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Purpose: Asthma is a clinical syndrome with various underlying pathomechanisms and clinical phenotypes. Genetic, ethnic, and geographic factors may influence the differences in clinical presentation, severity, and prognosis. We compared the characteristics of asthma based on the geographical background by analyzing representative cohorts from the United States, Europe, South America, and Asia using the Severe Asthma Research Program (SARP), Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED), Program for Control of Asthma in Bahia (ProAR), and Cohort for Reality and Evolution of Adult Asthma in Korea (COREA), respectively., Methods: The clinical characteristics and medications for the SARP (n = 669), U-BIOPRED (n = 509), ProAR (n = 996), and COREA (n = 3,748) were analyzed. Subgroup analysis was performed for severe asthma., Results: The mean age was highest and lowest in the COREA and SARP, respectively. The asthma onset age was lowest in the ProAR. The mean body mass index was highest and lowest in the SARP and COREA, respectively. Baseline pulmonary function was lowest and highest in the U-BIOPRED and COREA, respectively. The number of patients with acute exacerbation in the previous year was highest in U-BIOPRED. The mean blood eosinophil count was highest in COREA. The total immunoglobulin E was highest in the ProAR. The frequency of atopy was highest in the SARP. The principal component analysis plot revealed differences among all cohorts., Conclusions: The cohorts from 4 different continents exhibited different clinical and physiological characteristics, probably resulting from the interplay between genetic susceptibility and geographical factors., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2024 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Bestrhodopsins constitute a class of light-regulated pentameric ion channels that consist of one or two rhodopsins in tandem fused with bestrophin ion channel domains. Here, we report on the isomerization dynamics in the rhodopsin tandem domains of Phaeocystis antarctica bestrhodopsin, which binds all-trans retinal Schiff-base (RSB) absorbing at 661 nm and, upon illumination, converts to the meta-stable P540 state with an unusual 11- cis RSB. The primary photoproduct P682 corresponds to a mixture of highly distorted 11 -cis and 13- cis RSB directly formed from the excited state in 1.4 ps. P673 evolves from P682 in 500 ps and contains highly distorted 13- cis RSB, indicating that the 11- cis fraction in P682 converts to 13- cis . Next, P673 establishes an equilibrium with P595 in 1.2 µs, during which RSB converts to 11- cis and then further proceeds to P560 in 48 µs and P540 in 1.0 ms while remaining 11- cis . Hence, extensive isomeric switching occurs on the early ground state potential energy surface (PES) on the hundreds of ps to µs timescale before finally settling on a metastable 11- cis photoproduct. We propose that P682 and P673 are trapped high up on the ground-state PES after passing through either of two closely located conical intersections that result in 11- cis and 13- cis RSB. Co-rotation of C11=C12 and C13=C14 bonds results in a constricted conformational landscape that allows thermal switching between 11 -cis and 13- cis species of highly strained RSB chromophores. Protein relaxation may release RSB strain, allowing it to evolve to a stable 11- cis isomeric configuration in microseconds., Competing Interests: Competing interests statement:The authors declare no competing interest.

