Clinical characteristics of complete responders versus non-complete responders to omalizumab, benralizumab and mepolizumab in patients with severe asthma: a long-term retrospective analysis.

BACKGROUND: Some patients with severe asthma may benefit from treatment with biologics, but evidence has been mostly collected from randomized controlled trials (RCTs), in which patients' characteristics are different from those encountered in asthma patients in the real-world setting. The aim of this study was to describe the clinical features of complete responders versus non-complete responders to long-term treatment with biologics in patients with severe asthma attended in routine daily practice. METHODS: Data of a cohort of 90 patients with severe asthma who were treated with biologics (omalizumab, benralizumab, and mepolizumab) for at least 12 months and were followed up to March 2022. Data recorded included clinical characteristics and effectiveness of treatment (exacerbation, Asthma Control Test [ACT] score, lung function, use of maintenance oral corticosteroids [mOCS]), FeNO, and blood eosinophils at baseline, at 12 months, and at the end of follow-up. Complete response is considered if, in addition to not presenting exacerbations or the use of mOCS, the ACT score was >20 and, the FEV1 >80% predicted. RESULTS: An improvement in all asthma control parameters was observed after 12 months of treatment and a mean follow-up of 55 months. After 12 months of treatment 27.2% of patients met the criteria of complete response and this percentage even increased to 35.3% at the end of follow-up. Long-term complete response was associated to better lung function with mepolizumab and omalizumab treatment and to less previous exacerbations in the benralizumab group. The main cause of not achieving a complete response was the persistence of an airflow obstructive pattern. CONCLUSIONS: This study shows that omalizumab, benralizumab, and mepolizumab improved the clinical outcomes of patients with severe asthma in a clinic environment with similar effect sizes to RCTs in the long term follow-up. Airflow obstruction, however, was a predictor of a non-complete response to biologics.

Treatment with anti-IgE and anti-IL-5 biologics significantly improved clinical outcomes in severe asthma patients.The rate of complete responders of 27.2% at 12 months even increased to 35.3% at the end of a mean follow-up of 55 months.The persistence of an airflow obstructive pattern was the main cause of the failure to achieve complete response.

Characterization and Factors Associated with Poor Asthma Control in Adults with Severe Eosinophilic Asthma.

A study was conducted in 98 adult patients diagnosed with severe eosinophilic asthma (73.5% women, mean age 47.2 years) and followed prospectively for 1 year. The aim of the study was to characterize this population and to identify factors associated with poor prognosis at 1 year of follow-up. At the initial visit, uncontrolled severe asthma was diagnosed in 87.7% of patients. Allergic sensitization was observed in 81.7% (polysensitization in 17.3%), with clinically significant allergic asthma in 45%. The mean percentage of sputum eosinophils was 4.7% (standard deviation(SD) 6.3%) and the mean (SD) blood eosinophil count 467 (225) cells/µL. Almost half of the patients (48.3%) had sputum eosinophilia (>3% eosinophils). Sputum eosinophils correlated significantly with peripheral eosinophilia (p = 0.004) and, to a lesser extent, with fractional exhaled nitric oxide (FeNO) (p = 0.04). After 1 year, 48 patients (49%) had uncontrolled asthma in all visits, and 50 (51%) had controlled asthma in some visits. Airway obstruction (FEV1 < 80% predicted) was the main reason for uncontrolled asthma. In the multivariate analysis, an obstructive pattern (odds ratio (OR) 7.45, 95% confidence interval (CI) 2.41-23.03, p < 0.0001) and the patient's age (OR 1.045, 95% CI 1.005-1.086, p = 0.026) were independent predictors of poor asthma control. In adult-onset and long-standing asthma, serum interleukin (IL) IL-17 was higher in the uncontrolled asthma group. This study contributes to characterizing patients with severe eosinophilic asthma in real-world clinical practice.

Using Component-Resolved Diagnosis to Characterize the Sensitization to Specific Cat and Dog Allergens in Patients with Allergic Respiratory Diseases in Catalonia, Spain.

