Effective Treatment For Asthma Research Articles

Bronchial thermoplasty decreases airway remodeling by inhibiting autophagy via the AMPK/mTOR signaling pathway.

Bronchial thermoplasty (BT), an effective treatment for severe asthma, requires heat to reach the airway to reduce the mass of airway smooth muscle cells (ASMCs). Autophagy is involved in the pathological process of airway remodeling in patients with asthma. However, it remains unclear whether autophagy participates in controlling airway remodeling induced by BT. In this study, we aim to elucidate the autophagy-mediated molecular mechanisms in BT. Our study reveal that the number of autophagosomes and the level of alpha-smooth muscle actin (α-SMA) fluorescence are significantly decreased in airway biopsy tissues after BT. As the temperature increased, BT causes a decrease in cell proliferation and a concomitant increase in the apoptosis of human airway smooth muscle cells (HASMCs). Furthermore, increase in temperature significantly downregulates cellular autophagy, autophagosome accumulation, the LC3II/LC3I ratio, and Beclin-1 expression, upregulates p62 expression, and inhibits the AMPK/mTOR pathway. Furthermore, cotreatment with AICAR (an AMPK agonist) or RAPA (an mTOR antagonist) abolishes the inhibition of autophagy and attenuates the increase in the apoptosis rate of HASMCs induced by the thermal effect. Therefore, we conclude that BT decreases airway remodeling by blocking autophagy induced by the AMPK/mTOR signaling pathway in HASMCs.

Factors influencing poor response to type 2 targeted therapies in severe asthma: a retrospective cohort study

BackgroundA significant breakthrough has been made in treating severe asthma, with the recognition of various asthma phenotypes and an updated management guideline. Type 2 targeted therapies, such as benralizumab and omalizumab; have been identified as an effective treatment for severe asthma, improving patient response, lung function tests and asthma symptom control. This study aimed to evaluate factors contributing to poor response to therapy.MethodsA retrospective single-center cohort study of 162 patients with severe asthma who started biologic therapy; their data were retrieved from medical records for further analysis. Poor responders were patients remained clinically and functionally uncontrolled despite even after augmenting all treatment options.ResultsChildhood-onset asthma, bronchiectasis, poor symptom control (ACT below 19), severe airway obstruction (< 60% predicted), and maintenance oral corticosteroid (mOCS) use were significantly associated with poor response to omalizumab and benralizumab; p = 0.0.4 and 0.01; 0.003 and 0.01; 0.01 and 0.001, 0.05 and 0.04; 0.006 and 0.02, respectively. However, chronic rhinosinusitis and IgE < 220kIU/L were associated with higher poor response rates to omalizumab (p = 0.01 and 0.04, respectively). At the same time, female patients and those with blood eosinophils level < 500 cells/mm3 had a higher poor response rate to benralizumab (p = 0.02 and 0.01, respectively). Ischemic heart disease (IHD), bronchiectasis, and continued use of OCS increased the likelihood of poor response to omalizumab by 21, 7, and 24 times (p = 0.004, 0.008, and 0.004, respectively). In contrast, the female gender, childhood-onset asthma and higher BMI increased the likelihood of poor response to benralizumab by 7, 7 and 2 times more, p = 0.03, 0.02 and 0.05, respectively.ConclusionPoor response to omalizumab treatment was independently associated with ischemic heart disease (IHD), bronchiectasis, and a history of maintenance oral corticosteroid (mOCS) use. Conversely, poor response to benralizumab therapy was independently linked to female gender, childhood-onset asthma and higher body mass index (BMI).

Decreased prevalence and severity of asthma symptoms among adolescents in Ibadan, Nigeria, 1995-2018.