Rhodopsin guanylyl cyclases (RGCs) belong to the class of enzymerhodopsins catalyzing the transition from GTP into the second messenger cGMP, whereas light-regulation of enzyme activity is mediated by a membrane-bound microbial rhodopsin domain, that holds the catalytic center inactive in the dark. Structural determinants for activation of the rhodopsin moiety eventually leading to catalytic activity are largely unknown. Here, we investigate the mechanistic role of the D283-C259 (DC) pair that is hydrogen bonded via a water molecule as a crucial functional motif in the homodimeric C. anguillulae RGC. Based on a structural model of the DC pair in the retinal binding pocket obtained by MD simulation, we analyzed formation and kinetics of early and late photocycle intermediates of the rhodopsin domain wild type and specific DC pair mutants by combined UV-Vis and FTIR spectroscopy at ambient and cryo-temperatures. By assigning specific infrared bands to S-H vibrations of C259 we are able to show that the DC pair residues are tightly coupled. We show that deprotonation of D283 occurs already in the inactive L state as a prerequisite for M state formation, whereas structural changes of C259 occur in the active M state and early cryo-trapped intermediates. We propose a comprehensive molecular model for formation of the M state that activates the catalytic moiety. It involves light induced changes in bond strength and hydrogen bonding of the DC pair residues from the early J state to the active M state and explains the retarding effect of C259 mutants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Although airway remodeling in severe and/or fatal asthma is stil considered irreversible, its individual components as a cause of clinical symptoms and/or lung function changes remain largely unknown. While inhaled glucocorticoids have not consistently been shown to affect airway remodeling, biologics targeting specific pathways of airway inflammation have been shown to improve lung function, mucus plugging, and airway structural changes that can exceed those seen with glucocorticoids. This superiority of biologic treatment, which cannot be solely explained by insufficient doses or limited durations of glucocorticoid therapies, needs to be further explored. For this field of research, we propose a novel classification of the potential effects of biologics on airway remodeling into three temporal effects: early effects (days to weeks, primarily modulating inflammatory processes), late effects (months to years, predominantly affecting structural changes), and potential preventive effects (outcomes of early treatment with biologics). For the identification of potential preventive effects of biologics, we call for studies exploring the impact of early biological treatment on airway remodeling in patients with moderate-to-severe asthma, which should be accompanied by a long-term evaluation of clinical parameters, biomarkers, treatment burden, and socioeconomic implications., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The role of eosinophils in airway inflammation and asthma pathogenesis is well established, with raised eosinophil counts in blood and sputum associated with increased disease severity and risk of asthma exacerbation. Conversely, there is also preliminary evidence suggesting antiviral properties of eosinophils in the airways. These dual roles for eosinophils are particularly pertinent as respiratory virus infections contribute to asthma exacerbations. Biologic therapies targeting key molecules implicated in eosinophil-associated pathologies have been approved in patients with severe asthma and, therefore, the effects of depleting eosinophils in a clinical setting are of considerable interest. This review discusses the pathological and antiviral roles of eosinophils in asthma and exacerbations. We also highlight the significant reduction in asthma exacerbations seen with biologic therapies, even at the height of the respiratory virus season. Furthermore, we discuss the implications of these findings in relation to the role of eosinophils in inflammation and antiviral responses to respiratory virus infection in asthma., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Purpose of Review: The aim of this study was Describe the latest evidence related to the concept of clinical remission in patients with severe asthma, focusing on the lights and shadows of this concept., Recent Findings: The idea of clinical remission in severe asthma patients brings about a significant shift in the way asthma is treated and managed. Although there has yet to be unanimous agreement among various scientific societies on the precise definition, this concept can be extremely useful in advancing the treatment of the disease., Summary: Asthma is a common respiratory condition that affects more than 300 million people globally. It has variable symptoms and severity levels, with about 10% of patients experiencing severe asthma. While there have been advancements in treatment, severe asthma poses significant challenges. Recent approaches have focused on achieving clinical remission, which goes beyond symptom control to address underlying inflammation and biological processes. Clinical remission criteria include the absence of symptoms, reduced medication usage, and normalized inflammatory markers. Various biologic therapies show promise, with some patients achieving remission. However, remission's definition varies globally, hindering standardization and a valid comparison. Standardizing remission criteria and refining predictive factors are crucial for effective asthma management. Overall, achieving clinical remission offers hope for improved long-term outcomes in severe asthma patients., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: The aim is to update the information currently available for the use of biologics in severe asthma in children, in order to facilitate their prescription as far as possible., Recent Findings: The appearance of biologics for the treatment of severe asthma has meant a revolutionary change in the therapeutic approach to this disease. Currently, five biologics have been approved for severe asthma in children and/or adolescents by the regulatory agencies: omalizumab, mepolizumab, benralizumab, dupilumab and tezepelumab. But despite their positive results in terms of efficacy, there are still relevant points of debate that should induce caution when selecting the most appropriate biologic in a child with severe asthma. Indeed, safety is essential and, for several of the existing treatments, the availability of medium-term to long-term data in this regard is scarce., Summary: The use of biologics can facilitate the therapeutic paradigm shift from pleiotropic treatments to personalized medicine. However, the choice of the most appropriate biologics remains a pending issue. On the other hand, to the extent that several of the biologics have been available for a relatively short time, the most robust evidence in terms of efficacy and safety in children is that of omalizumab., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Little is known about central nervous system (CNS) responses to emotional stimuli in asthma. Nitric oxide in exhaled breath (FE NO ) is elevated in asthma due to allergic immune processes, but endogenous nitric oxide is also known to modulate CNS activity. We measured fMRI blood oxygen-dependent (BOLD) brain activation to negative (blood-injection-injury themes) and neutral films in 31 participants (15 with asthma). Regions-of-interest analysis was performed on key areas relevant to central adaptive control, threat processing, or salience networks, with dorsolateral prefrontal cortex (PFC), anterior insula, dorsal anterior cingulate cortex (dACC), amygdala, ventral striatum, ventral tegmentum, and periaqueductal gray, as well as top-down modulation of emotion, with ventrolateral and ventromedial PFC. Both groups showed less BOLD deactivation from fixation cross-baseline in the left anterior insula and bilateral ventromedial PFC for negative than neutral films, and for an additional number of areas, including the fusiform gyrus, for film versus recovery phases. Less deactivation during films followed by less recovery from deactivation was found in asthma compared to healthy controls. Changes in PCO 2 did not explain these findings. FE NO was positively related to BOLD activation in general, but more pronounced in healthy controls and more likely in neutral film processing. Thus, asthma is associated with altered processing of film stimuli across brain regions not limited to central adaptive control, threat processing, or salience networks. Higher levels of NO appear to facilitate CNS activity, but only in healthy controls, possibly due to allergy's masking effects on FE NO ., (© 2024 Society for Psychophysiological Research.)

Purpose of Review: Severe asthma patients suffer from decreased quality of life, and increased asthma symptoms, exacerbations, hospitalizations, and risk of death. Biologics have revolutionized treatment for severe asthma. However, with multiple biologic agents now available, clinicians must consider initial selection the long-term effectiveness of biologics. Additionally, patients have overlapping eligibilities and clinicians may consider switching between biologics for improved response. Finally, careful assessment of biologics cessation is needed for severe asthma patients who depend on these add-on therapies for asthma control., Recent Findings: Evidence for long-term durability and safety varies by biologic agent. In general, initial benefits noted from these agents (ex. exacerbation reduction) is, at minimum, sustained with long term use. Rates of adverse events and serious adverse events, including those requiring cessation of a biologics are low with long term use. Further studies are needed to understand the development of antidrug antibodies but currently their prevalence rates are low. Adverse events and insufficient efficacy are common reasons for biologic cessation or switching. Discontinuation maybe associated with waning of benefits but can be considered in certain situations. Biologic switching can be associated with improved asthma control., Summary: Biologics are safe and effective long-term therapies for the management of asthma. Discontinuation must be carefully considered and if possible avoided. Reasons for insufficient efficacy must be evaluated and if needed, biologic switching should be considered., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Allergen immunotherapy (AIT)-associated adverse events (AEs) limit its usage in the management of allergic diseases. The monoclonal anti-IgE antibody (omalizumab) and AIT have complementary actions. However, no consensus has been reached on whether their combination could exert superior efficacy and safety., Objective: To evaluate whether the combination of AIT with omalizumab is superior to AIT alone in treating allergic diseases., Methods: The MEDLINE/PubMed, Embase, Scopus and Cochrane Library databases were searched to identify randomized control trials (RCTs) reporting the outcomes of omalizumab combined with AIT (omalizumab + AIT) versus AIT alone. A random-effect model was established to estimate outcomes with a 95% confidence interval (CI)., Results: A total of 11 eligible RCTs (involving 901 patients) were screened out for the meta-analysis. According to a pooled analysis, omalizumab + AIT significantly increased the number of patients achieving the target maintenance dose (TMD) and sustained unresponsiveness (SU) to allergens (odds ratio [OR] = 2.43; 95% CI: 1.33-4.44; p = 0.004; I 2  = 35%, and OR = 6.77; 95% CI: 2.10-21.80; p = 0.001; I 2  = 36%, respectively). Similarly, individuals receiving the combination therapy reported significantly fewer episodes of severe systemic AEs than AIT alone (OR = 0.32; 95% CI: 0.18-0.59; p = 0.0003; I 2  = 0%). Meanwhile, the improvements in symptom severity score (mean difference [MD] = -0.26), rescue medication daily means score (MD = -0.14), and number of patients consuming epinephrine in AIT (OR = 0.20) were all more evident than those in AIT alone., Conclusion: Omalizumab + AIT can significantly enhance the efficacy and safety of AIT by increasing TMD and SU to allergens, while decreasing severe systemic AEs., (© 2023 ARS‐AAOA, LLC.)

