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

Rationale: Extrapulmonary manifestations of asthma, including fatty infiltration in tissues, may reflect systemic inflammation and influence lung function and disease severity. Objectives: To determine if skeletal muscle adiposity predicts lung function trajectory in asthma. Methods: Adult SARP III (Severe Asthma Research Program III) participants with baseline computed tomography imaging and longitudinal postbronchodilator FEV1% predicted (median follow-up 5 years [1,132 person-years]) were evaluated. The mean of left and right paraspinous muscle density (PSMD) at the 12th thoracic vertebral body was calculated (Hounsfield units [HU]). Lower PSMD reflects higher muscle adiposity. We derived PSMD reference ranges from healthy control subjects without asthma. A linear multivariable mixed-effects model was constructed to evaluate associations of baseline PSMD and lung function trajectory stratified by sex. Measurements and Main Results: Participants included 219 with asthma (67% women; mean [SD] body mass index, 32.3 [8.8] kg/m2) and 37 control subjects (51% women; mean [SD] body mass index, 26.3 [4.7] kg/m2). Participants with asthma had lower adjusted PSMD than control subjects (42.2 vs. 55.8 HU; P

BACKGROUND: Children with asthma are at risk for low lung function extending into adulthood, but understanding of clinical predictors is incomplete. OBJECTIVE: We sought to determine phenotypic factors associated with FEV1 throughout childhood in the Severe Asthma Research Program 3 pediatric cohort. METHODS: Lung function was measured at baseline and annually. Multivariate linear mixed-effects models were constructed to assess the effect of baseline and time-varying predictors of prebronchodilator FEV1 at each assessment for up to 6 years. All models were adjusted for age, predicted FEV1 by Global Lung Function Initiative reference equations, race, sex, and height. Secondary outcomes included postbronchodilator FEV1 and prebronchodilator FEV1/forced vital capacity. RESULTS: A total of 862 spirometry assessments were performed for 188 participants. Factors associated with FEV1 include baseline Feno (B, -49 mL/log2 PPB; 95% CI, -92 to -6), response to a characterizing dose of triamcinolone acetonide (B, -8.4 mL/1% change FEV1 posttriamcinolone; 95% CI, -12.3 to -4.5), and maximal bronchodilator reversibility (B, -27 mL/1% change postbronchodilator FEV1; 95% CI, -37 to -16). Annually assessed time-varying factors of age, obesity, and exacerbation frequency predicted FEV1 over time. Notably, there was a significant age and sex interaction. Among girls, there was no exacerbation effect. For boys, however, moderate (1-2) exacerbation frequency in the previous 12 months was associated with -20 mL (95% CI, -39 to -2) FEV1 at each successive year. High exacerbation frequency (≥3) 12 to 24 months before assessment was associated with -34 mL (95% CI, -61 to -7) FEV1 at each successive year. CONCLUSIONS: In children with severe and nonsevere asthma, several clinically relevant factors predict FEV1 over time. Boys with recurrent exacerbations are at high risk of lower FEV1 through childhood.