BACKGROUND: Phases I and III of the International Study of Asthma and Allergies in Childhood (ISAAC) documented increased asthma symptoms among Nigerian 13-14-year old adolescents. We investigated the trend further using the Global Asthma Network (GAN) surveillance.METHODS: Using ISAAC methodology, GAN Phase I data on symptoms and risk factors for asthma and asthma management were obtained from February to July 2018.RESULTS: There were 2,897 adolescents from 23 secondary schools. For current wheeze, there was an absolute prevalence fall per decade of -1.4 with -1 standard error (SE) in 16 years from 2002 (ISAAC Phase III) to 2018 (GAN Phase I). This pattern was evident for prevalence of reported asthma ever, severe asthma symptoms and night cough with ≥1 SE. During the 23-year interval between ISAAC Phase I and GAN Phase I, there was a fall (≥1 SE) in the absolute prevalence of reported asthma ever, severe asthma symptoms and night cough, except for severe asthma symptoms (-0.2 SE). Respectively 36% and 43% of symptomatic adolescents purchased and used salbutamol and prednisolone.CONCLUSION: The prevalence and severity of asthma symptoms remain high among adolescents in Ibadan. This could be mitigated by improved access to affordable and effective asthma treatments.

Development of a new inhaled swellable microsphere system for the dual delivery of naringenin-loaded solid lipid nanoparticles and doxofylline for the treatment of asthma

This study developed a new dual delivery system of naringenin (NRG), a polyphenol, and doxofylline (DOX), a xanthine derivative, as an inhaled microsphere system. In this system, NRG has been first loaded into glyceryl tristearate-based solid lipid nanoparticles (NRG SLN), which were further loaded with DOX into swellable chitosan-tripolyphosphate-based microspheres (NRG SLN DOX sMS). The system was characterised based on particle size, PDI, zeta potential, surface morphology (SEM, AFM, and TEM), solid-state and chemical properties (XRD, IR, and NMR), aerodynamic parameters, drug loading, entrapment efficiency and in vitro drug release study. The optimised NRG SLN DOX sMS exhibited particle size, zeta potential, and PDI of 2.1 µm, 31.2 mV, and 0.310, respectively; a drug entrapment efficiency > 79%; a drug loading efficiency > 13%; cumulative drug releases of about 78% for DOX and 72% for NRG after 6 and 12 hours, respectively; good swelling and desirable aerodynamic properties. In addition, in vivo studies conducted in mice, a murine model of asthma showed significant reductions in serum bicarbonate and eosinophil counts and improvement in respiratory flow rate, tidal volume, and bronchial wall lining compared with the asthmatic control group. Overall, this novel inhalable dual-delivery system may represent a good alternative for the effective treatment of asthma.

The Therapeutic Role of Inspiratory Muscle Training in The Management of Asthma: A Narrative Review.

Asthma is a disorder of the airways characterized by chronic airway inflammation, hyperresponsiveness, and variable recurring airway obstruction. Treatment options for asthma include pharmacological strategies, while non-pharmacological strategies are limited. Established pharmacological approaches to treating asthma may cause unwanted side effects and do not always afford adequate protection against asthma, possibly due to an individual's variable response to medications. A potential non-pharmacological intervention that is most available and cost-effective is inspiratory muscle training (IMT), which is a technique targeted at increasing the strength and endurance of the diaphragm and accessory muscles of inspiration. Studies examining the impact of IMT on asthma have reported increases in inspiratory muscle strength, and a reduction in the perception of dyspnea and medication use. However, due to the limited number and discordant methods between studies more evidence is required to elucidate in asthmatics the efficacy of IMT on inspiratory muscle endurance, exercise capacity, asthma control, symptoms, quality of life, as well as adolescents with differing severities of asthma. Large randomized controlled trials would be a significant step forward in clarifying the effectiveness of IMT in asthmatics. While IMT may have favorable effects on inspiratory muscle strength, dyspnea and medication use, the current evidence that IMT is an effective treatment for asthma is inconclusive.

Anti-IL-5 dans l’asthme sévère associé à une granulomatose éosinophilique avec polyangéite. Étude en vie réelle

Eosinophilic granulomatosis with polyangiitis (EGPA) is a form of necrotizing vasculitis affecting small vessels and typically characterized by severe glucocorticoid (GC)-dependent eosinophilic asthma. While mepolizumab, which is indicated at a dose of 100mg/4weeks in severe eosinophilic asthma, has been shown to be an effective treatment for EGPA-related asthma at a dose of 300mg/4weeks, it was only recently approved at this dose. This retrospective, single-center, observational study was conducted to investigate over a 5-year period (2014-2019) the effect of mepolizumab 100mg/4weeks at 12months in patients with EGPA and glucocorticoid-dependant severe asthma. Response to treatment was defined as reduction in daily dose of oral corticosteroids to at most 5mg/day or reduction in annual exacerbation by at least 50%. Thirty patients were included, of whom twenty-three were treated (two were not fully evaluable). Among the 21 evaluable treated patients, 13 (62%) had responded at 12months. At baseline, non-responders had lower FEV1 levels and lower blood eosinophil levels than responders. Mepolizumab at a "severe asthma" dose (100mg/4weeks) is effective in treatment of GC-dependent severe asthma in most patients with EGPA.