Vitamin D is a key molecule in calcium and phosphate homeostasis; however, increasing evidence has recently shown that it also plays a crucial role in the immune system, both innate and adaptive. A deregulation of vitamin D levels, due also to mutations and polymorphisms in the genes of the vitamin D pathway, determines severe alterations in the homeostasis of the organism, resulting in a higher risk of onset of some diseases, including osteoporosis. This review gives an overview of the influence of vitamin D levels on the pathogenesis of osteoporosis, between bone homeostasis and immune system. [ABSTRACT FROM AUTHOR]

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 12months, 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 12months of treatment and a mean follow-up of 55months. After 12months 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. [ABSTRACT FROM AUTHOR]

Pyroptosis is a form of inflammatory programmed cell death, and is activated by pathogen infections or endogenous danger signals. The canonical pyroptosis process is characterized by the inflammasome (typically NLRP3)-mediated activation of caspase-1, which in turn cleaves and activates IL-1β and IL-18, as well as gasdermin D, which is a pore-forming executor protein, leading to cell membrane rupture, and the release of proinflammatory cytokines and damage-associated molecular pattern molecules. Pyroptosis is considered a part of the innate immune response. A certain level of pyroptosis can help eliminate pathogenic microorganisms, but excessive pyroptosis can lead to persistent inflammatory responses, and cause tissue damage. In recent years, pyroptosis has emerged as a crucial contributor to the development of chronic inflammatory respiratory diseases, such as asthma. The present study reviews the involvement of pyroptosis in the development of asthma, in terms of its role in different inflammatory phenotypes of the disease, and its influence on various immune and non-immune cells in the airway. In addition, the potential therapeutic value of targeting pyroptosis for the treatment of specific phenotypes of asthma is discussed. [ABSTRACT FROM AUTHOR]

Asthma, a pervasive pulmonary disorder, affects countless individuals globally. Characterized by chronic inflammation of the bronchial passages, its symptoms include cough, wheezing, dyspnea, and chest tightness. While many manage their symptoms through pharmaceutical interventions and self‐care, a significant subset grapples with severe asthma, posing therapeutic challenges. This study delves into the intricate etiology of asthma, emphasizing the pivotal roles of immune cells such as T cells, eosinophils, and mast cells in its pathogenesis. The recent emergence of monoclonal antibodies, including mepolizumab, reslizumab, and benralizumab, offers therapeutic promise, yet their efficacy varies due to the heterogeneous nature of asthma. Recognizing the potential of personalized medicine, this research underscores the need for a comprehensive understanding of asthma's immunological diversity. We employ single‐sample gene set enrichment analysis (ssGSEA) and Least Absolute Shrinkage and Selection Operator (LASSO) algorithms to identify differentially expressed immune cells and utilize machine learning techniques, including Extreme Gradient Boosting (XGBoost) and random forest, to predict severe asthma outcomes and identify key genes associated with immune cells. Using a murine asthma model and an online database, we aim to elucidate distinct immune‐centric asthma subtypes. This study seeks to provide novel insights into the diagnosis and classification of severe asthma through a transcriptomic lens. [ABSTRACT FROM AUTHOR]

Due to the vital importance of the lungs, lung-related diseases and their control are very important. Severe inflammatory responses mediated by immune cells were among the leading causes of lung tissue pathology and damage during the COVID-19 pandemic. In addition, uncontrolled immune cell responses can lead to lung tissue damage in other infectious and non-infectious diseases. It is essential to control immune responses in a way that leads to homeostasis. Immunosuppressive drugs only suppress inflammatory responses and do not affect the homeostasis of reactions. The therapeutic application of mesenchymal stem cells (MSCs), in addition to restoring immune homeostasis, can promote the regeneration of lung tissue through the production of growth factors and differentiation into lung-related cells. However, the communication between MSCs and immune cells after treatment of pulmonary diseases is essential, and investigating this can help develop a clinical perspective. Different studies in the clinical phase showed that MSCs can reverse fibrosis, increase regeneration, promote airway remodeling, and reduce damage to lung tissue. The proliferation and differentiation potential of MSCs is one of the mechanisms of their therapeutic effects. Furthermore, they can secrete exosomes that affect the function of lung cells and immune cells and change their function. Another important mechanism is that MSCs reduce harmful inflammatory responses through communication with innate and adaptive immune cells, which leads to a shift of the immune system toward regulatory and hemostatic responses. [ABSTRACT FROM AUTHOR]

Obesity is a prevalent metabolic disease that reduces bacterial diversity, colonizes the epidermis with lipophilic bacteria, and increases intestinal pro-inflammatory species, all of which lead to impaired epithelial barriers. Adipose tissue secretes immunomodulatory molecules, such as adipokines, leptin, and adiponectin, which alters the morphology of adipocytes and macrophages as well as modulates T cell differentiation and peripheral Th2-dominated immune responses. Atopic dermatitis (AD) and obesity have similar pathological manifestations, including inflammation as well as insulin and leptin resistance. This review examines the major mechanisms between obesity and AD, which focus on the effect on skin and gut microbiota, immune responses mediated by the toll like receptor (TLR) signaling pathway, and changes in cytokine levels (TNF-a, IL-6, IL-4, and IL13). Moreover, we describe the potential effects of adipokines on AD and finally mechanisms by which PPAR-γ suppresses and regulates type 2 immunity. [ABSTRACT FROM AUTHOR]