Background: To date, studies investigating the association between pre-biologic biomarker levels and post-biologic outcomes have been limited to single biomarkers and assessment of biologic efficacy from structured clinical trials. Aim: To elucidate the associations of pre-biologic individual biomarker levels or their combinations with pre-to-post biologic changes in asthma outcomes in real-life. Methods: This was a registry-based, cohort study using data from 23 countries, which shared data with the International Severe Asthma Registry (May 2017-February 2023). The investigated biomarkers (highest pre-biologic levels) were immunoglobulin E (IgE), blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO). Pre- to approximately 12-month post-biologic change for each of three asthma outcome domains (i.e. exacerbation rate, symptom control and lung function), and the association of this change with pre-biologic biomarkers was investigated for individual and combined biomarkers. Results: Overall, 3751 patients initiated biologics and were included in the analysis. No association was found between pre-biologic BEC and pre-to-post biologic change in exacerbation rate for any biologic class. However, higher prebiologic BEC and FeNO were both associated with greater post-biologic improvement in FEV1 for both anti-IgE and anti-IL5/5R, with a trend for anti-IL4Rα. Mean FEV1 improved by 27-178 mL post-anti-IgE as pre-biologic BEC increased (250 to 1000 cells/µL), and by 43-216 mL and 129-250 mL post-anti-IL5/5R and -anti-IL4Rα, respectively along the same BEC gradient. Corresponding improvements along a FeNO gradient (25-100 ppb) were 41-274 mL, 69-207 mL and 148-224 mL for anti-IgE, anti-IL5/5R, and anti-IL4Rα, respectively. Higher baseline BEC was also associated with lower probability of uncontrolled asthma (OR 0.39; p=0.001) post-biologic for anti-IL5/5R. Prebiologic IgE was a poor predictor of subsequent pre-to-post-biologic change for all outcomes assessed for all biologics. The combination of BEC + FeNO marginally improved the prediction of post-biologic FEV1 increase (adjusted R²: 0.751), compared to BEC (adjusted R²: 0.747) or FeNO alone (adjusted R²: 0.743) (p=0.005 and <0.001, respectively); however, this prediction was not improved by the addition of IgE. Conclusions: The ability of higher baseline BEC, FeNO and their combination to predict biologic-associated lung function improvement may encourage earlier intervention in patients with impaired lung function or at risk of accelerated lung function decline. [ABSTRACT FROM AUTHOR]

Background: In its severe form, where possible, asthma is treated using biological drugs in order to reduce, as much as possible, the use of systemic steroids. Mepolizumab is effective for severe asthma based on key outcomes such as exacerbation and steroid dependence. Its efficacy in terms of the criteria for clinical remission in the short and long term has become of interest. Objective: We aimed to evaluate the effect of mepolizumab in the achievement of clinical remission after 3 years of administration. Methods: In this study, 71 patients who continued mepolizumab for 3 years were assessed for clinical remission according to six different published sets of remission criteria. Results: According to the criteria, 39–52% of patients experienced complete remission in the first year, increasing to 51–73% at 3 years. By classifying patients according to partial and complete remission criteria, proposed by the SANI, we observe 22% of patients in partial remission at one year, achieving complete remission after three years. The baseline factors associated with earlier remission were a higher FEV1, if we consider classifications requiring an FEV1 ≥ 80%, a low OCS dose, and low FeNO levels, in the patients requiring FEV1 stabilization. Conclusions: Clinical remission is possible for patients treated with mepolizumab. The observations at three years compared with the first year indicated that the factors negatively affecting remission delayed rather than prevented it. Earlier treatment could increase the chances of remission. [ABSTRACT FROM AUTHOR]

Background: Since the last guidance was published by the Canadian Thoracic Society, there have been several advances in the clinical management of severe asthma. To gain a better understanding of the current standards of care and treatment patterns of patients, the CASCADE practice reflective program was established to conduct a real-world analysis of severe asthma management among specialists in Canada with a goal of identifying areas of opportunity to enhance patient management and outcomes. Methods: The CASCADE program was a two-part practice reflective and assessment program delivered through an on-line portal for selected specialists (Respirologists and Allergists) in Canada. The program consisted of a one-time overview survey of physician practice to establish overall practice parameters, followed by a review of at least 5 severe asthma patients to establish the current landscape of severe asthma management. Results: The program collected practice overview surveys from 78 specialists (52 Respirologists, 24 Allergists, and 2 General practice physicians with an interest in respiratory disease) in 8 provinces. Practices included a variety of types in both large metropolitan centres and smaller regional settings. There were 503 patients reviewed and included in the program. Most (65%) patients were currently using a biologic treatment, 30% were biologic naive, and 5% had used a biologic treatment in the past. Most patients (53%) were reported to have mixed allergic and eosinophilic phenotypes, despite a perception that allergic, eosinophilic and mixed phenotypes were evenly balanced in the physician practice. Overall, patients currently treated with biologic agents had parameters suggesting higher control and were more satisfied with treatment. However, there was less than optimal treatment satisfaction for more than half of all patients, particularly for those patients not treated with a biologic agent. Conclusions: Phenotyping is hampered by poor availability for several assessments, and the full range of treatments are not currently fully utilized, partly due to physician familiarity with the agents and partly due to prescribing restrictions. Even when treated with biologic agents, patient satisfaction can still be improved. [ABSTRACT FROM AUTHOR]