INTRODUCTION: Sensitization to cat and dog allergens is common in patients with allergic respiratory diseases. The study objective was to determine the prevalence of immunoglobulin E (IgE) sensitization to specific cat and dog allergens using component-resolved diagnosis (CRD) in patients with allergic respiratory diseases plus cat and/or dog sensitization. METHODS: We included 87 patients aged 8-62 years, diagnosed with allergic asthma and/or rhinitis plus cat and/or dog sensitization, and attended at the allergy section of a tertiary hospital in Badalona (Catalonia, Spain). We used CRD to determine IgE sensitization to specific cat/dog allergens and skin prick tests (SPTs) to determine differences between diagnostic test results. RESULTS: Patients were monosensitized to cats (20.7%) or dogs (3.4%) or sensitized to both (75.9%). The highest positive allergen rates were for Fel d 1 (91.7%) and Fel d 4 (41%) in patients sensitized to cat allergens and for Can f 5 (80%) and Can f 1 (70%) in those sensitized to dog allergens. CRD and SPT results differed somewhat: 16.1% and 27.6% of patients CRD positive for cat or dog sensitization, respectively, were SPT negative, and 6.9% SPT positive for dog sensitization were CRD negative. Few statistically significant relationships were found between any allergen components and any respiratory disease characteristic or contact with furry animals. CONCLUSIONS: CRD may be used to determine the prevalence of IgE sensitization to specific cat and dog allergens in patients with allergic respiratory diseases plus cat and/or dog sensitization. As SPT may not correctly identify all patients sensitized to cats and dogs, our results support the use of CRD.

Effectiveness and safety of a microcrystalline tyrosine-adjuvanted Dermatophagoides pteronyssinus allergoid immunotherapy in adult patients with allergic asthma and rhinitis: A real-life prospective observational study.

INTRODUCTION: Although clinical trials have shown the efficacy and safety of allergen-specific immunotherapy (AIT) in the treatment of allergic asthma, there is a need for real-life studies. We aimed to assess the effectiveness and safety of a microcrystalline tyrosine-adjuvanted Dermatophagoides pteronyssinus allergoid (Acarovac Plus®) in patients with house dust mite (HDM)-induced allergic asthma in a real-life study. METHODS: A subanalysis of a multicenter, prospective, observational, real-life study. Patients with rhinitis and allergic asthma caused by HDMs were assessed before AIT with Acarovac Plus® and at 6 and 12 months after this treatment. Assessment parameters were percentage of days with asthma symptoms, percentage of days on asthma medication, classification of asthma according to Spanish guidelines for the management of asthma, asthma-related quality of life (quality of life in adults with asthma questionnaire [QLAAQ]), perception of symptoms (visual analog scale [VAS]), and treatment satisfaction (treatment satisfaction questionnaire for medication [TSQM]). Safety was assessed by the number and severity of adverse reactions. RESULTS: This subanalysis included 55 patients. Treatment with Acarovac Plus® showed significant differences in the analyzed variables when the baseline visit was compared with the 12-month visit: reduction of the mean (SD) percentage of days with asthma symptoms (23.9 [9.2] vs. 5.1 [12.8]; p = .002), of the mean [SD] percentage of days on asthma medication (67.6 [42.9] vs. 45.1 [46.8]; p = .002), and of the percentage of patients with persistent asthma (78.2% vs. 38.9%; p = .009). Acarovac Plus® significantly improved asthma-related quality of life, as shown by a decrease of 1.39 points in QLAAQ score at 12 months (p < .001), and in the subjective perception of symptoms on the VAS (-3.50, p < .0001). Patients showed high treatment satisfaction according to the TSQM, and it was well tolerated. No serious adverse events were reported. CONCLUSIONS: Acarovac Plus® was effective and safe for the treatment of patients with HDM-induced allergic asthma in a real-life study.

Immunological parameters as biomarkers of response to MicroCrystalline Tyrosine-adjuvanted mite immunotherapy.

