Asthma

Background: Asthma is a chronic inflammatory condition linked to hyperresponsiveness in the airways. There is currently no cure available for asthma, and therapy choices are limited. Asthma is the result of the interplay between genes and the environment. The exact molecular genetic mechanism of asthma remains elusive. Aims: The aim of this study is to provide a comprehensive, detailed molecular etiology profile for the molecular factors that regulate the severity of asthma and pathogenicity using integrative bioinformatics tools. Methods: The GSE43696 omnibus gene expression dataset, which contains 50 moderate cases, 38 severe cases, and 20 healthy controls, was used to investigate differentially expressed genes (DEGs), susceptible chromosomal loci, gene networks, pathways, gene ontologies, and protein–protein interactions (PPIs) using an intensive bioinformatics pipeline. Results: The PPI network analysis yielded DEGs that contribute to interactions that differ from moderate-to-severe asthma. The combined interaction scores resulted in higher interactions for the genes STAT3, AGO2, COL1A1, CLCN6, and KSR for moderate asthma and JAK2, INSR, ERBB2, NR3C1, and PTK6 for severe asthma. Enrichment analysis (EA) demonstrated differential enrichment between moderate and severe asthma phenotypes; the ion transport regulation pathway was significantly enhanced in severe asthma phenotypes compared to that in moderate asthma phenotypes and involved PER2, GCR, IRS-2, KCNK7, KCNK6, NOX1, and SCN7A. The most enriched common pathway in both moderate and severe asthma is the development of the glucocorticoid receptor (GR) signaling pathway followed by glucocorticoid-mediated inhibition of proinflammatory and proconstrictory signaling in the airway of smooth muscle cell pathways. Gene sets were shared between severe and moderate asthma at 16 chromosome locations, including 17p13.1, 16p11.2, 17q21.31, 1p36, and 19q13.2, while 60 and 48 chromosomal locations were unique for both moderate and severe asthma, respectively. Phylogenetic analysis for DEGs showed that several genes have been intersected in phases of asthma in the same cluster of genes. This could indicate that several asthma-associated genes have a common ancestor and could be linked to the same biological function or gene family, implying the importance of these genes in the pathogenesis of asthma. Conclusion: New genetic risk factors for the development of moderate-to-severe asthma were identified in this study, and these could provide a better understanding of the molecular pathology of asthma and might provide a platform for the treatment of asthma.

Advances in adult asthma diagnosis and treatment in 2012: Potential therapeutics and gene-environment interactions

To investigate the relationship between the severity of allergic asthma and the levels of atrial natriuretic peptide (ANP), and to analyze the potential role of ANP signaling in the pathogenesis of asthma. We recruited 96 subjects, including 23 healthy volunteers, 25 stable allergic asthmatics, 21 mild allergic asthmatics and 27 moderate allergic asthmatics, from the Affiliated Hospital of Guilin Medical University. ANP, IFN-γ and IL-4 levels in serum were detected by enzyme-linked immunosorbent assay (ELISA), and the mRNA and protein expressions of natriuretic peptide receptor A (NPRA), transcription factor T-bet and GATA3 were measured by RT-PCR and Western blot. The levels of ANP in serum and the expressions of NPRA mRNA and protein in the peripheral blood mononuclear cell (PBMC) from the mild asthma group or the moderate group were elevated compared with those in the stable asthma group or the mild group, respectively (P<0.05). Consistently, expressions of GATA3 and levels of IL-4 showed the same tendency (P<0.05). In addition, levels of ANP in serum were positively correlated with the severity of asthma, whereas negatively correlated with the ratio of T-bet/GATA3 and IFN-γ/IL-4 (r=-0.85, P<0.05; r=-0.88, P<0.05, respectively). Levels of ANP signaling in serum were significantly increased with the severity of allergic asthma, suggesting a close relation with the pathogenesis of asthma; ANP signaling may play a role in the pathogenesis of allergic asthma through inducing the Th2-type immune response.

BackgroundPhase III studies have demonstrated reduced exacerbation rates with tiotropium Respimat® (tioR) add-on to ICS + LABA in patients with symptomatic asthma (Kerstjens et al. NEJM 2012;367:1198–207). There are currently...