Background/Objectives: Several studies have demonstrated the positive clinical and functional impact of adding Long-Acting Muscarinic Antagonist (LAMA) to Inhaled Corticosteroids (ICS) and Long-Acting Beta-Agonists (LABA) therapy in the treatment of severe asthma. Aim and objectives: To demonstrate that treating Small Airways Disease (SAD) in severe asthma patients who are candidates for biologics can improve respiratory symptoms, lung function, and airways inflammation, potentially avoiding or delaying the use of biological therapy. Methods: Thirty-two severe asthma patients with SAD were transitioned from separate inhalers for ICS/LABA and LAMA to extrafine single-inhaler beclomethasone, formoterol, and glycopyrronium. None of these patients underwent biological therapy before the study. Follow-up evaluations were conducted at baseline (T0) and three months after initiation (T3). Assessments included clinical evaluations, spirometry, oscillometry, and inflammation markers. Results: Transitioning to single-inhaler triple therapy from T0 to T3 resulted in significant improvements in Asthma Control Test (ACT) and SAD parameters, including increased Forced Expiratory Volume in the mid-range of lung capacity and improved airway resistance and reactance measurements using impulse oscillometry. A significant reduction in airway inflammation was evidenced by lower levels of Fractional Exhaled Nitric Oxide 350 (FeNO 350) (p < 0.001 for all). Conclusions: Adopting a single-inhaler triple therapy notably enhanced clinical control and small airway function in patients with severe asthma and SAD, supporting the positive impact of target-therapy for the achievement of a stable state termed "Quiet Asthma". [ABSTRACT FROM AUTHOR]

Introduction: Aerobic physical training (APT) reduces eosinophilic airway inflammation, but its effects and mechanisms in severe asthma remain unknown. Methods: An in vitro study employing key cells involved in the pathogenesis of severe asthma, such as freshly isolated human eosinophils, neutrophils, and bronchial epithelial cell lineage (BEAS-2B) and lung fibroblasts (MRC-5 cells), was conducted. Additionally, an in vivo study using male C57Bl/6 mice, including Control (Co; n = 10), Trained (Exe; n = 10), house dust mite (HDM; n = 10), and HDM + Trained (HDM + Exe; n = 10) groups, was carried out, with APT performed at moderate intensity, 5x/week, for 4 weeks. Results: HDM and bradykinin, either alone or in combination, induced hyperactivation in human neutrophils, eosinophils, BEAS-2B, and MRC-5 cells. In contrast, IL-10, the primary anti-inflammatory molecule released during APT, inhibited these inflammatory effects, as evidenced by the suppression of numerous cytokines and reduced mRNA expression of the B1 receptor and ACE-2. The in vivo study demonstrated that APT decreased bronchoalveolar lavage levels of bradykinin, IL-1β, IL-4, IL-5, IL-17, IL-33, TNF-α, and IL-13, while increasing levels of IL-10, klotho, and IL-1RA. APT reduced the accumulation of polymorphonuclear cells, lymphocytes, and macrophages in the peribronchial space, as well as collagen fiber accumulation, epithelial thickness, and mucus accumulation. Furthermore, APT lowered the expression of the B1 receptor and ACE-2 in lung tissue and reduced bradykinin levels in the lung tissue homogenate compared to the HDM group. It also improved airway resistance, tissue resistance, and tissue damping. On a systemic level, APT reduced total leukocytes, eosinophils, neutrophils, basophils, lymphocytes, and monocytes in the blood, as well as plasma levels of IL-1β, IL-4, IL-5, IL-17, TNF-α, and IL-33, while elevating the levels of IL-10 and IL-1RA. Conclusion: These findings indicate that APT inhibits the severe asthma phenotype by targeting kinin signaling. [ABSTRACT FROM AUTHOR]