BACKGROUND: Despite the effectiveness of allergen immunotherapy (AIT), some patients are unresponsive for reasons still unknown; yet validated response biomarkers remain unavailable. OBJECTIVE: To analyze immunological parameters as biomarkers to monitor and predict clinical response to a MicroCrystalline Tyrosine-adjuvanted house dust mite (HDM) AIT in patients with allergic rhinitis (AR). METHODS: Observational, prospective, multicenter study including adult patients (aged 18-65 years) with AR, with and without asthma, sensitized to the HDM Dermatophagoides pteronyssinus (DP) and prescribed Acarovac Plus® DP 100% in the routine practice. Serum concentrations of total IgE, specific IgE, specific IgG4, IL-4, IL-5, IL-10, IL-13, and IFN-γ were compared between baseline and 12 months after AIT. The relationship between patients' baseline immunological profiles and classification as low, high, and non-responders and between their sensitization profile to DP allergens and effectiveness were analyzed. RESULTS: Of 141 patients recruited, 118 (mean [SD] age of 33.6 [9.5] years) were evaluable. One year after treatment, Der p 1-specific IgE, DP-specific IgG4, and IL-10 increased by a mean (SD) of 3.4 (13.6) kU/L (p = 0.016), 0.43 (0.55) mg/L (p < 0.0001), and 1.35 (7.56) pg/mL (p = 0.033), respectively. Non-responders showed increased baseline levels of IL-13 compared to high responders (p = 0.037). Changes in effectiveness variables between baseline and after AIT were similar regardless of the sensitization profile. CONCLUSION: Non-responsive patients to AIT showed increased baseline IL-13 concentrations, suggesting its value as prognostic biomarker. DP-specific AIT increased Der p 1-specific IgE, DP-specific IgG4, and IL-10 concentrations in patients with AR. All patients benefited from treatment regardless of their sensitization profile to major DP allergens.

Real-life effect of a microcrystalline tyrosine adjuvanted mite immunotherapy in patients with allergic rhinitis.

Aim: Evaluate the effectiveness and safety of immunotherapy with Acarovac Plus® in a 1-year prospective multicentered real-life study. Methods: A total of 118 adults with allergic rhinitis sensitized to Dermatophagoides received subcutaneous immunotherapy with Acarovac Plus. Treatment outcomes were evaluated at baseline, 6 months and 1 year after treatment initiation. Primary end point was the evolution of the combined symptom and medication score. Secondary end points included other effectiveness outcomes and measurement of product tolerability. Results: Acarovac Plus induced significant improvements in primary and secondary end points after 6 months compared with baseline. These differences persisted after 1 year of treatment (p < 0.001; baseline vs 1 year): combined symptom and medication score (1.60 vs 0.79). No serious adverse events were recorded. Conclusion: Acarovac Plus for 1 year was effective and well tolerated in a real-life setting.

Immunotheraphy in Allergic Diseases.

The prevalence of allergic diseases is increasing worldwide. It is estimated that more than 30% of the world population is now affected by one or more allergic conditions and a high proportion of this increase is in young people. The diagnosis of allergy is dependent on a history of symptoms on exposure to an allergen together with the detection of allergen-specific IgE. Accurate diagnosis of allergies opens up therapeutic options. Allergen specific immunotherapy is the only successful disease-modifying therapy for IgE-mediated allergic diseases. New therapeutic strategies have been developed or are currently under clinical trials. Besides new routes of administration, new types of allergens are being developed. The use of adjuvants may amplify the immune response towards tolerance to the antigens. In this review, we analyze different antigen-specific immunotherapies according to administration route, type of antigens and adjuvants, and we address the special case of food allergy.

A budget impact analysis of Spiromax(®) compared with Turbuhaler(®) for the treatment of moderate to severe asthma: a potential improvement in the inhalation technique to strengthen medication adherence could represent savings for the Spanish Healthcare System and five Spanish regions.

OBJECTIVE: To assess the economic impact of the introduction of DuoResp(®) Spiromax(®) by focusing on a potential improvement in the inhalation technique to strengthen medication adherence for the treatment of moderate to severe asthmatics in Spain and five Spanish regions including Andalusia, Catalonia, Galicia, Madrid, and Valencia. METHODS: A 4-year budget impact model was developed for the period 2015-2018 from the Spanish Healthcare System perspective. Budesonide-formoterol fixed-dose combination delivered by Turbuhaler(®) was considered to be the most appropriate comparator for assessing the budget impact with the introduction of DuoResp(®) Spiromax(®). National and regional data on asthma prevalence were obtained from the literature. Input parameters on health care resources were obtained by consulting experts from different Spanish hospitals. Resources used included medical visits, emergency room visits, and hospitalizations. The average numbers of primary care and specialist visits per year were also gathered. Based on health care resource use per patient, the total treatment cost per patient was estimated. RESULTS: The population with moderate to severe asthma treated with budesonide-formoterol fixed-dose combinations delivered by Turbuhaler(®) in 2015 was estimated to be 166,985 in Spain. Region-specific prevalence data resulted in 25,081, 12,392, 16,097, 17,829, and 15,148 patients in Andalusia, Catalonia, Galicia, Madrid, and Valencia, respectively. Based on the forecast uptake of DuoResp(®) Spiromax(®), the total budget savings in Spain were expected to be €1.509 million over the next 4 years. Region-specific rates imply that the total savings were expected to be €229,706 in Andalusia, €90,145 in Catalonia, €188,327 in Galicia, €122,669 in Madrid, and €165,796 in Valencia over 2015-2018. CONCLUSION: The introduction of DuoResp(®) Spiromax(®), which represents a potential improvement in the inhalation technique to strengthen medication adherence for the treatment of moderate to severe asthma, could represent savings for the Spanish National Health Society and five Spanish regions.