Introduction: The risk of asthma in patients with psoriasis and that of psoriasis in patients with asthma have increased, but relevant data for the pediatric population are lacking. Therefore, we performed a meta-analysis to assess the pooled association between psoriasis and asthma in children and adolescents. Methods: We conducted an extensive search of the medical literature databases through to July 2024. The estimated risk ratios (RRs) and corresponding 95% confidence intervals (CIs) were computed. Results: Three studies, involving 5310 children with psoriasis and 1,539,029 control participants, were included to evaluate the incidence of asthma in children with psoriasis. The meta-analysis indicated a significantly increased risk of asthma in children with psoriasis [RR 1.38 (95% CI, 1.28–1.49)]. Additionally, two studies involving 104,369 asthmatic children and 1,539,029 controls were included to evaluate the incidence of psoriasis in children with asthma. The meta-analysis indicated a significant increase in the risk of psoriasis in children with asthma [RR 1.17 (95% CI, 0.70–1.95)]. Conclusions: This meta-analysis offers evidence supporting the association between psoriasis and asthma in pediatric populations. Therefore, physicians should make patients aware of the connection between these two chronic diseases. [ABSTRACT FROM AUTHOR]

Background: Allergic rhinitis (AR) is quite common and sometimes it requires systemic steroids and can be accompanied by coronavirus disease-2019 (COVID-19), rhinosinusitis, or asthma. We aimed to determine the comparative effect of different types of AR medications on clinical prognosis in real-world settings. Methods: We used national claims data provided by the National Health Insurance Service in the Republic of Korea. We enrolled 275,895 adult patients who were first diagnosed with AR and started AR medications between 1 January 2018 and 31 December 2018. We classified them into five groups according to the type of AR medication prescribed and analyzed their 3-year follow-up data. Results: The prescription rate of systemic steroids was low in the INCS group (19%), whereas it was 35–40% in other groups. INCS users needed less systemic steroids than other AR medication users (hazard ratio [HR], 0.503; 95% confidence interval [CI], 0.452–0.560; p-value < 0.001). The incidence of rhinosinusitis was approximately 11% in the other AR medication group and 6–8% in the other groups. AH (HR, 0.745; 95% CI, 0.616–0.903; p = 0.003), AH-LTRA (HR, 0.667; 95% CI, 0.551–0.808; p < 0.001), and INCS (HR, 0.746, 95% CI, 0.615–0.904; p = 0.003) significantly prevent rhinosinusitis, compared with other AR medication. However, other prognosis factors were not significantly correlated with the type of AR medications. Conclusions: INCS can reduce systemic steroid requirements and AH, AH-LTRA, and INCS prevent rhinosinusitis compared with other AR medications. As choosing an appropriate AR medication can determine the clinical outcomes, clinicians should be careful in prescribing proper AR medications. [ABSTRACT FROM AUTHOR]

This review addresses the ongoing challenges in asthma management, particularly focusing on patient adherence to inhaler therapy. Asthma, a chronic condition characterized by variable respiratory symptoms and airflow obstruction, can lead to significant morbidity and mortality if not properly managed. Despite advances in inhaler technology and therapeutic options, non-adherence remains a significant barrier to optimal asthma control. This review explores both intentional and unintentional non-adherence, influenced by factors such as age, socioeconomic status, and the complexity of inhaler devices. The Global Initiative for Asthma (GINA) provides guidelines aimed at improving adherence through targeted interventions, and this review examines their application. Common inhaler technique errors, including incorrect inhalation speed, not exhaling before inhaling, and failure to hold breath post-inhalation, are identified as major contributors to inadequate asthma control. Furthermore, the review explores the emerging role of electronic monitoring devices (EMDs), such as CapMedic and DigiHaler, which offer real-time feedback to enhance inhaler technique and adherence. The role of biomarkers in assessing adherence and the potential of personalized treatment strategies, including biologic therapies, are also discussed. Overall, addressing adherence requires a comprehensive approach that integrates patient education, tailored interventions, and technological innovations to achieve better clinical outcomes in asthma management. [ABSTRACT FROM AUTHOR]

Background/Objectives: Achieving disease control is the main goal in asthmatic patients in order to prevent future risks and exacerbations. There are several clinical guidelines that set different definitions of asthma control, and these differences may affect management and treatment in many patients. Our aim was to describe asthma control patterns according to the Global Initiative for Asthma (GINA) 2023 in patients considered to have uncontrolled asthma as per previous GINA 2010 guidelines. Methods: A total of 1299 patients from the COAS study were analyzed. The COAS study was a cross-sectional multicenter study conducted in routine clinical practice that included patients with uncontrolled asthma according to GINA 2010. These patients were then re-classified using the now updated GINA 2023 asthma control criteria. Results: After applying GINA 2023 control criteria, previously uncontrolled patients were now classified as having controlled asthma in 24.3% of cases and partially controlled asthma in 16.3% of cases. Only 59.4% maintained their previous diagnosis of uncontrolled asthma. ACT in the uncontrolled patients remained similar after re-classification, as did the percentage of active smokers, respiratory allergy, rhinitis, and lung function. Conclusions: Changes in clinical guideline criteria affect the definition of asthma control. When excluding pulmonary function abnormalities in GINA 2023 asthma control criteria, the percentage of controlled patients greatly increased. [ABSTRACT FROM AUTHOR]