Synergy between interleukin-1β, interferon-γ and glucocorticoids to induce TLR2 expression involves NF-κB, STAT1 and GR.

Glucocorticoids act via the glucocorticoid receptor (GR; NR3C1) to downregulate inflammatory gene expression and are effective treatments for mild-moderate asthma. However, in severe asthma and virus-induced exacerbations, glucocorticoid therapies are less efficacious, possibly due to reduced repressive ability and/or the increased expression of pro-inflammatory genes. In human A549 epithelial and primary human bronchial epithelial cells (pHBECs), toll-like receptor (TLR) 2 mRNA and protein were supra-additively induced by interleukin-1β (IL1B) plus dexamethasone (IL1B+Dex), interferon-γ (IFNG) plus dexamethasone (IFNG+Dex) and IL1B plus IFNG plus dexamethasone (IL1B+IFNG+Dex). Indeed, ~34-2100-fold increases were apparent at 24 h for IL1B+IFNG+Dex and this was greater than for any single or dual treatment. Using the A549 cell model, TLR2 induction by IL1B+IFNG+Dex was antagonized by Org34517, a competitive GR antagonist. Further, when combined with IL1B, IFNG, or IL1B+IFNG, the enhancements by dexamethasone on TLR2 expression required GR. Likewise, inhibitor of κB kinase 2-inhibitors reduced IL1B+IFNG+Dex-induced TLR2 expression, and TLR2 expression induced by IL1B+Dex, with or without IFNG, required the nuclear factor (NF)-κB subunit, p65. Similarly, signal transducer and activator of transcription (STAT) 1 phosphorylation and γ-interferon-activated-sequence-dependent transcription were induced by IFNG. These, along with IL1B+IFNG+Dex-induced TLR2 expression, were inhibited by Janus kinase (JAK) inhibitors. As IL1B+IFNG+Dex-induced TLR2 expression also required STAT1, this study reveals cooperation between JAK-STAT1, NF-κB, and GR to upregulate TLR2 expression. Since TLR2 agonism elicits inflammatory responses, we propose that synergies involving TLR2 may occur within the cytokine milieu present in the immunopathology of glucocorticoid-resistant disease, and this could promote glucocorticoid resistance. Significance Statement This study highlights that in human pulmonary epithelial cells, glucocorticoids, when combined with the inflammatory cytokines, IL1B and IFNG, can synergistically induce the expression of inflammatory genes, such as TLR2. This effect involved positive combinatorial interactions between NF-κB/p65, GR and JAK-STAT1 signalling to synergistically upregulate TLR2 expression. Thus, synergies involving glucocorticoid-enhancement of TLR2 expression may occur in the immunopathology of glucocorticoid-resistant inflammatory diseases, including severe asthma.

From preschool wheezing to asthma: Immunological determinants.

Asthma represents a chronic respiratory disease affecting millions of children worldwide. The transition from preschool wheezing to school-age asthma involves a multifaceted interplay of various factors, including immunological aspects in early childhood. These factors include complex cellular interactions among different immune cell subsets, induction of pro-inflammatory mediators and the molecular impact of environmental factors like allergens or viral infections on the developing immune system. Furthermore, the activation of specific genes and signalling pathways during this early phase plays a pivotal role in the manifestation of symptoms and subsequent development of asthma. Early identification of the propensity or risk for asthma development, for example by allergen sensitisation and viral infections during this critical period, is crucial for understanding the transition from wheeze to asthma. Favourable immune regulation during a critical 'window of opportunity' in early childhood can induce persistent changes in immune cell behaviour. In this context, trained immunity, including memory function of innate immune cells, has significant implications for understanding immune responses, potentially shaping long-term immunological outcomes based on early-life environmental exposures. Exploration of these underlying immune mechanisms that drive disease progression will provide valuable insights to understand childhood asthma development. This will be instrumental to develop preventive strategies at different stages of disease development for (i) inhibiting progression from wheeze to asthma or (ii) reducing disease severity and (iii) uncovering novel therapeutic strategies and contributing to more tailored and effective treatments for childhood asthma. In the long term, this shall empower healthcare professionals to develop evidence-based interventions that reduce the burden of asthma for children, families and society overall.

