was week 8. MK-8237, 12 DU, is appropriate for further evaluation to determine the magnitude of effect in an uncontrolled allergen exposure environment.

Alleviation of Allergic Rhinoconjunctivitis Symptoms in Participants Treated with a 0.005% Tacrolimus Eye-Drop Solution.

Purpose: This randomized, placebo-controlled, crossover, double-blind trial aimed to evaluate the efficacy and safety of Tacrosolv, a novel 0.005% tacrolimus eye-drop solution, in adults with grass pollen-induced allergic conjunctivitis. Methods: A total of 64 adult participants were randomized to receive 2.5 µg or 5 µg tacrolimus/eye/day or placebo treatment for 8 days, with grass pollen exposure on day 1 and day 8. After a 2-week washout period, placebo participants crossed over to Tacrosolv treatment and vice versa, with repeated treatment and exposure. During exposure, participants recorded ocular, nasal, and respiratory allergy symptoms every 15 minutes. The primary endpoint was the mean total ocular symptom score (TOSS) on day 8. Objective ocular safety parameters were assessed before, during, and after exposure. Adverse events were recorded throughout the study. Results: On day 8, high-dose Tacrosolv reduced the TOSS compared to placebo towards the end of exposure (p<0.05 at time points 3 hours, 45 minutes and 4 hours). A 26% reduction in baseline adjusted TOSS from day 1 to day 8 was observed in participants treated with high-dose Tacrosolv, whereas placebo-treated participants showed no difference in TOSS between day 1 and day 8. Nasal symptoms were reduced on both day 1 and day 8 in participants treated with high-dose Tacrosolv (p<0.05). No safety concerns were raised. All adverse events were resolved within the study period. Conclusion: High-dose Tacrosolv is safe and effective for alleviating symptoms of allergic rhinoconjunctivitis. Trial Registration: NCT04532710; EudraCT No. 2019-002847-62.

Carrageenan-Containing Nasal Spray Alleviates Allergic Symptoms in Participants with Grass Pollen Allergy: A Randomized, Controlled, Crossover Clinical Trial.

Purpose: Nonpharmacological, barrier-forming nasal sprays are used to manage symptoms of allergic rhinitis. We aim to evaluate the safety and effectiveness of Callergin (investigational product, IP), a nasal spray containing barrier-forming iota-carrageenan, in the treatment of allergic rhinitis (AR). Methods: In this randomized, controlled, crossover trial, adults with grass pollen allergy underwent a treatment sequence with IP, VisAlpin (comparator product, CP), and no treatment in random order. Treatment blocks consisted in prophylactic administration of the assigned treatment or no treatment, followed by a 3-hr allergen exposure, and were separated by a washout period of 7 days. Primary endpoint was a mean change from baseline in "Total Nasal Symptom Score" (TNSS, sum of rhinorrhea, itching, sneezing, and congestion scores) over 3 hr, recorded every 15 min during the challenge period. Results: A total of 42 participants underwent randomization. Exposure to grass pollen for 3 hr induced a notable TNSS increase from baseline in all participants at all times. Mean TNSS change from baseline over 3 hr was lower when participants received IP compared to no treatment, although the difference did not reach statistical significance (untreated 6.96 ± 2.30; IP 6.59 ± 1.93; difference 0.37 points [95% CI (confidence interval) -0.17 to 0.91]; p=0.170). In a post-hoc analysis, mean TNSS at 3 hr was significantly reduced after IP treatment compared to no treatment (untreated 8.29 ± 2.64; IP 7.70 ± 2.56; difference 0.60 points [95% CI -0.10 to 1.29] p=0.028). While all individual nasal symptoms contributed to this effect, rhinorrhea (p=0.013) and congestion (p=0.076) contributed most. Consistently, nasal secretion weight was slightly reduced with IP treatment (p=0.119). IP was safe and well-tolerated, with similar incidence of adverse events across treatment groups. Conclusion: Prophylactic treatment with the iota-carrageenan nasal spray IP is safe, well-tolerated, and alleviates nasal allergy symptoms in adults with grass pollen-induced AR. Trial Registration: NCT04531358.

The effects of a TRPV1 antagonist, SB-705498, in the treatment of seasonal allergic rhinitis.

BACKGROUND: Current pharmacotherapy for allergic rhinitis (AR) does not totally ameliorate all symptoms for all patients. Residual symptoms could be due to nasal neuronal hyperresponsiveness caused by stimulation of the ion channel transient receptor potential vanilloid 1 (TRPV1). SB-705498 is a TRPV1 antagonist that has been developed in an intranasal formulation for treatment of AR. METHODS: This randomized, double-blind, 3-way incomplete block crossover study evaluated the effects of 8 days treatment with SB-705498 12 mg alone, SB-705498 12 mg plus fluticasone propionate 200 µg (FP), FP 200 µg alone or placebo on allergen-induced symptoms in 70 patients with AR. The primary endpoint was total nasal symptom score (TNSS), expressed as mean over 4 hours or maximum TNSS during allergen challenge in the Vienna Challenge Chamber on 8th day of treatment. RESULTS: At the end of treatment, there were no differences in allergen-induced mean TNSS between SB-705498 alone and placebo or between SB-705498 plus FP and FP alone. Treatment with FP and SB-705498 plus FP resulted in a significant decrease in TNSS vs. placebo. Mean (90% CI) treatment differences in TNSS over 0 - 4 hours were: SB-705498 - placebo: -0.2 (-0.9, 0.4); SB-705498 plus FP - FP: 0.7 (0.2, 1.2); FP - placebo: -2.9 (-3.4, -2.5); SB-705498 plus FP - placebo: -2.3 (-2.8, -1.8). SB-705498 had no impact on diary card symptoms, nasal airflow or Rhinoconjunctivitis Quality of Life Questionnaire scores. SB-705498 was well tolerated and pharmacokinetics exposure results supported the dosing regimen. CONCLUSION: SB-705498 12 mg for 8 days did not alleviate the allergen-induced symptoms of AR, or provide additional relief of symptoms when in combination with FP. Despite engagement of the TRPV1 receptor there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.