Bronchial thermoplasty (BT) is a treatment for patients with poorly controlled, severe asthma. However, predictors of treatment response to BT are defined poorly. Do baseline radiographic and clinical characteristics exist that predict response to BT? We conducted a longitudinal prospective cohort study of participants with severe asthma receiving BT across eight academic medical centers. Participants received three separate BT treatments and were monitored at 3-month intervals for 1 year after BT. Similar to prior studies, a positive response to BT was defined as either improvement in Asthma Control Test results of ≥ 3 or Asthma Quality of Life Questionnaire of ≥ 0.5. Regression analyses were used to evaluate the association between pretreatment clinical and quantitative CT scan measures with subsequent BT response. From 2006 through 2017, 88 participants received BT, with 70 participants (79.5%) identified as responders by Asthma Control Test or Asthma Quality of Life Questionnaire criteria. Responders were less likely to undergo an asthma-related ICU admission in the prior year (3% vs 25%; P =.01). On baseline quantitative CT imaging, BT responders showed less air trapping percentage (OR, 0.90; 95% CI, 0.82-0.99; P =.03), a greater Jacobian determinant (OR, 1.49; 95% CI, 1.05-2.11), greater SD of the Jacobian determinant (OR, 1.84; 95% CI, 1.04-3.26), and greater anisotropic deformation index (OR, 3.06; 95% CI, 1.06-8.86). To our knowledge, this is the largest study to evaluate baseline quantitative CT imaging and clinical characteristics associated with BT response. Our results show that preservation of normal lung expansion, indicated by less air trapping, a greater magnitude of isotropic expansion, and greater within-lung spatial variation on quantitative CT imaging, were predictors of future BT response. ClinicalTrials.gov; No.: NCT01185275; URL: www.clinicaltrials.gov [ABSTRACT FROM AUTHOR]

Introduction: Previous bronchoalveolar lavage fluid (BALF) proteomic analysis has evaluated limited numbers of subjects for only a few proteins of interest, which may differ between asthma and normal controls. Our objective was to examine a more comprehensive inflammatory biomarker panel in quantitative proteomic analysis for a large asthma cohort to identify molecular phenotypes distinguishing severe from nonsevere asthma. Methods: Bronchoalveolar lavage fluid from 48 severe and 77 nonsevere adult asthma subjects were assessed for 75 inflammatory proteins, normalized to BALF total protein concentration. Validation of BALF differences was sought through equivalent protein analysis of autologous sputum. Subjects' data, stratified by asthma severity, were analysed by standard statistical tests, principal component analysis and 5 machine learning algorithms. Results: The severe group had lower lung function and greater health care utilization. Significantly increased BALF proteins for severe asthma compared to nonsevere asthma were fibroblast growth factor 2 (FGF2), TGFα, IL1Ra, IL2, IL4, CCL8, CCL13 and CXCL7 and significantly decreased were platelet‐derived growth factor a‐a dimer (PDGFaa), vascular endothelial growth factor (VEGF), interleukin 5 (IL5), CCL17, CCL22, CXCL9 and CXCL10. Four protein differences were replicated in sputum. FGF2, PDGFaa and CXCL7 were independently identified by 5 machine learning algorithms as the most important variables for discriminating severe and nonsevere asthma. Increased and decreased proteins identified for the severe cluster showed significant protein–protein interactions for chemokine and cytokine signalling, growth factor activity, and eosinophil and neutrophil chemotaxis differing between subjects with severe and nonsevere asthma. Conclusion: These inflammatory protein results confirm altered airway remodelling and cytokine/chemokine activity recruiting leukocytes into the airways of severe compared to nonsevere asthma as important processes even in stable status. [ABSTRACT FROM AUTHOR]

This article presents a post hoc analysis of the RELight study, which investigated the clinical benefit of switching from omalizumab to mepolizumab in patients with severe asthma. The study found that patients who switched to mepolizumab experienced a reduction in asthma exacerbations, improved asthma control, and a decrease in oral corticosteroid intake. These improvements were observed regardless of whether the patients had previously received omalizumab treatment. The findings suggest that switching therapies may be beneficial for patients with severe asthma who do not achieve optimal disease control. [Extracted from the article]

