Efficacy and safety of levosalbutamol in patients with mild to moderate asthma compared with racemic salbutamol: results of a crossover placebo-controlled study

Aim. Effectiveness and safety of levosalbutamol metered dose inhaler (MDI) in comparison with placebo and salbutamol. Materials and methods. In this multicenter, randomized, placebo-controlled, 3-period crossover study, all asthma patients (n=91) received levosalbutamol (90 mcg), salbutamol (180 mcg), and placebo using standard MDI. Pulmonary function testing – forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) – was performed 45 and 15 minutes before and 5, 10, 15, 30, 60, 90, 120, 180, 240, 300 and 360 minutes after dosing. The primary efficacy endpoint was the baseline-corrected area under FEV1 curve from 0 to 6 hours (AUC(0–6h)). Secondary endpoints were the baseline adjusted FEV1 and FVC peak values, as well as the onset of drug action. Results. The FEV1 AUC0–6 hours analysis confirmed similar bronchodilatory levosalbutamol and salbutamol effect (p=0.595), significantly improved compared with placebo (p0.001). The peak values of FEV1 and FVC after levosalbutamol or salbutamol dosing were similar (p=0.643) and significantly higher compared with placebo group (p0.001). The active therapy effect was observed 5 minutes after dosing and throughout the entire observation period up to 6 hours, however, there was some tendency towards a longer duration of action of levosalbutamol compared to salbutamol. Levosalbutamol was well tolerated by patients; after levosalbutamol dosing twiсе fewer adverse reactions were observed compared to salbutamol. Conclusion. Levosalbutamol at a 90-mcg dose showed efficacy similar to that of salbutamol at a dose of 180 mcg, assosiated with a good safety profile

Practical recommendations for choosing an immunobiological preparation for the treatment of severe bronchial asthma of T2-endotype

Biological therapy of bronchial asthma (BA) is a modern method of treating severe forms of the disease, that are uncontrolled by traditional pharmacotherapeutic approaches. Currently, 5 monoclonal antibody (AT) preparations are registered in the world for the treatment of severe bronchial asthma (SBA) of the T2 endotype (T2-SBA) – antibodies, binding to immunoglobulin (Ig) E (anti-IgE – omalizumab), interleukin antagonists (IL)-5 (anti-IL-5 – mepolizumab, resizumab) and its receptor (anti-IL-5Rα – benralizumab), as well as antibodies, that selectively bind to the IL-4 and -13 receptor (anti-IL-4 /13Rα – dupilumab). The article presents data on the effectiveness of these drugs in relation to the key characteristics of SBA, formulates clinical and laboratory criteria, the study of which in real practice can potentially predict the likelihood of a clinical response to a particular type of biological therapy. An algorithm is proposed for choosing a targeted therapy strategy for patients with SBA, clinically associated with allergies, for patients with severe non-allergic eosinophilic BA and for patients with eosinophilic BA of a combined phenotype.Биологическая терапия бронхиальной астмы (БА) представляет собой современный метод лечения тяжелых форм заболевания, неконтролируемых при помощи традиционных фармакотерапевтических подходамов. В настоящее время в мире зарегистрированы 5 препаратов моноклональных антител (АТ) для лечения тяжелой бронхиальной астмы (ТБА) Т2-эндотипа (Т2-ТБА) – АТ, связывающие иммуноглобулин (Ig) Е (анти-IgE – омализумаб), антагонисты интерлейкина (IL)-5 (анти-IL-5 – меполизумаб, реслизумаб) и его рецептора (анти-IL-5Rα – бенрализумаб), а также АТ, избирательно связывающиеся с рецептором IL-4 и -13 (анти-IL-4/13Rα – дупилумаб). В статье приведены данные об эффективности указанных препаратов в отношении ключевых характеристик ТБА, сформулированы клинико-лабораторные критерии, при исследовании которых в реальной практике потенциально может быть предсказана вероятность клинического ответа на тот или иной вид биологической терапии. Предложен алгоритм выбора стратегии таргетной терапии для пациентов с ТБА, клинически ассоциированной с аллергией, для больных тяжелой неаллергической эозинофильной БА и для страдающих эозинофильной БА сочетанного фенотип

Statement on Management of Children with Allergic Diseases During New Coronaviral Infection SARS-CoV-2 Pandemic (COVID-19 Infection)