Efficacy of Trigonella foenum-graecum Linné in an animal model of particulate matter-induced asthma exacerbation

Ethnopharmacological relevanceThe seeds of Trigonella foenum-graecum Linné (TFG) has traditionally been used in Central Asia to relieve inflammation. Aim of the studyThis study investigated the efficacy of TFG in a bronchial cell model and an animal model of asthma exacerbation caused by PM. MethodsBEAS-2B bronchial epithelial cells were simultaneously treated with tumor necrosis factor-α/interleukin (IL)-4 and PM, and the expression of inflammatory cytokines, DNA damage, and autophagy mechanisms were analyzed. In an animal model of asthma exacerbation, we analyzed changes in organ weight, distribution of inflammatory cytokines and inflammatory cells in the bronchoalveolar lavage fluid, and intra-tissue mucus production. ResultsIn the cell model, TFG suppressed the expression of the inflammatory cytokines IL-6, granulocyte-macrophage colony stimulating factor, monocyte chemoattractant protein-1, and IL-8; reactive oxygen species levels and DNA damage; and the phosphorylation of ERK, JNK, P38, AKT, and mTOR. In the animal model, TFG significantly reduced weight gain of the liver, lung, and spleen; IgE, IL-6, and IFN-γ levels; and bronchial mucus secretion and smooth muscle thickness. ConclusionTFG alleviated the PM-exacerbated inflammatory response by inhibiting the MAPK and autophagy signaling pathways; it is expected to be an effective treatment for asthma.

Benralizumab for eosinophilic granulomatosis with polyangiitis

BackgroundBenralizumab is effective in the treatment of eosinophilic asthma and is being investigated for the treatment of other eosinophil-associated diseases. Reports on the use of benralizumab for the treatment of...

COMPUTER-AIDED DESIGN OF MUSCARINIC ACETYLCHOLINE RECEPTOR M3 INHIBITORS: PROMISING COMPOUNDS AMONG TRIFLUOROMETHYL CONTAINING HEXAHYDROPYRIMIDINONES/THIONES.

The new high selective mAChRs M3 inhibitors with IC 50 in nanomolecular ranges, which can be the prototypes for effective COPD and asthma treatment drugs, were discovered with computational approaches among trifluoromethyl containing hexahydropyrimidinones/thiones. Compounds [6-(4-ethoxy-3-methoxy-phenyl)-4-hydroxy-2-thioxo-4-(trifluoromethyl)hexahydropyrimidin-5-yl]-phenyl-methanone (THPT-1) and 5-benzoyl-6-(3,4-dimethoxyphenyl)-4-hydroxy-4-(trifluoromethyl)hexahydropyrimidin-2-one (THPO-4) have been proved to be a highly effective (with IC 50 values of 1.62·10 -7 M and 3.09·10 -9 M, respectively) at the same concentrations significantly competitive inhibit the signal conduction through mAChR3 in comparison with ipratropium bromide, without significant effect on mAChR2, nicotinic cholinergic and adrenergic receptors.

Exploring redox imbalance and inflammation for asthma therapy.

Asthma is a prolonged inflammatory disorder of the airways, that affects an estimated 300 million people worldwide. Asthma is triggered by numerous endogenous and exogenous stimuli with symptoms like wheezing, cough, short of breath, chest tightening, airway obstruction, and hyperreactivity observed in patients. The review seeks to identify targets of redox imbalance and inflammation that could be explored to create effective treatments for asthma. Themethodology involved a search and review of literature relating to asthma pathogenesis, redox homeostasis, and inflammation. Eosinophils and neutrophils are involved in asthma pathogenesis. These inflammatory cells generate high levels of endogenous oxidants such as hydrogen peroxide and superoxide, which could result in redox imbalance in the airways of asthmatics. Redox imbalance occurs when the antioxidant systems becomes overwhelmed resulting in oxidative stress. Oxidative stress and inflammation have been linked with asthma inflammation and severity. Reactive oxygen species (ROS)/reactive nitrogen species (RNS) cause lung inflammation by activating nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), activator protein-1, as well as additional transcription factors. These factors stimulate cytokine production which ultimately activates inflammatory cells in the bronchi, causing lung cellular injury and destruction. ROS/RNS is also produced by these inflammatory cells to eradicate invading bacteria. Antioxidant treatments for asthma have not yet been fully explored. Redox and inflammatory processes are viable targets that could be explored to create better therapy for asthma.