Introduction: Biologic therapies have demonstrated benefits for individuals with severe asthma, including reduced daily symptoms and severe exacerbations. However, data describing patient perspectives on these treatments are limited. This study sought to understand the preferences and priorities of Canadians with severe asthma in the context of novel biologic treatment options. Methods: Semi-structured, qualitative interviews were conducted among Canadians with severe asthma from July to August 2022. Purposeful sampling included individuals with and without biologic therapy experience. All participants described daily life with severe asthma, experiences and priorities related to asthma treatment and their impressions of biologics. Reflexive thematic analysis was used to explore patterns in the data. Results: Among 18 individuals included, 10 were currently taking or had prior experience with biologic treatment for asthma. Those who had never been treated with biologics were unfamiliar with them, considering treatment, or believed that they may not be eligible. Four themes were developed to convey the perspectives of participants on biologics: (1) life-changing benefits, but not for all; (2) navigating barriers to being prescribed and remaining adherent to biologic treatments; (3) treatment administration preferences are not only about convenience; (4) concerns about safety and the unknown as a source of treatment hesitancy. Conclusions: Findings suggest that the clinical benefits of biologics align with patient perceptions of achieving good asthma control. However, treatment gaps persist among individuals who do not experience a meaningful improvement in their asthma symptoms and those who face barriers accessing biologics. People with severe asthma attributed importance to greater availability of at-home treatment options, improved access to financial support to cover treatment costs and support to address safety concerns. This research provides insight into patient-based treatment priorities and preferences for biologics, which may help inform decision-making related to emerging therapies for severe asthma. Plain Language Summary: For people with severe asthma, biologics are a treatment option that can be taken in addition to their regular medication. In this study, we asked 18 Canadians with severe asthma about how having severe asthma affects their lives, their current and previous asthma treatments, and their views on biologics. Ten people in this study were currently taking or had previously taken biologics for severe asthma. We found that biologics can be life changing. Also, people with severe asthma can find it difficult to get on and stay on biologics. They would like financial and educational support when considering biologics and prefer to take biologics at home, if possible. This study helps us understand the priorities and preferences related to biologics of patients with severe asthma. [ABSTRACT FROM AUTHOR]

Background: Monoclonal antibodies (biologics) drastically changed severe asthma therapy. Mepolizumab (anti-interleukin (IL) 5), benralizumab (anti-IL5 receptor alpha), and dupilumab (anti-IL4/13) are the most used biologics in this context. While all biologics are efficient individually, the choice of biologic is complicated by insufficient data on their comparative long-term treatment efficacy. Here, we compare the real-life efficacy of these biologics in asthma therapy over 12 months. Methods: 280 severe asthma patients treated with mepolizumab (129/280, 46%), benralizumab (83/280, 30%) or dupilumab (68/280, 24%) for one year were analyzed retrospectively. Data were collected at baseline and after 6 and 12 months of therapy. Endpoints were changes pulmonary function (PF), exacerbation rate, oral corticosteroid (OCS) use and dose, asthma control test (ACT) score and fractional exhaled nitric oxide (FeNO) levels as well as responder status measured by the recently published "Biologic Asthma Response Score" (BARS). Results: All biologics led to significant improvements in PF, ACT and OCS dose. Only Mepolizumab and Benralizumab significantly decreased the exacerbation rate, while only Mepolizumab and Dupilumab significantly decreased FeNO. Responder rates measured by BARS were high across all groups: roughly half of all patients achieved full response and most of the remainder achieved at least partial responder status. Overall, outcomes were similar between groups after both 6 and 12 months. Conclusions: All biologics showed great efficacy in individual parameters and high responder rates measured by BARS without a clinically relevant advantage for any antibody. Response was usually achieved after 6 months and retained at 12 months, emphasizing the utility of early response assessment. [ABSTRACT FROM AUTHOR]