The COVID-19 infection caused by the new coronavirus SARS-CoV-2 has become the real pandemic. Children account for 1–6% of all diagnosed COVID-19 cases. Generally, children have mild disease in comparison to adults, and their mortality rates are extremely low. Despite the fact that all the main efforts of the medical and political community are now focused on preventing the pandemic spread and organizing medical care for patients with moderate and severe COVID-19 course, we still have to remember to implement adequate help for patients with chronic diseases, especially for children with allergic diseases. The pandemic period coincided with natural weather period of dusting of causative plants, that led to annual escalation of both allergic rhinitis and asthma in patient group with specific sensitization to tree pollen. Leading experts of allergology (adapting to modern conditions) have created key guidelines on management of children with allergic diseases during the COVID-19 pandemic. These guidelines are based on the data and results from the Union of Pediatricians of Russia, Russian Association of Allergologists and Clinical Immunologists, European Academy of Allergy and Clinical Immunology (EAACI), European Respiratory Society (ERS), American Thoracic Society (ATS), Global Strategy for Asthma Management (GINA), Initiative on Allergic Rhinitis and its Impact on Asthma (ARIA/MACVIA)

Galba: genome annotation with miniprot and AUGUSTUS

Abstract Background The Earth Biogenome Project has rapidly increased the number of available eukaryotic genomes, but most released genomes continue to lack annotation of protein-coding genes. In addition, no transcriptome data is available for some genomes. Results Various gene annotation tools have been developed but each has its limitations. Here, we introduce GALBA, a fully automated pipeline that utilizes miniprot, a rapid protein-to-genome aligner, in combination with AUGUSTUS to predict genes with high accuracy. Accuracy results indicate that GALBA is particularly strong in the annotation of large vertebrate genomes. We also present use cases in insects, vertebrates, and a land plant. GALBA is fully open source and available as a docker image for easy execution with Singularity in high-performance computing environments. Conclusions Our pipeline addresses the critical need for accurate gene annotation in newly sequenced genomes, and we believe that GALBA will greatly facilitate genome annotation for diverse organisms

Patients' and physicians’ perspectives on the burden and management of asthma: Results from the APPaRENT 2 study

International audienceBackground: The 2021 Global Initiative for Asthma (GINA) report recommends 2 treatment tracks depending on choice of reliever therapy: either inhaled corticosteroid (ICS)/formoterol, or short-acting β2-agonist (SABA) with ICS to be used whenever a SABA is taken.Objective: The Asthma Patients' and Physicians’ Perspectives on the Burden and Management of Asthma (APPaRENT) 2 study aimed to understand current real-world treatment approaches and their alignment with GINA recommendations.Methods: Patients and physicians were recruited for the online survey from online panels from August–November 2021. Inclusion criteria: adults, physician diagnosis of asthma, ≥6 months prescribed inhaler use (patients); primary care, ≥4 patients with asthma per month, ≥3 years clinical practice (physicians).Results: 1650 patients and 1080 physicians were included. For patients with moderate to severe asthma, physicians prescribed proactive regular dosing (PRD) with ICS/long-acting β2-agonist (LABA) combination with (47%) or without (15%) SABA as initial therapy. Most pulmonologists (75%) and general practitioners (57%) selected a PRD approach. The majority of patients, 85% (79–91%), considered to be using maintenance and reliever therapy (MART), were also prescribed non-ICS rescue inhaler.Conclusions: Physicians preferred a preventive regular dosing approach to achieve symptom control for patients with moderate to severe asthma, which is more aligned with GINA 2021 Track 2 recommendations than Track 1. Many patients on MART request additional rescue inhalers, suggesting that MART is being misapplied in most instances and that patients may perceive their asthma as inadequately controlled with MART therapy

Plasma-derived C1 esterase inhibitor pharmacokinetics and safety in patients with hereditary angioedema