A novel microcrystalline tyrosine-adsorbed, mite-allergoid subcutaneous immunotherapy: 1-year follow-up report.

AIM: A 1-year follow-up study comparing the safety and tolerability of the dosing schedules, satisfaction and effectiveness of a novel microcrystalline tyrosine-adsorbed mite (Dermatophagoides pteronyssinus)-allergoid subcutaneous immunotherapy (Acarovac Plus™) in 30 adult patients (18-65 years) with allergic rhinitis and/or asthma. MATERIALS & METHODS: The effectiveness of the product was assessed by nasal provocation test measuring peak nasal inspiratory flow/symptoms, in vitro immunologic changes (IgE, IgG4 and IL-10) and Treatment Satisfaction Questionnaire for Medication. RESULTS: No adverse events were reported during dosing schedules. Significant decreases in symptom scores and drop of peak nasal inspiratory flow in follow-up visits (4 weeks and 1 year) were recorded. Significant increases in IgG4-specific antibody titers and IL-10 were exhibited. CONCLUSION: Significant decreases in clinical symptoms and immunological parameters were observed, accompanying a high level of patient satisfaction and tolerance.

Comprehensive Study of Patients' Compliance with Sublingual Immunotherapy in House Dust Mite Perennial Allergic Rhinitis.

INTRODUCTION: Allergen immunotherapy is a long-term treatment that has been associated with patient adherence issues. The aim of the study was to increase the knowledge on compliance of patients allergic to house dust mites, receiving sublingual immunotherapy (SLIT). METHODS: A retrospective observational study was performed in 53 Spanish allergy units. We enrolled patients undergoing the SLIT treatment for house dust mites including a scheduled control visit 12 months after initiating the therapy. We conducted a comprehensive assessment of compliance using three methods. In the first step, an allergist evaluated the patients according to the results of an interview and the existing medical records. The subjects taking more than 80% of the overall prescription were defined as compliant. The remaining noncompliant patients were divided into groups taking less than 25%, 25-50%, and 50-80% of the prescribed SLIT. In the second stage, we conducted the Morisky-Green test. Finally, the noncompliant patients were asked to fill a self-report assessment form. Data were stratified into age groups. The potential factors affecting compliance were also investigated. RESULTS: Overall, 380 subjects participated in the study. The compliance rate was 79.7%, and the treatment discontinuation rate was 22.5%, while 66.8% of patients were adherent (both compliant and continuing with the treatment). The results showed that children were the most compliant and adolescents the least compliant (86.6% and 60.9%, respectively). The main reason for noncompliance was "forgetting some doses" in 31.0% of the children, 48.0% of the adolescents, and 53.2% of the adults. Compliance was associated with the following factors: age, number of annual control visits, and reduction in symptomatic medication. CONCLUSION: Our results showed that two out of three patients with house dust mite-induced allergic rhinitis adhered to the SLIT treatment. Multidisciplinary and integral solutions are needed to improve the compliance, with special attention paid to adolescents. FUNDING: Stallergenes Greer Spain.

A Versatile High-Vacuum Cryo-transfer System for Cryo-microscopy and Analytics.