Group 2 Innate Lymphoid Cells (ILC2) are critical drivers of both innate and adaptive type 2 immune responses, known to orchestrate processes involved in tissue restoration and wound healing. In addition, ILC2 have been implicated in chronic inflammatory barrier disorders in type 2 immunopathologies such as allergic rhinitis and asthma. ILC2 in the context of allergen-driven airway inflammation have recently been shown to influence local and systemic metabolism, as well as being rich in lipid-storing organelles called lipid droplets. However, mechanisms of ILC2 lipid anabolism and catabolism remain largely unknown and the impact of these metabolic processes in regulating ILC2 phenotypes and effector functions has not been extensively characterized. ILC2 phenotypes and effector functions are shaped by their metabolic status, and determining the metabolic requirements of ILC2 is critical in understanding their role in type 2 immune responses and their associated pathophysiology. We detail here a novel experimental method of implementing flow cytometry for large scale analysis of fatty acid uptake, storage of neutral lipids, and fatty acid oxidation in primary murine ILC2 with complementary morphological analysis of lipid storage using confocal microscopy. By combining flow cytometry and confocal microscopy, we can identify the metabolic lipid requirements for ILC2 functions as well as characterize the phenotype of lipid storage in ILC2. Linking lipid metabolism pathways to ILC2 phenotypes and effector functions is critical for the assessment of novel pharmaceutical strategies to regulate ILC2 functions in type 2 immunopathologies. [ABSTRACT FROM AUTHOR]

Purpose: Omalizumab, the anti-IgE monoclonal antibody used to treat severe asthma, reduces asthma exacerbations, hospitalizations, and corticosteroid use. Although allergic asthma is a therapeutic target of omalizumab, omalizumab is not effective in all patients with severe allergic asthma and is not always available for long-term use. We retrospectively investigated factors related to long-term (≥ 2 years) use of omalizumab for severe asthma. Patients and Methods: Of the 116 patients treated with omalizumab for severe asthma at our hospital between 2009 and 2017, 82 were included in this retrospective analysis. Thirty-four were excluded because of adverse events, financial difficulties, or hospital transfers. The number of asthma exacerbations, unscheduled visits, corticosteroid doses, asthma control test scores, pulmonary function test results, and fractional exhaled nitric oxide levels were evaluated. Results: The median age of the study population was 58 years, with 66% female and 26% taking regular oral corticosteroids. After 2 years of treatment, 52 responders were identified using the global evaluation of treatment effectiveness (GETE) score. Improvements in asthma control test scores, airflow limitation, exacerbations, and oral corticosteroid use were observed in the responders. Multivariate analysis revealed that a peripheral blood eosinophil count of ≥ 200 or a perennial antigen-specific IgE antibody positivity of ≥ 2 predicted a response at the 2-year mark. However, Kaplan–Meier analysis demonstrated that neither high eosinophil counts nor perennial antigen-specific IgE positivity influenced the prolongation of treatment beyond 2 years, and responders at 2 years underwent omalizumab treatment for a significantly longer period than non-responders (HR = 9.89, p < 0.001), with GETE at 2 years being the only predictor of long-term omalizumab use. Conclusion: In this retrospective study the GETE after 2 years of omalizumab therapy emerged as the most meaningful predictor of the long-term effectiveness of omalizumab treatment in patients with severe asthma, highlighting the benefits of prolonged therapy in certain populations. These findings may guide future therapeutic strategies for severe asthma. [ABSTRACT FROM AUTHOR]

Purpose: With the advent of biological therapies, emerging concepts regarding establishing new targets in asthma management, such as disease modification, have entered the debate among the scientific community. The definitions that form the conceptual basis of this goal need to be agreed upon. Methods: A multidisciplinary expert group was assembled as the steering committee. A systematic literature review was conducted to identify the scientific background for constructing appropriate definitions. Based on the literature review and the clinical experience of the experts, the committee built a list of statements that could be applied to establish the definition of disease modification in asthma. After that, a Delphi validation was performed to assess the appropriateness of the list of statements. The questionnaire included a total of 22 statements, divided into "Essential criteria for disease modification in asthma" (5 statements) and "Disease modification indicators and other considerations" (17 statements). Panelists used a 9-point Likert scale to measure agreement on each statement. The cut-off point for high consensus was defined as a minimum score of 7 and had to be reached by at least two-thirds of the experts. Results: A total of 192 asthma experts voted on statements anonymously. Of those, 104 (54%) were Pneumologists, 65 (34%) were allergologists, and 23 (12%) were Pediatricians. An interim analysis of round 1 data was performed. All statements reached consensus on the first round, with a median score above 7 in all cases. Conclusion: In conclusion, in this Delphi study, a large number of experts in the management of severe asthma from different specialties agreed on the clinical-functional and pathophysiological aspects to be considered in order to try to achieve disease modification. [ABSTRACT FROM AUTHOR]

Milk protein sensitivity is a major challenge in infant feeding, especially for infants who cannot receive adequate breastfeeding. Hydrolyzed milk protein is a mainstream way to address this difficulty. The aim of this study was to assess the effect of differences in whey protein concentrate (WPC) source and the degree of hydrolysis on blocking allergy and to analyze the possible mechanisms by which hydrolyzed infant formula (IF) blocks allergy through colony‐metabolism–immunity response. First, we prepared six groups of goat's milk IF with unhydrolyzed, partially, and extensively hydrolyzed WPC, which come from cow's milk WPC and goat's milk WPC. Subsequently, we evaluated their effects on allergy. The results showed that the hydrolyzed IF improved the allergic characteristics of mice, including low levels of total immunoglobulin E (IgE), specific IgE, histamine, and mucosal mast cell protease‐1 (mMCP‐1). Furthermore, the hydrolyzed IF promoted the immune response of T helper 1 (Th1) and regulatory T (Treg) cells by enhancing the messenger RNA (mRNA) expression of T‐box transcription factor 21 (T‐bet) and forkhead box protein P3 (Foxp3), which in turn suppressed the T helper 2 (Th2) overexpressed immune response in allergy (GATA‐binding protein 3 (GATA‐3) and retinoic‐acid‐receptor‐related orphan receptor gamma t (RORγt) mRNA expression, as well as interleukin 4 (IL‐4) and interleukin 5 (IL‐5) levels). Hydrolyzed IF promoted an increase in beneficial gut microbe Lactobacillus and Alistipes, which in turn promoted an increase in intestinal butyrate levels. The beneficial bacteria and their metabolized butyrate may have suppressed the abundance of the allergy‐characterizing bacterium Rikenellaceae‐RC9‐gut‐group. The final result we obtained was that for both cow's milk WPC and goat's milk WPC, at similar levels of hydrolysis, they did not bring about a significant effect on allergy symptoms. The hydrolyzed IF improved the allergic characteristics of mice, the deeper the degree of hydrolysis of WPC, the more obvious the effect of reducing allergic symptoms in model mice. [ABSTRACT FROM AUTHOR]