Intrinsically bioactive and biomimetic nanoparticle-derived therapies alleviate asthma by regulating multiple pathological cells

Asthma is a serious global public health concern. Airway neutrophilic inflammation is closely related to severe asthma, for which effective and safe therapies remain to be developed. Here we report nanotherapies capable of simultaneously regulating multiple target cells relevant to the pathogenesis of neutrophilic asthma. A nanotherapy LaCD NP based on a cyclic oligosaccharide-derived bioactive material was engineered. LaCD NP effectively accumulated in the injured lungs of asthmatic mice and mainly distributed in neutrophils, macrophages, and airway epithelial cells after intravenous or inhalation delivery, thereby ameliorating asthmatic symptoms and attenuating pulmonary neutrophilic inflammation as well as reducing airway hyperresponsiveness, remodeling, and mucus production. Surface engineering via neutrophil cell membrane further enhanced targeting and therapeutic effects of LaCD NP. Mechanistically, LaCD NP can inhibit the recruitment and activation of neutrophils, especially reducing the neutrophil extracellular traps formation and NLRP3 inflammasome activation in neutrophils. Also, LaCD NP can suppress macrophage-mediated pro-inflammatory responses and prevent airway epithelial cell death and smooth muscle cell proliferation, by mitigating neutrophilic inflammation and its direct effects on relevant cells. Importantly, LaCD NP showed good safety performance. Consequently, LaCD-derived multi-bioactive nanotherapies are promising for effective treatment of neutrophilic asthma and other neutrophil-associated diseases.

Advances in the Discovery of Novel Inhaled PI3Kδ Inhibitors for the Treatment of Asthma.

Bronchial asthma is the most common chronic respiratory illness, the incidence of which continues to increase annually. Currently, effective treatments for CS-resistant asthma and severe asthma are still lacking, and new therapeutic regimens are urgently required. PI3Kδ is a key enzyme in hematopoietic cells and represents a major target for oncology and inflammatory disease (particularly respiratory disease, asthma and COPD). In the case of respiratory disease, the ability to inhibit PI3Kδ in the lungs shows a higher safety and therapeutic index relative to systemic inhibition. In recent years, paradigm shifts have occurred in inhalation therapeutics for systemic and topical drug delivery due to the favorable properties of lungs, including their large surface area and high permeability. Pulmonary drug delivery possesses many advantages, including a non-invasive route of administration, low metabolic activity, a controlled environment for systemic absorption and the ability to avoid first bypassing metabolism. In this review, we focus on the discovery and development of inhaled drugs targeting PI3Kδ for asthma by focusing on their activity and selectivity, in addition to their potential in drug design strategies using inhaled administration.

Differential therapeutic activity of a cargo-free nanoparticle in eosinophilic and neutrophilic asthma mouse models

Asthma is a complex, heterogeneous chronic airway inflammatory disorder, which can be simply categorized into eosinophilic and neutrophilic asthma. Although most patients with eosinophilic asthma can be well managed by glucocorticoid therapy, the patients with neutrophilic asthma have poor responses to corticosteroids, and there are no effective clinical treatments for neutrophilic asthma. Studies have shown that M1 macrophages are associated with the pathophysiology of neutrophilic asthma. We previously developed a novel cargo-free anti-inflammatory nanoparticle (P12), which can promote macrophage polarization from M1 to the M2 phenotype. Herein, we aim to explore the therapeutic activities of P12 in eosinophilic asthma and neutrophilic asthma and the mechanisms of action behind. Using the mouse models of eosinophilic and neutrophilic asthma, we found that the intratracheally administered P12 reduced the airway resistance in both models. However, P12 had higher therapeutic effects in neutrophilic asthma than in eosinophilic asthma, particularly on the pathological score, the serum IgE level, the BAL differential cell count and the proinflammatory cytokine IL-17A and IL-6 levels. Mechanistically, P12 facilitated M2 macrophage polarization by inhibiting transcription factors NF-κB and STAT1 activation and up-regulating STAT3 signaling in vitro; in the asthma models, P12 promoted M2 polarization of both alveolar and interstitial macrophages, and reduced the downstream Th17/Treg ratio in mice with neutrophilic asthma. Finally, P12 showed a good biosafety profile in healthy mice, facilitating the clinical translation of P12. This study provides a new strategy and lung macrophage targeted nanotherapeutics for the treatment of neutrophilic asthma.