Background: Over 40 years of use demonstrates that complement 1 esterase inhibitor (C1-INH) concentrate is effective and well tolerated for acute edema attacks and prophylaxis in patients with hereditary angioedema. OCTA-C1-INH is a new stable, virus-inactivated, nanofiltrated concentrate of C1-INH derived from human plasma. Objective: We investigated the pharmacokinetics and safety profile of new C1-INH in people with hereditary angioedema during an attack-free period. Methods: In this prospective, multicenter, open-label, single-arm study, adults with hereditary angioedema type I/II received a single intravenous dose of 20 IU/kg C1-INH. Blood samples were taken ≤30 minutes before infusion, and 0, 0.25, 1, 2, 6, 12, 24, 48, 72, 120, 144, and 168 hours after infusion. The primary end point was assessing the pharmacokinetic parameters of C1-INH measured by C1-INH activity. Safety end points were also examined. Results: Twenty patients received a single dose of 20 IU/kg new C1-INH with a mean (standard deviation) total dose of 1457.3 (356.51) IU. Mean (standard deviation) area under the curve normalized by dose was 51.6 (17.9) h∙IU/mL/IU, maximum blood concentration was 1.14 (0.989) IU/mL, incremental recovery was 0.0466 (0.051) (IU∙kg)/(IU∙mL), half-life was 0.598 (0.716) hours, and time to maximum concentration was 0.598 (0.716) hours. No thromboembolic events were recorded. No treatment-emergent adverse events were rated as severe/serious. Conclusion: PK parameters of new C1-INH were in line with those reported for other C1-INH concentrates. New C1-INH demonstrated a favorable safety profile in patients with C1-INH deficiency. Further studies are warranted to determine the effectiveness and longer-term safety of new C1-INH

Согласованные рекомендации по ведению детей с аллергическими болезнями в период пандемии нового коронавируса SARS-CoV-2 (инфекции COVID-19)

The COVID-19 infection caused by the new coronavirus SARS-CoV-2 has become the real pandemic. Children account for 1–6% of all diagnosed COVID-19 cases. Generally, children have mild disease in comparison to adults, and their mortality rates are extremely low. Despite the fact that all the main efforts of the medical and political community are now focused on preventing the pandemic spread and organizing medical care for patients with moderate and severe COVID-19 course, we still have to remember to implement adequate help for patients with chronic diseases, especially for children with allergic diseases. The pandemic period coincided with natural weather period of dusting of causative plants, that led to annual escalation of both allergic rhinitis and asthma in patient group with specific sensitization to tree pollen. Leading experts of allergology (adapting to modern conditions) have created key guidelines on management of children with allergic diseases during the COVID-19 pandemic. These guidelines are based on the data and results from the Union of Pediatricians of Russia, Russian Association of Allergologists and Clinical Immunologists, European Academy of Allergy and Clinical Immunology (EAACI), European Respiratory Society (ERS), American Thoracic Society (ATS), Global Strategy for Asthma Management (GINA), Initiative on Allergic Rhinitis and its Impact on Asthma (ARIA/MACVIA).Инфекция COVID-19, вызванная новым коронавирусом SARS-CoV-2, стала настоящей пандемией. Среди всех диагностированных случаев COVID-19 на долю детей приходится 1–6%. Дети, как правило, имеют более легкое течение заболевания, чем взрослые, показатели смертности у них крайне низкие. Несмотря на то, что основные усилия медицинской и политической общественности в настоящее время направлены на предотвращение распространения пандемии и организацию медицинской помощи больным со среднетяжелым и тяжелым течением COVID-19, нельзя забывать и об адекватной поддержке пациентов с хроническими заболеваниями, особую когорту среди которых составляют дети с аллергическими болезнями. Период пандемии совпал с естественным погодным периодом пыления причинно-значимых растений, что обусловило ежегодное обострение как аллергического ринита, так и астмы в группе пациентов, имеющих специфическую сенсибилизацию к пыльце деревьев. Адаптируясь к современным условиям, ведущие специалисты в области аллергологии составили ключевые рекомендации по ведению детей с аллергией в период пандемии COVID-19, основываясь на результатах наблюдений Союза педиатров России, Российской ассоциации аллергологов и клинических иммунологов, Европейской академии астмы и клинической аллергологии (EAACI), Европейского респираторного общества (ERS), Американского торакального общества (ATS), Глобальной стратегии по достижению контроля над астмой (GINA), Инициативы по аллергическому риниту и его влиянию на астму (ARIA/MACVIA)

Heterogeneity in the use of biologics for severe asthma in Europe: a SHARP ERS study