Rhinovirus C (RV-C) infection can trigger asthma exacerbations in children and adults, and RV-C-induced wheezing illnesses in preschool children correlate with the development of childhood asthma. Surfactant protein A (SP-A) plays a critical role in regulating pulmonary innate immunity by binding to numerous respiratory pathogens. Mature SP-A consists of multiple isoforms that form the hetero-oligomers of SP-A1 and SP-A2, organized in 18-mers. In this report, we examined the efficacy of SP-A to antagonize RV-C infection using the wild-type (RV-C15) and reporter-expressing (RV-C15-GFP) viruses in differentiated nasal epithelial cells (NECs) from asthmatic and non-asthmatic children. We also determined the antiviral mechanism of action of SP-A on RV-C15 infection. The native SP-A was purified from alveolar proteinosis patients. The recombinant (r) SP-A1 and SP-A2 variants were expressed in FreeStyle™ 293-F cells. SP-A reduced the fluorescent focus-forming units (FFUs) after RV-C15-GFP infection of NECs by 99%. Both simultaneous and 4 h post-infection treatment with SP-A inhibited RV-C15 and RV-C15-GFP viral RNA load by 97%. In addition, the antiviral genes and chemokines (IFN-λ, IRF-7, MDA-5, and CXLC11) were not induced in the infected NECs due to the inhibition of RV-C propagation by SP-A. Furthermore, SP-A bound strongly to RV-C15 in a dose- and Ca2+-dependent manner, and this interaction inhibited RV-C15 binding to NECs. In contrast, rSP-A1 did not bind to solid-phase RV-C15, whereas the rSP-A2 variants, [A91, K223] and [P91, Q223], had strong binding affinities to RV-C15, similar to native SP-A. This study demonstrates that SP-A might have potential as an antiviral for RV infection and RV-induced asthma exacerbations. [ABSTRACT FROM AUTHOR]

(1) Background: The importance of total eosinophil count in peripheral blood (EOS) as a type 2 inflammation marker is known to be fundamental in asthma, chronic sinusitis, and vasculitis. In cancer, despite their questionable antiproliferative effect, their role remains unclear. Our purpose was to describe the relationship between baseline blood EOS and overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC) patients. (2) Methods: We retrospectively analyzed data from 137 adult patients who underwent surgical treatment for pancreatic ductal adenocarcinoma (PDAC) between the years 2012 and 2019. Patients with no recent history of systemic steroid use and without intraoperative metastases were included. Patients were categorized into two groups based on EOS (≥0.1 G/l and <0.1 G/l). Survival outcomes were analyzed using Cox proportional hazards regression models. (3) Results: According to EOS and PDAC stage, median OS values were as follows: in stage I–III, EOS ≥ 0.1 G/l group: 14.5 months, in stage I–III, EOS < 0.1 G/l group: 8.0 months, in stage IV, EOS ≥ 0.1 G/l group: 7.0 months, and in stage IV, EOS < 0.1 G/l group: 5.0 months. EOS < 0.1 G/l (vs. ≥0.1 G/l) was an independent prognostic factor for OS in both the uni- and multivariate Cox regression, respectively (HR = 1.48, p = 0.035 and HR = 1.57, p = 0.021). (4) Conclusions: Peripheral eosinophilia seems to be a potential independent prognostic factor. Further studies are necessary to confirm this hypothesis, since our findings suggest that type 2 inflammation may be the factor directly or indirectly lengthening the survival of patients with PDAC. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic esophagitis (EoE) is a rare, chronic immune-mediated disorder with limited treatment options. Despite the U.S. Food and Drug Administration (FDA) approval of dupilumab for EoE, other monoclonal antibodies remain unapproved and are used off-label with limited evidence on their efficacy and safety. This systematic review rigorously and comprehensively evaluates the evidence for monoclonal antibody therapies used off-label to treat EoE. Methods: We conducted a systematic review across PubMed, EMBASE, Cochrane Central, and ClinicalTrials.gov, assessing the efficacy and safety of off-label monoclonal antibodies in EoE through clinical outcomes and the FDA Adverse Event Reporting System (FAERS) data. Results: Among ten monoclonal antibodies reviewed, mepolizumab that targets IL-5 showed the most promise with a moderate recommendation based on Level 2 evidence. Others like omalizumab (anti-IgE), dectrekumab (anti-IL-13), and reslizumab (anti-IL-5) showed limited utility. Safety evaluations via the FAERS database revealed significant adverse drug reactions, including serious events like asthmatic crises, pneumonia, and adrenal insufficiency for mepolizumab and reslizumab, as well as chronic obstructive pulmonary disease and gastroenteritis for omalizumab. Dectrekumab's safety profile remains unclear due to a lack of data. Conclusions: While mepolizumab demonstrates potential as an off-label treatment, none of the antibodies reviewed have FDA approval for EoE. Clinicians should consider the balance between local and systemic effects and exercise caution, closely monitoring for adverse effects, particularly in patients with respiratory comorbidities. Continued research is crucial to establish a more robust evidence base for these therapies. [ABSTRACT FROM AUTHOR]