Decreased salivary beta-defensin 2 in children with asthma after treatment with corticosteroid inhaler.

Asthma is the most common chronic disorder in childhood. Inhaled corticosteroid therapy is currently the most effective treatment for Asthma. The oral cavity complications related to this treatment may be in terms of the changes in the innate immune system of mouth. Salivary defensin has many immunomodulatory properties. The expression of beta-defensin 2 was measured before and after inhaled corticosteroid treatment in children with asthma to determine the potential impact of corticosteroids on defensin expression. The present study was a cohort study conducted on the patients referred to Children's Medical Center for whom a diagnosis of Asthma was confirmed, and inhaled corticosteroid therapy was prescribed. Saliva was sampled once at the stage of diagnosis and before receiving any treatment. Another salivary sample was collected 4weeks after receiving corticosteroids. ELISA was performed to assess beta-defensin 2. The beta-defensin 2 salivary level after inhaled corticosteroid therapy was significantly lower than before treatment. There is no significant difference in the salivary flow rate before and after treatment. Considering the limitations of the present study, the following conclusions can be made salivary beta-defensin 2 is decreased in children with asthma after treatment with a corticosteroid inhaler. Regular dental and oral soft tissue examinations in Asthmatic children under corticosteroid therapy could be suggested.

Recent developments in the use of monoclonal antibodies targeting the type 2 cytokines for severe asthma treatment.

Severe or refractory asthma is seen in approximately 5% of asthmatic subjects who have unsatisfactory symptom control despite adherence to high-dose inhaled glucocorticoid therapies resulting in significant morbidity, reduced quality of life with attendant implications for healthcare costs. Marked heterogeneity in symptoms and at the molecular phenotypic level are hallmarks of asthma resulting in the requirement of specifically targeted treatments to block the key pathways of the disease. Monoclonal antibody (mAb)-based biologics targeted at inhibition of the type 2 cytokines IL-4, IL-5 and IL-13 have become established as effective treatments for severe asthma, with significant clinical benefit seen in carefully selected patient populations that take asthma phenotypes and endotypes into account. The further development of reproducible and straightforward discriminatory biomarkers may aid identification of those patients most likely to benefit from treatment with these interventions.

ПЕРЕШКОДИ У ДОСЯГНЕННІ КОНТРОЛЮ БРОНХІАЛЬНОЇ АСТМИ В КЛІНІЧНІЙ ПРАКТИЦІ В УМОВАХ ПАНДЕМІЇ COVID-19)

The main goals of bronchial asthma (BA) treatment are to achieve good symptoms control and to minimize future risk of asthma-related mortality, exacerbations, persistent airflow limitation and adverse effects of therapy. Despite the availability of effective treatments for asthma the real life asthma control is lower than expected. The aim of this study was to evaluate the barriers in achieving asthma control in clinical practice during the COVID-19 pandemic according to the literature data. There are both general and COVID-19-related barriers in achieving the goals of asthma treatment. In most patients, the causes for the lack of asthma control are incorrect inhaler technique, poor adherence to treatment, overuse of short-acting bronchodilators, comorbidities, the influence of adverse environmental conditions and psychosocial factors. The COVID-19 pandemic has affected the asthma control through quarantine restrictions and the influence of post-acute COVID-19 disorders. On the one hand, quarantine restrictions had a positive effect on the asthma course: there was a decrease in the seasonal respiratory viral infections and the asthma exacerbations frequency. On the other hand, asthma patients were significantly affected by the pandemic due to a high level of anxiety, stress and limited access to routine medical care. Health disorders in post-COVID-19 period negatively affect the control of BA. After recovery from acute COVID-19 a proportion of asthma patients experienced poorer control and required increased asthma maintenance therapy. Approaches to improving asthma control include adherence to established asthma management guidelines, patient and healthcare professional education, regular asthma monitoring and assessment, review of inhaler technique, provision of a written asthma action plan, use of digital technologies. Key words: bronchial asthma, asthma control, COVID-19.