International audienceIntroduction Treatment with biologics for severe asthma is informed by international and national guidelines and defined by national regulating bodies, but how these drugs are used in real-life is unknown. Materials and methods The ERS SHARP clinical research collaboration conducted a 3-step survey collecting information on asthma biologics use in Europe. Five geographically distant countries defined the survey questions, focusing on 7 endpoints: biologics availability and financial issues, prescription and administration modalities, inclusion criteria, continuation criteria, switching biologics, combining biologics, and evaluation of corticosteroid toxicity. The survey was then sent to SHARP National Leads of 28 European countries. Finally, selected questions were submitted to a broad group of 263 asthma experts identified by national societies. Results Availability of biologics varied between countries, with 17/28 countries having all 5 existing biologics. Authorised prescribers (pulmonologists and other specialists) also differed. In-hospital administration was the preferred deliverance modality. While exacerbation rate was used as an inclusion criterion in all countries, FEV 1 was used in 46%. Blood eosinophils were an inclusion criterion in all countries for IL5- and IL4/IL13- targeted biologics, with varying thresholds. There were no formally established criteria for continuing biologics. Reduction in exacerbations represented the most important benchmark, followed by improvement in asthma control and quality of life. Only 73% (191/263) of surveyed clinicians assessed their patients for corticosteroid-induced toxicity. Conclusion Our study reveals important heterogeneity in the use of asthma biologics across Europe. To what extent this impacts on clinical outcomes relevant to patients and healthcare services needs further investigation

Long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma (TRAVERSE): an open-label extension study

Background: Clinical trials have shown treatment benefits of dupilumab in patients with uncontrolled asthma for up to 1 year. This study aimed to evaluate the long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma, as data for extended treatment with dupilumab beyond 1 year are not available. Methods: TRAVERSE was an open-label extension study in 362 hospitals and clinical centres across 27 countries that assessed the safety and efficacy of dupilumab 300 mg every 2 weeks up to 96 weeks in adults and adolescents (aged 12-84 years) with moderate-to-severe or oral-corticosteroid-dependent severe asthma who had completed a previous dupilumab asthma study (phase 2A EXPEDITION, phase 2B DRI [P2b], phase 3 QUEST, or VENTURE). The primary endpoint was the number and percentage of patients with any treatment-emergent adverse events. Secondary endpoints included annualised exacerbation rate (AER) over the treatment period and change from parent study baseline in pre-bronchodilator FEV1, the five-item asthma control questionnaire (ACQ-5), the asthma quality of life questionnaire (AQLQ), type 2 biomarkers (blood eosinophils and serum total IgE), and anti-drug antibodies (ADAs). Statistical analyses were descriptive. We report safety in all enrolled patients, and efficacy in patients with non-oral-corticosteroid-dependent asthma and in subgroups, including patients with a type 2 inflammatory phenotype who received 148 weeks of treatment. This study is registered with ClinicalTrials.gov, NCT02134028. Findings: Between Aug 5, 2014, and Oct 11, 2019, of 2302 patients assessed for eligibility, 2282 adults and adolescents were enrolled (median age 50 years, 62·1% female and 37·9% male). Safety during TRAVERSE was consistent with the known dupilumab safety profile. The proportion of patients reporting treatment-emergent adverse events throughout the study duration was similar to that observed in the parent studies and ranged from 76·3% to 94·7%. The most frequently reported treatment-emergent adverse events were nasopharyngitis (17·5-25·9%), injection-site erythema (2·2-23·4%), and bronchitis (9·3-19·0%). Serious asthma exacerbations (0·5-3·6%) and pneumonia (0·7-2·7%) were the most frequently reported serious adverse events. There were four treatment-emergent adverse events leading to death. Efficacy during TRAVERSE was also consistent with the results of parent studies. In patients who were non-oral-corticosteroid-dependent, AER remained low (0·277-0·327) across parent study and treatment groups, pre-bronchodilator FEV1 improvements were sustained to the end of treatment at week 96 (mean changes from parent study baseline ranged from 0·22 L [SD 0·44] to 0·33 L [0·44] across parent study and treatment groups), and improvements in ACQ-5 and AQLQ scores were sustained to the last timepoint assessed at week 48. Rapid improvements were observed in pre-bronchodilator FEV1 and sustained improvements were seen in all outcome measures for patients given dupilumab who previously received placebo in parent studies; further improvements in AER, asthma control, and health-related quality of life were observed in patients who continued receiving dupilumab. Blood eosinophils and serum total IgE decreased progressively. ADA status had no effect on safety or efficacy. In the subgroup of patients with a type 2 inflammatory phenotype followed-up for 148 weeks, AER decreased progressively, and initial lung function improvements were sustained over 148 weeks. Interpretation: Data show that safety and efficacy of dupilumab in adult and adolescent patients with moderate-to-severe asthma are sustained when treatment is extended up to 148 weeks. These findings therefore support the long-term use of dupilumab in this patient population