Asthma is a widespread chronic lung disease characterized by airway inflammation and hyperresponsiveness. This airway inflammation is classified by either the presence (T2-high) or absence (T2-low) of high levels of eosinophils. Because most therapies for asthma target eosinophils and related pathways, treatment options for T2-low disease are limited. New pathophysiologic targets are needed. Oxidant stress is a common feature of T2-low disease. Airway epithelial expression of the antioxidant enzyme Paraoxonase 2 (PON2) is decreased in a well-recognized population of people with T2-low asthma and people with obesity and asthma. As a potential mechanism of increased oxidant stress, we measured the role of PON2 in lung oxidant responses using an environmentally relevant in vivo murine oxidant exposure (i.e., ozone) and in vitro studies with an immortalized human airway epithelial cell line BEAS-2B. Pon2-deficient (Pon2−/−) mice developed increased airway hyper-responsiveness compared to wild-type controls. Despite reduced alveolar macrophage influx, Pon2−/− mice exhibited increased nitrite production. In human airway epithelial cells incubated with hydrogen peroxide, PON2 knockdown (PON2KD) decreased mitochondrial function and inner mitochondrial membrane potential. These findings suggest that PON2 functions in defending against airway epithelial oxidant stress. Further studies are needed to elucidate the mechanisms linking PON2, oxidant stress, and asthma pathogenesis. [ABSTRACT FROM AUTHOR]

Airway inflammatory diseases, such as asthma, are a global public health concern owing to their chronic inflammatory effects on the respiratory mucosa. Molecular hydrogen (H2) has recently been recognized for its antioxidant and anti-inflammatory properties. In this study, we examined the therapeutic potential of H2 in airway inflammation using an ovalbumin (OVA)-induced BALB/c mouse model of allergic asthma. Female BALB/c mice were sensitized and challenged with OVA to induce airway inflammation, and 30 mice were randomly divided into five groups: NT (non-treatment), HTC (3% H2 treatment only), NC (negative control, OVA only), PC (positive control, OVA + intranasal 1 mg/mL salbutamol 50 μL), and HT (H2 treatment, OVA + inhaled 3% H2). Various inflammatory and oxidative stress (OS)-induced markers such as white blood cells (WBCs) and their differential counts, lung histology, cytokine levels such as interleukin (IL)-4, (IL)-5, (IL)-13, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF), (IL)-10, reactive oxygen species (ROS), nitric oxide (NO), glutathione peroxidase (GPx), and catalase (CAT), and total immunoglobulin E (IgE) levels were investigated. Our results showed that inhaled H2 significantly reduced inflammatory cell infiltration, OS markers, and pro-inflammatory cytokine expression while upregulating antioxidant enzyme activity. Furthermore, H2 also significantly decreased serum IgE levels, a marker of allergic inflammation. Collectively, our findings suggest that H2 inhalation is a promising treatment option for airway inflammation, offering a novel approach with potential clinical applications. [ABSTRACT FROM AUTHOR]

Introduction: Worldwide, asthma is the most common non-communicable respiratory disease and causes considerable morbidity and mortality. Most people with asthma can be treated effectively with low-dose medications if these are taken correctly and regularly. Around 10% of people with asthma have an uncontrolled form of the disease or can only achieve control with high-dose medications, incurring disproportionately high health care costs. Areas Covered: PubMed and personal archives were searched for relevant articles on the definition, management and pharmacotherapy of severe asthma. The WHO classification of severe asthma and the treatment levels encompassed in the definition are discussed. Most children and young people referred for consideration of 'beyond-guidelines therapy' can in fact be managed on standard treatment after a multi-disciplinary team assessment focusing on ensuring correct basic management, and these steps are described in detail. Options for those with true therapy-resistant asthma are described. These include monoclonal antibodies, most of which target type 2 inflammation. Expert Opinion: Getting the basics right is still the most important aspect of asthma care. For those with severe, therapy-resistant asthma, an increasing number of life-transforming monoclonals have been developed, but there is still little understanding of, and a paucity of treatment options for, non-eosinophilic asthma. [ABSTRACT FROM AUTHOR]

Asthma and food allergy are two complex allergic diseases with an increasing prevalence in childhood. They share risk factors, including atopic family history, atopic dermatitis, allergen sensitization, and T2 inflammatory pathways. Several studies have shown that in children with a food allergy, the risk of developing asthma, particularly in early childhood, is high. Food allergen intake or the inhalation of aerosolized allergens can induce respiratory symptoms such as bronchospasm. Patients with both conditions have an increased risk of severe asthma exacerbations, hospitalization, and mortality. The current management of clinical food hypersensitivity primarily involves the dietary avoidance of food allergens and the use of self-injectable adrenaline for severe reactions. Poorly controlled asthma limits the prescription of oral immunotherapy to foods, which has emerged as an alternative therapy for managing food allergies. Biological therapies that are effective in severe asthma have been explored for treating food allergies. Omalizumab improves asthma control and, either alone or in combination with oral immunotherapy, increases the threshold of allergen tolerance. Understanding the interplay between asthma and food allergy is crucial for developing successful treatment approaches and ameliorating patient results. [ABSTRACT FROM AUTHOR]

Introduction: Severe uncontrolled asthma (SUA) affects approximately 5% of asthma patients, leading to frequent exacerbations, reduced lung function, and lower quality of life. Recent biologic therapies target specific inflammatory pathways, offering new options for SUA. Objective: This study aimed to evaluate clinical characteristics, treatment outcomes, and biomarkers in patients with SUA treated with biologics (Omalizumab, Benralizumab, and Dupilumab) at our clinic. Material and Methods: A six-month retrospective longitudinal study was conducted on 28 patients aged 36–83 years with SUA. Patients were divided into three groups: Omalizumab (n = 4), Benralizumab (n = 18), and Dupilumab (n = 6). Lung function tests and biomarkers such as eosinophil and IgE levels were measured over 3-month periods (T0, T1, and T2). Asthma control was assessed using asthma control tests (ACT), and non-parametric statistical methods were applied. Results: The median patient age was 64 years, with 75% showing elevated eosinophil counts (>300 cells/µL). Benralizumab significantly improved lung function (p < 0.05) and ACT scores (p < 0.001), reducing eosinophil counts to zero (p < 0.001). Patients on Dupilumab and Omalizumab showed improved asthma control (p < 0.05) and reduced exacerbations, albeit to a lesser extent (p > 0.05). Conclusions: Biologics, particularly Benralizumab and Dupilumab, improved asthma control, lung function, and quality of life in SUA patients, with improved ACT scores and spirometry values. Some patients remained poorly controlled, emphasizing the need for personalized treatment and regular biomarker monitoring. Multidisciplinary management and lifestyle changes are critical for better outcomes in SUA. [ABSTRACT FROM AUTHOR]