Cryogenic microscopy methods have gained increasing popularity, as they offer an unaltered view on the architecture of biological specimens. As a prerequisite, samples must be handled under cryogenic conditions below their recrystallization temperature, and contamination during sample transfer and handling must be prevented. We present a high-vacuum cryo-transfer system that streamlines the entire handling of frozen-hydrated samples from the vitrification process to low temperature imaging for scanning transmission electron microscopy and transmission electron microscopy. A template for cryo-electron microscopy and multimodal cryo-imaging approaches with numerous sample transfer steps is presented.

Randomized dose-response study of subcutaneous immunotherapy with a Dermatophagoides pteronyssinus extract in patients with respiratory allergy.

AIM: To evaluate the efficacy of Dermatophagoides pteronyssinus (DPT) subcutaneous immunotherapy in allergic rhinoconjunctivitis patients. PATIENTS & METHODS: This 17-week double-blind study randomized 136 patients (95 evaluable) to five dose groups of DPT depot extract (0.0625-0.75 skin prick test [SPT] units) or placebo, administered in a six updosing schedule. RESULTS: A dose-response was observed for clinical efficacy (allergen concentration needed to induce a positive nasal provocation test response from baseline to final visit) and safety (adverse reactions). Local and systemic reactions occurred with 14.8 and 6.4% of administered doses, respectively; a single anaphylactic reaction occurred in each of Groups 3, 4 and 5 (0.3% of doses). CONCLUSION: The risk-benefit profile appeared most favorable with a DPT dose of 0.125 SPT units.

Refinement of biodegradation tests methodologies and the proposed utility of new microbial ecology techniques.

Society's reliance upon chemicals over the last few decades has led to their increased production, application and release into the environment. Determination of chemical persistence is crucial for risk assessment and management of chemicals. Current established OECD biodegradation guidelines enable testing of chemicals under laboratory conditions but with an incomplete consideration of factors that can impact on chemical persistence in the environment. The suite of OECD biodegradation tests do not characterise microbial inoculum and often provide little insight into pathways of degradation. The present review considers limitations with the current OECD biodegradation tests and highlights novel scientific approaches to chemical fate studies. We demonstrate how the incorporation of molecular microbial ecology methods (i.e., 'omics') may improve the underlying mechanistic understanding of biodegradation processes, and enable better extrapolation of data from laboratory based test systems to the relevant environment, which would potentially improve chemical risk assessment and decision making. We outline future challenges for relevant stakeholders to modernise OECD biodegradation tests and put the 'bio' back into biodegradation.

A review of the value of innovation in inhalers for COPD and asthma.

BACKGROUND: Appropriate use of inhaled therapies for asthma and chronic obstructive pulmonary disease (COPD) is critical to ensuring good patient outcomes, efficient use of healthcare resources and limiting the effects of high-morbidity. The appropriate choice of inhaler and active therapy, incorporating patient preferences, can help improve treatment adherence and long-term outcomes. Despite this, many current inhalers are non-intuitive to use, and require extensive training. METHODS: In this review, an expert panel considers the evidence for the use of inhaler devices in management of COPD and asthma. The panel also evaluates the value of innovation in inhaler technologies, which optimise the use of existing molecules from a clinical, economic and societal perspective. CONCLUSIONS: The panel conclusion is that there remains a substantial unmet need in inhaler technology and that innovation in inhaler devices can provide real-world health benefits to patients. Furthermore, we recommend that these innovations should be supported by healthcare systems through appropriate pricing and reimbursement mechanisms.

A novel and well tolerated mite allergoid subcutaneous immunotherapy: evidence of clinical and immunologic efficacy.