Background: Severe asthma can cause poor health status, poor health-related quality of life (HRQoL) and an impaired functioning at work. However, to date, limited data are available on the impact of the biological therapies on such outcomes. Therefore, aim of the present study was to prospectively assess the clinical, quality of life and work functionality issues in severe asthma patients both at baseline and after 6 months of biological therapies and determine which individual, pathological and occupational factors can influence such parameters. Methods: Fifty-two patients were enrolled between December 2022 and June 2023. Patients' personal, clinical, functional and occupational features were assessed. The Short Form Health Survey (SF-12), the Work Productivity and Activity Impairment (WPAI) questionnaire and the Work Ability Index (WAI) were employed to assess HRQoL, the employee's productivity and perception of work ability, respectively. Results: Among the enrolled patients, 30 (57.70%) were employed. Biological therapy induced a significant improvement in clinical and functional parameters, e.g., FEV1% (72 ± 12 vs.87 ± 13%; 72 ± 14 vs. 86 ± 14%), FVC% (92 ± 11 vs. 101 ± 11%; 90 ± 13 vs. 98 ± 14%) and FEV1/FVC (62 ± 11 vs. 71 ± 8%; 64 ± 9 vs. 70 ± 8%) in workers and non-workers, respectively (P < 0.001). Comparably, the perception of life quality significantly improved, as physical and mental health scores, in the overall cohort, increased from 40.7 ± 10.3 and 48.5 ± 8.5 to 46.8 ± 8.6 and 51.6 ± 6.4, respectively (P < 0.001). The work ability perception significantly improved from a moderate to a good one (34 ± 6 vs. 40 ± 6, P = 0.001). A significant reduction in the absenteeism (19 ± 15 vs. 3 ± 11%; P < 0.001) and presenteeism rate (53 ± 24 vs. 29 ± 26%; P < 0.001), and an improvement in daily (40 ± 27.5% vs. 28.9 ± 24.7%, P < 0.001, in the overall population) and work activities (57 ± 25 vs. 29 ± 27%, P < 0.001) was determined. Gender, age, symptoms control and pulmonary functionality were correlated with the physical and mental health perception, daily activity impairment and work ability. Conclusions: Our study pointed out that biological therapies improved clinical, general life and occupational outcomes in patients with severe asthma. The correlation between clinical aspects and psychological and occupational issues suggest the relevance for a multidisciplinary management of the disease for an effective participation of patients in the world of work. [ABSTRACT FROM AUTHOR]

Mitochondria are key metabolic hubs involved in cellular energy production and biosynthesis. ATP is generated primarily by glucose and fatty acid oxidation through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in the mitochondria. During OXPHOS there is also production of reactive oxygen species (ROS), which are involved in the regulation of cellular function. Mitochondria are also central in the regulating cell survival and death, particularly in the intrinsic apoptosis pathway. Severe asthma is a heterogeneous disease driven by various immune mechanisms. Severe eosinophilic asthma entails a type 2 inflammatory response and peripheral and lung eosinophilia, associated with severe airflow obstruction, frequent exacerbations and poor response to treatment. Mitochondrial dysfunction and altered metabolism have been observed in airway epithelial and smooth muscle cells from patients with asthma. However, the role of mitochondria in the development of eosinophilia and eosinophil-mediated inflammation in severe asthma is unknown. In this review, we discuss the currently limited literature on the role of mitochondria in eosinophil function and how it is regulated by asthma-relevant cytokines, including interleukin (IL)-5 and granulocyte-macrophage colonystimulating factor (GM-CSF), as well as by corticosteroid drugs. Moreover, we summarise the evidence on the role of mitochondria in the regulation of eosinophils apoptosis and eosinophil extracellular trap formation. Finally, we discuss the possible role of altered mitochondrial function in eosinophil dysfunction in severe asthma and suggest possible research avenues in order to better understand their role in disease pathogenesis, and identify novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Severe asthma is characterized by frequent exacerbations, altered lung function, and impaired quality of life. Tailored patient education allows for the improvement of both asthma management and quality of life. Our study aimed to assess the needs of severe asthma patient in therapeutic education, according to previous therapeutic patient education background and asthma phenotype. Methods: Consecutive patients monitored for severe asthma in a tertiary referral center were considered for inclusion and answered a questionnaire detailing their patient education needs and the topics they would like to discuss. Asthma history, clinical and biological data, and lung function results were recorded. Results: Fifty-three patients were included and 47 (88.7%) expressed at least one need. The most frequently selected topics were "life with asthma" (83%), "treatment use" (68%), and "exacerbation management" (60%), independent of previous participation in a patient education program dedicated to asthma. Patients of older age at inclusion, uncontrolled asthma, and T2-high phenotypes were associated with different profiles of patient education needs. Conclusion: Our study identified frequent and various patient educational needs among severe asthmatics, highlighting the importance of an in-depth assessment of severe asthmatics expectations and the crucial need for the development of dedicated educational tools. [ABSTRACT FROM AUTHOR]