Background: Patients with asthma with an eosinophilic phenotype may be eligible for additional treatment options to improve disease control; however, the prevalence and frequency of eosinophil testing is unknown. This study assessed blood eosinophil count testing prevalence in patients with asthma by exacerbation frequency and healthcare provider (HCP) type. Methods: This was a retrospective, longitudinal, real-world study (GSK ID: 214470) utilizing the Merative Explorys® Universe electronic health records database. Eligible patients had ≥ 2 asthma diagnostic codes (January 2016–December 2018) (Index date: first asthma diagnosis). Outcomes included patient demographics and clinical characteristics (12 months pre-index [baseline]), and prevalence of blood eosinophil count testing, stratified by exacerbation frequency (infrequent exacerbations [< 2]) or frequent exacerbations [≥ 2] or primary HCP (Allergist/Pulmonologist, a primary care physician [PCP] or other HCP) during the 12 months post-index (follow-up). Results: Of 400,254 patients included (mean age: 51.2 years; 70.8% female), the most common provider type at baseline was a PCP (76.8%). A higher proportion of patients with frequent exacerbations had blood eosinophil count tests at baseline (55.4–69.5%) and follow-up (67.9–75.1%), compared with patients with infrequent exacerbations (55.5–63.7%, 62.4–67.3%). Significantly more patients in the Allergist/Pulmonologist subgroup had ≥ 1 blood eosinophil count test result compared with patients in the PCP subgroup at both baseline (59.9% vs. 50.7%; p < 0.001) and follow-up (59.0% vs. 56.2%; p < 0.001). In the total population, the mean (SD) number of tests ordered was 3.4 (5.3) and 4.1 (6.4) during the baseline and follow-up periods, respectively. A greater mean number of tests were ordered for patients with frequent exacerbations, most apparently in the Allergist/Pulmonologist subgroup during baseline and follow-up (7.4 vs. 4.9). For patients with frequent exacerbations and blood eosinophil count test results, the mean (SD) number of tests ranged from 3.1 (4.6) to 5.8 (8.3) at baseline and 5.1 (8.5) to 7.4 (10.6) during follow-up. Conclusions: The prevalence of blood eosinophil count testing in patients with asthma remains suboptimal. Routine blood eosinophil count testing should be considered by HCPs for patients with asthma to increase identification of the eosinophilic asthma phenotype, which may inform the decision to advance to targeted biologic therapy. [ABSTRACT FROM AUTHOR]

Intruduction and purpose: Patients with severe asthma account for approximately 3% to 10% of all asthma patients. They have higher hospital utilization rates and treatment costs than patients with non-severe asthma. Previously, treatment options for these patients were limited due to unacceptable side effects. However, the advent of biologic therapies has provided promising targeted therapy for these patients. State of knowledge: Biologic therapies target inflammatory modulators that play a key role in the pathogenesis of asthma, particularly in patients with high T2 cells. These therapies have shown promising results in reducing asthma symptoms, improving lung function, decreasing the use of oral corticosteroids, and enhancing patients' quality of life. Conclusions: This article reviews the mechanism of action, efficacy, and indications of currently approved biologic drugs available in Poland, as well as potential therapeutic targets for the future. [ABSTRACT FROM AUTHOR]

Introduction: Patients with severe asthma may be prescribed biologic therapies to improve disease control. The EVEREST study aimed to characterize the global disease burden of patients with severe asthma without access to biologics and those who have access but do not receive biologics, as well as the remaining unmet need despite use of these therapies. Methods: This was a historical cohort study of patients with severe asthma (aged ≥ 18 years) in the International Severe Asthma Registry receiving Global Initiative for Asthma (GINA) 2018 step 5 treatment, or with uncontrolled disease at GINA step 4. Prospective data on patient clinical characteristics, healthcare resource utilization, and medication use over a 12-month period between December 2017 and May 2022 were assessed for the following five groups: biologics accessible (omalizumab, mepolizumab, reslizumab, benralizumab, or dupilumab); biologics inaccessible; biologics accessible but not received; biologics accessible and received; and biologic recipients whose asthma remained suboptimally controlled. Results: Overall, 9587 patients from 21 countries were included. Among patients in the biologics accessible (n=5073), biologics inaccessible (n=3041), and biologics accessible but not received (n=382) groups, 41.4%, 18.7%, and 49.6% experienced at least two exacerbations, 11.5%, 10.5%, and 6.2% required at least one hospitalization, 47.9%, 54.6%, and 71.2% had uncontrolled asthma, and 23.9%, 8.6%, and 11.0% received long-term oral corticosteroids (LTOCS), respectively. Following biologic therapy, among patients who received biologics overall (n=2666) and among those whose asthma remained suboptimally controlled (n=1780), 19.1% and 23.0% experienced at least two exacerbations, 2.7% and 2.9% required at least one hospitalization, and 16.7% and 22.0% received LTOCS, respectively. Conclusion: There is a substantial disease burden in both patients without access to biologics and those with access who do not receive these therapies, although specific outcomes may vary between these groups. There also remains a high unmet need among biologic recipients, many of whom have a suboptimal response to treatment. [ABSTRACT FROM AUTHOR]

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Copyright of Journal of New Medicine is the property of Sun Yat Sen University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)