Responsiveness of Inhaled Corticosteroid Treatment in Children with Asthma: The Role of rs242941 Polymorphism of CRHR1 Gene.

Inhaled corticosteroid (ICS) is the most widely used and effective treatment of asthma. However, some patients do not respond to ICS, which might be due to various genetic factors. Hence, understanding the genetic factors involved in the ICS response could help physicians to individualize their treatment decision and action plans for given patients. This study aimed to analyze the characteristics of corticotropin-releasing hormone receptor 1 (CRHR1) genotypes in children with asthma and the correlation between rs242941 polymorphism of CRHR1 gene and ICS responsiveness. This prospective study included children with uncontrolled asthma, assessing their eosinophil count, IgE concentration, lung function, and fractional concentration of nitric oxide in exhaled breath (FENO) and performing CRHR1 polymorphism sequencing. The level of asthma control was assessed by asthma control test (ACT); the responsiveness of asthma treatment with ICS was evaluated by measuring the change of ACT and forced expiratory volume in 1s (FEV1) after treatment versus at inclusion. In total, 107 patients were analyzed for CRHR1 at rs242941. Among these, 86 (80.3%) had homozygous wild-type GG, 20 (18.7%) had heterozygous GT genotypes, and 1 (1.0%) had a homozygous variant for TT. Children with personal and family history of atopy were more likely to have GT and TT genotypes. The severity of asthma was similar between children with asthma in the three groups of GG, GT, and TT genotypes of CRHR1 at rs242941. FENO level, total IgE concentration, and eosinophilic count in children with asthma were not significantly different between GG and GT genotypes. The patient with a TT homozygous variant genotype had a higher level of FENO. There was no correlation between CRHR1 polymorphism at rs242941 and asthma control evaluated by asthma control test and lung function parameters. TT genotype of rs242941 in the CRHR1 gene is not frequent. Clinical and functional characteristics of children with asthma with rs242941 polymorphism of CRHR1 gene remain homogeneously similar. There is no correlation between rs242941 polymorphism and ACT or FEV1.

EFFECT OF SEX ON RESPONSE TO OMALIZUMAB IN PATIENTS WITH ASTHMA

<h3>Introduction</h3> There are sex-related disparities in asthma. Before puberty, males have increased prevalence and severity of asthma compared with females, and this pattern reverses after the onset of puberty. Omalizumab, an IgE antibody, is an effective treatment for allergic asthma, but sex-specific responses have not been studied in detail. <h3>Methods</h3> Post hoc analysis examined data from randomized, placebo-controlled IA05 trial of omalizumab treatment (52 weeks; 75-375 mg sc every 2-4 weeks; N=627; 6 to <12 years, ie children) and open-label, single-arm PROSPERO study (NCT01922037; 48-weeks; N=801; ≥12 years ie adolescents/adults (n=732 ≥18 years); both included patients with moderate-severe allergic asthma. <h3>Results</h3> In IA05/PROSPERO, baseline characteristics of mean age and IgE levels were similar for female and male participants (females 8.4/47.8 versus males 8.6/46.2 years; IgE levels females 463.2/560.3 versus males 472.8/615.0 IU/mL). Asthma exacerbation rates following omalizumab treatment were similar for females and males. In IA05 (children), asthma exacerbation rates were: females - placebo 0.74 versus omalizumab 0.46, males - placebo 0.55 versus omalizumab 0.43, and the interaction test of effect of sex on omalizumab response was not significant (p=0.4821). In PROSPERO (adolescents/adults), asthma exacerbation rates in females were 0.74 versus males 0.77 (p=0.787). Overall safety reported previously for IA05, Lanier JACI 2009;124;1210-6 and PROSPERO, Casale JACI:IP 2019;7(1):156-64. <h3>Conclusions</h3> Despite differences in asthma between females and males, we found no evidence that the effect of omalizumab in children was dependent on sex, and no evidence that the rate of exacerbations was dependent on sex following omalizumab initiation in adolescents/adults.