The data on the use of dual biologics are scant, but a topic of current interest. In this report, the treatment regimen of a patient with two T helper 2 pathway-related comorbidities, severe asthma, and chronic spontaneous urticaria, was presented. Both urticaria and asthma symptoms of the patient could not be controlled entirely with monotherapy while both diseases could be controlled after omalizumab-mepolizumab dual treatment. No adverse events were observed after 6 months of dual biologics use. This report supports other publications in the literature involving the use of dual biologics and provides a summary of the literature. [ABSTRACT FROM AUTHOR]

There is a lack of information on house dust mite (HDM) sensitization and phenotype distribution in patients with severe asthma (SA) living permanently at high-altitude (HA) in tropical regions, which may be different. The aim of this study was to characterize adults with SA in a tropical high altitude city (2,640 m): Bogotá, Colombia. This observational cross-sectional study included severe asthmatic outpatients (n = 129) referred to the ASMAIRE program of the Fundación Neumológica Colombiana in Bogotá (2,640 m). Clinical history, spirometry, total IgE, blood eosinophils, and skin prick test (SPT), including HDM allergens, were performed. Phenotype definitions: Allergic/atopic (AA): IgE ≥100 IU/mL and/or at least one positive SPT; eosinophilic (EOS): blood eosinophils ≥300 cells/µL; type 2-high: AA and/or EOS phenotype; type 2-low: non-AA/non-EOS phenotype (IgE <100 IU/mL, negative SPT, and blood eosinophils <300 cells/µL). A total of 129 adults with SA were included, 79.8% female. Phenotype distribution: AA: 61.2%; EOS: 37.2%; type 2-high: 72.1%; type 2-low: 27.9%. Among AA patients, HDM sensitization was present in 87% and 34.9% were non-eosinophilic. There was a significant overlap between the phenotypes. In contrast to non-tropical high-altitude regions, we found a high frequency of HDM sensitization in patients with AA phenotype living in a tropical high-altitude city. We also found a discrete lower frequency of EOS phenotype with no other significant differences in the phenotypic distribution compared to that described at low altitudes. We propose that tropical location may modify the effect of high altitude on HDM concentrations and allergenicity. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis (CRS) with severe asthma are associated with breathing pattern disorder (BPD). Mouth breathing is a sign of breathing pattern disorder, and nose breathing a fundamental part of breathing pattern retraining for BPD. The prevalence of BPD in relation to CRS subtypes and the relationship of nasal obstruction to BPD in CRS and associated severe asthma is unknown. The breathing pattern assessment tool (BPAT) can identify BPD. Our objective was to thus investigate the prevalence of BPD, nasal airflow obstruction and measures of airway disease severity in CRS with (CRSwNP) and without nasal polyps (CRSsNP) in severe asthma. We determined whether CRS status, peak nasal inspiratory flow (PNIF) or polyp disease increased BPD prevalence. Demographic factors, measures of airway function and breathlessness in relation to BPD status and CRS subtypes were also evaluated. 130 Patients were evaluated (n = 69 had BPD). The prevalence of BPD in CRS with severe asthma was 53.1%. There was no difference between BPD occurrence between CRSwNP and CRSsNP. The mean polyp grade and PNIF were not statistically different between the BPD and non-BPD group. The presence of nasal polyps did not increase breathlessness. BPD and CRS are commonly co-associated. CRS status and nasal obstruction per se does not increase BPD prevalence. [ABSTRACT FROM AUTHOR]