Allergy to house dust mite is one of the most common causes of allergic rhinitis. A novel tyrosine-adsorbed, modified allergen product, Acarovac Plus, developed for the treatment of perennial mite allergy seeks to address the underlying cause of allergic rhinitis in this instance. One of two dosing regimens may be used, either the Conventional Regimen or the Cluster Regimen. We sought to compare the efficacy and safety of a specific immunotherapy, developed for the treatment of perennial mite allergy, administered under a Conventional and Clustered dosing schedule in patients with persistent allergic rhinitis. Thirty adult patients, between 18 and 65 years old, with allergic rhinitis and/or asthma secondary to hypersensitivity to Dermatophagoides pteronyssinus were administered with either conventional or cluster initial regime, with a final visit one week after the last dose administration. The efficacy to the Conventional and Cluster regimens was measured using a Nasal Challenge Test monitoring clinical symptoms and peak nasal inspiratory flow. Total IgE, serum-specific inmunoglobulins (IgE and IgG4) to Dermatophagoides pteronyssinus and relevant cytokines (IFN-γ, IL-4, IL-5, IL-10 and IL-13) were assessed. A Satisfaction Questionnaire (TSQM) was completed after each patient's final visit. The tolerability of the vaccine was assessed monitoring adverse reactions. No adverse events were recorded in either conventional or cluster regime. The specific Nasal Challenge Test led to a decrease in symptom scores and a significant decrease in mean nasal peak inspiratory flow drop was recorded in both dosing regimen groups. A significant increase in IgG4-specific antibody titres was assessed. No significant changes were observed in concentrations of total IgE, specific IgE or cytokines (IFN-γ, IL-4, IL-5, IL-10 and IL-13). Patients declared themselves most satisfied in relation to "Secondary effects", with high overall satisfaction in both groups. Cluster and conventional specific immunotherapy resulted in no adverse reaction(s) and led to similar improvements in immunological parameters, clinical efficacy (Nasal Challenge Test) and high overall satisfaction.

Observational study of the safety of an ultra-rush sublingual immunotherapy regimen to treat rhinitis due to house dust mites.

BACKGROUND: Ultra-rush regimens for administering sublingual immunotherapy to patients with allergies are becoming more widespread. We aimed to assess treatment safety for patients with allergic rhinitis with or without asthma caused by Dermatophagoides house dust mites. METHODS: This observational study at 5 Spanish centers included 218 patients aged 4-64 years, of whom 117 were women and 122 were under 15 years old. Ultra-rush regimen consisted of incremental doses of an allergen extract comprising a 50% mixture of Dermatophagoides pteronyssinus and Dermatophagoides farinae (30, 60, 120, 240 IR every 30 min) followed by maintenance therapy. Adverse reactions were monitored and asthmatic patients underwent spirometric testing at baseline and after each dose. Follow-up was scheduled after 2 weeks of maintenance with 240 IR three times a week. RESULTS: Five patients had to modify ultra-rush regimen because of mild local adverse reactions. In total, 32 adverse reactions were reported in 27 patients during the ultra-rush regimen. Seven of these events were local gastrointestinal reactions, and the remaining 17 were local reactions, mainly labial or mouth itching and burning. Eight events were systemic reactions [rhinitis (n = 3), general malaise (n = 1), general malaise and vomiting (n = 1), dizziness (n = 1), asthma (n = 1), dyspnea (n = 1)]. All adverse reactions were mild or moderate. Serious adverse events or life-threatening anaphylactic reactions were not reported. CONCLUSIONS: High-dose sublingual immunotherapy with Dermatophagoides allergen extracts can be safely administered in an ultra-rush regimen, although its usefulness and benefit for perennial allergens (e.g. house dust mites) must be evaluated.

Patient assessment of onset of action and overall satisfaction with ebastine fast-dissolving tablets in allergic rhinitis.

AIM: To evaluate patient perception of the onset of action and overall satisfaction with a fast-dissolving tablet (FDT) formulation of ebastine in patients with intermittent or persistent allergic rhinitis. PATIENTS AND METHODS: This was a cross-sectional, multicenter, pharmacy-based survey involving adult patients (>18 years) with allergic rhinitis who presented with a prescription for ebastine FDT. Via a telephone interview, patients were asked to evaluate the characteristics of ebastine FDT in comparison with their previous experience with other antihistamines. RESULTS: 100 patients with allergic rhinitis were included in the study (41 had intermittent disease, 57 persistent disease and two with unknown disease states). Patients rated ebastine FDT very highly (mean scores: 4.5-4.7 out of a possible 5) for all characteristics related to convenience, such as easy to take, easy to carry around in a bag or pocket, suitable for taking anytime/anywhere, and convenient to use. A total of 85% of patients perceived ebastine FDTs onset of action to be fast or very fast, and 77% indicated that it acted faster than their usual antihistamine. A total of 96% were satisfied or very satisfied with ebastine FDT and 98% were interested in using the drug again. CONCLUSIONS: Patients with rhinitis rate ebastine FDT very highly in terms of its formulation, convenience of use and its rapid onset of action. These characteristics resulted in a high level of individual satisfaction with the new formulation and a clear preference by the majority of patients to use ebastine FDT in the future.