Clinical characteristics in 545 patients with severe asthma on biological treatment during the COVID-19 outbreak

The increased interest in the process of autophagy in various physiological and pathological conditions is the focus of this study. Therefore, the aim was to assess the involvement of lymphocyte autophagy in the pathogenesis of bronchial asthma. Forty-five patients with mild persistent asthma, 45 patients with severe persistent asthma, and 45 normal healthy controls were involved in this study. Autophagy was evaluated based on the expression of microtubule-associated protein light chain 3 (LC3) by western blot, Fluorescence microscopy, and flow cytometry. Transmission Electron Microscopy was used to detect autophagosome. The results showed that autophagy was activated in T-cells of patients with mild and severe asthma compared to the normal healthy control. Stress conditions induced autophagy in T-cells of asthmatic patients with mild and severe form, but not in the control group. Dexamethasone treatment of T-cells stimulated apoptosis in mild asthma patients and in the control group but in the group with severe asthma, dexamethasone induced autophagy. Thus, autophagy could play an important role in the pathogenesis of asthma especially of severe asthma, and may contribute to the survival and the activation of T-lymphocyte in patients with severe asthma.

Eosinophil Cationic Protein Levels in Induced Sputum Correlate With the Severity of Bronchial Asthma

Asthma is a heterogeneous respiratory disease characterized by usually reversible bronchial obstruction, which is clinically expressed by different phenotypes driven by complex pathobiological mechanisms (endotypes). In recent years several molecular effectors and signaling pathways have emerged as suitable targets for biological therapies of severe asthma, refractory to standard treatments. Indeed, various therapeutic mono-clonal antibodies currently allow one to intercept at different levels the chain of pathogenic events leading to type 2 (T2) airway inflammation. Pro-allergic immunoglobulin E (IgE) is the first molecule against which an anti-asthma monoclonal antibody (omalizumab) was developed; today other targets are successfully being exploited by biological treatments for severe asthma. In particular, pro-eosinophilic interleukin 5 (IL-5) can be targeted by mepolizumab or reslizumab, whereas benralizumab is a selective blocker of IL-5 receptor, and IL-4 and IL-13 can be targeted by dupilumab. Besides these drugs, which are already available in medical practice, other biologics are under clinical development such as those targeting innate cytokines, including the alarmin thymic stromal lymphopoietin (TSLP), which plays a key role in the pathogenesis of type 2 asthma. Therefore, ongoing and future biological therapies are significantly changing severe asthma management on a global level. These new therapeutic options make it possible to implement phenotype/endotype-specific treatments, which are delineating personalized approaches precisely addressing the individual traits of asthma pathobiology. The aim of the study is to review the immunopathology and treatment efficacy for severe asthma and focused on new biological agents with benralizumab (anti-IL-5) and tezepelumab (anti-TSLP).

Asthma Update

Is Theophylline Obsolete?

Aims . To analyze the costs of pharmacotherapy in children hospitalized with bronchial asthma exacerbations. Materials and methods . The data from 336 medical reports were used. In this study, patients with severe bronchial asthma were analyzed separately from those with moderate asthma. The economic analysis of pharmacotherapy was carried out in accordance with the ABC guidelines for an international non-proprietary name. In relation to the field of medicinal use, the analyzed drugs were distributed into three classes (A, B and C) according to the selected criteria. In the present study, the selection criterion was the amount of expenses needed to purchase the given medicine. Results. The ABCanalysis showed that about 80% of the amounts spent for the treatment of moderately severe asthma were due to the costs of medications. Among them, Montelukast – 31.27%; Budesonide – 28,49%; Umifenovir – 5.69%; Azithromycin – 5.50%; Salmeterol / fluticasone propionate – 4.74%; Formoterol / budesonide – 3.32%; Ipratropium bromide / fenoterol hydrobromide acetylcysteine – 3.20%; (In total, the percentage amounts to 82.15%). In the treatment of severe asthma, the same 80% of the costs consisted of: Montelukast – 28.13%; Salmeterol / fluticasone propionate – 25.54%; Formoterol / budesonide – 13.51%; Acetylcysteine 6.64%; Budesonide – 5.67% (in total, the percentage amounts to 79.48%). In moderately severe asthma, the largest part of the costs is due to inhaled glucocorticosteroids – budesonide (28.42%), while in severe cases, it is due to combined salmeterol / fluticasone propionate (25.54%) and formoterol / budesonide (13.51%). In the treatment of asthma of moderate severity, a certain part of segment A is taken by macrolide antibiotics of the azithromycin group (they account for 5.50% of the total costs) and antiviral drugs – umifenovir (5.59%). The introduction of antibiotics and anti-viral drugs is rationalized by asthma exacerbations developing on the background of viral and / or bacterial, often “atypical” infections. Conclusion. This pharmacoepidemiological analysis shows that the costs of treatment with Montelukast of moderate (31.27%) and severe (28.13%) bronchial asthma are comparable. For other drugs, the treatment costs significantly differ between the moderate and severe asthma therapies.

Bronchial asthma is a major public health problem in the world. A considerable proportion of patients suffer from severe asthma, which is manifested by a decrease in the quality of life, an increase in the frequency of exacerbations, hospitalisations, and mortality. The ineffectiveness of conventional therapy in such patients contributes to the development of biological treatment methods with higher specificity, aimed at the pathogenetic links of the disease. The purpose of the study was to analyse the effectiveness of the treatment of severe bronchial asthma with monoclonal antibodies based on literature data. The study examines publications over the past 5 years that are available on the Internet. The following terms were used for the search: monoclonal antibodies, endotype, phenotype. Five monoclonal antibody biological agents targeting IgE, IL-5, IL-4, and IL-13, which are approved for use in patients with severe asthma, were analysed: omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab. The use of these medications has led to progress in the treatment of bronchial asthma. It was found that determining disease endotypes based on the assessment of biomarkers such as eosinophil count in blood and sputum, fractional exhaled nitric oxide, and serum periostin contributes to the greater effectiveness of biological therapy. It was investigated that monoclonal antibody treatment improves lung function, reduces exacerbation frequency, and decreases the need for additional medications. Many other biological agents, particularly those targeting key cytokines, are in the clinical development stage. Approved monoclonal antibodies targeting IgE, IL-5, and IL-4/IL13 demonstrate high efficacy in the treatment of severe bronchial asthma. The use of these agents in patients with severe asthma and high Th2 levels considerably improves lung function, symptom control, and reduces the frequency of disease exacerbations

Clinical studies have shown that pranlukast (Ono Pharmaceutical Co., Osaka, Japan) is effective for mild and moderate asthma. However, it is not well known that pranlukast is also effective on moderate and severe persistent asthma in the long term. We studied the effect of pranlukast on moderate and severe asthmatics by evaluating the change of peak expiratory flow (PEF) and therapeutic scores for 1 year before and during pranlukast therapy. We gave pranlukast 225 mg twice daily orally to 25 patients who were receiving more than 400 micrograms/day beclomethasone inhalation and beta 2 stimulant inhalation with or without oral corticosteroid. Pranlukast increased PEF more than 10 L/min in 14 patients in the first 4 weeks. In these 14 patients, 10 patients continued to monitor PEF and kept asthma diaries for 1 year. We compared the data for 1 year before and during the pranlukast therapy. During the pranlukast therapy, PEF significantly increased, puffs of beta 2 stimulant inhalation significantly decreased. The incidence of oral corticosteroid rescue therapy reduced, and the mean daily dose of oral corticosteroid decreased; however, they were not statistically significant. During treatment with pranlukast, no side effect was observed. From these results, we suggest that pranlukast is effective for more than half of the moderate and severe persistent asthmatics, and that the effectiveness continues for more than 1 year.

What’s on the Horizon for the Targeted Treatment of Type 2-low Asthma?

1UBC James Hogg Research Centre, Institute for Heart + Lung Health, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada, 2The Prince Charles Hospital and The University of Queensland, Brisbane, Queensland, Australia, 3Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, and 4Department of Medicine, National University Hospital, Singapore, Singapore