This article discusses a study published in the journal Respirology that examines the impact of Staphylococcal enterotoxin-specific IgE sensitization on the effectiveness of omalizumab therapy in severe asthma. The study found that Staphylococcus aureus, a bacteria commonly found in the upper airways, produces Staphylococcal enterotoxins (SEs) that can stimulate the production of specific IgE antibodies. High levels of SE-IgE have been associated with severe late-onset asthma. The study conducted a prospective observational study to evaluate the clinical efficacy of omalizumab in patients with severe asthma who are allergic and non-allergic to aeroallergens, with and without positive SE-IgE. The results provide valuable insights into the characteristics of these patient groups. The study found that omalizumab reduced acute exacerbation rates and improved asthma control in patients with allergic asthma, regardless of SE-IgE sensitization. However, in non-allergic asthma patients, only those with SE-IgE sensitization responded to omalizumab. The study also discovered that patients who responded well to omalizumab had higher levels of eosinophils and lower levels of neutrophils in their sputum. Additionally, the addition of clarithromycin to omalizumab treatment improved asthma control in patients who had a poor or partial response to omalizumab. [Extracted from the article]

Introduction: Targeting the parasympathetic nervous system innervating the airway with pharmacologic products has been proved to improve the clinical outcomes of severe asthma. Bronchial cryo-denervation (BCD) is a novel non-pharmacologic treatment for severe asthma using an endobronchial cryo-balloon administered via bronchoscopy to denervate parasympathetic pulmonary nerves. Preclinical studies have demonstrated that BCD significantly disrupted vagal innervation in the lung. Methods: A total of 15 patients with severe asthma were enrolled in this prospective, single-center pilot study. Patients underwent bifurcated BCD treatment at a 30-day interval after baseline assessment. Follow-up through 12 months included assessment of adverse events, technical feasibility, and changes in pulmonary function; asthma control questionnaire-7 (ACQ-7); and asthma control test (ACT). Results: BCD was performed on all 15 severe asthma patients, with technical feasibility of 96.7%. There were no device-related and 2 procedure-related serious adverse events through 12 months, which resolved without sequelae. The most frequent nonserious procedure-related adverse event was increased cough in 60% (9 of 15) patients. Pulmonary function remained unchanged, and significant improvements from baseline ACQ-7 (mean, −1.19, p = 0.0032) and ACT (mean, 3.18, p = 0.0011) scores were observed since the first month's follow-up after a single lung airway treatment, with similar trends till the end of the 12-month follow-up. Conclusion: This study provides the first clinical evidence of the safety, feasibility, and initial efficacy of BCD in patients with severe asthma. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether sensitization patterns differentiate children with severe recurrent wheeze (SRW)/severe asthma (SA) from those with non‐severe recurrent wheeze (NSRW)/non‐severe asthma (NSA). Our objective was to determine whether sensitization patterns can discriminate between children from the French COBRAPed cohort with NSRW/NSA and those with SRW/SA. Methods: IgE to 112 components (c‐sIgE) (ImmunoCAP® ISAC) were analyzed in 125 preschools (3–6 years) and 170 school‐age children (7–12 years). Supervised analyses and clustering methods were applied to identify patterns of sensitization among children with positive c‐sIgE. Results: We observed c‐sIgE sensitization in 51% of preschool and 75% of school‐age children. Sensitization to house dust mite (HDM) components was more frequent among NSRW than SRW (53% vs. 24%, p <.01). Sensitization to non‐specific lipid transfer protein (nsLTP) components was more frequent among SA than NSA (16% vs. 4%, p <.01) and associated with an FEV1/FVC < −1.64 z‐score. Among sensitized children, seven clusters with varying patterns were identified. The two broader clusters identified in each age group were characterized by "few sensitizations, mainly to HDM." One cluster (n = 4) with "multiple sensitizations, mainly to grass pollen, HDM, PR‐10, and nsLTP" was associated with SA in school‐age children. Conclusions: Although children with wheeze/asthma display frequent occurrences and high levels of sensitization, sensitization patterns did not provide strong signals to discriminate children with severe disease from those with milder disease. These results suggest that the severity of wheeze/asthma may depend on both IgE‐ and non‐IgE‐mediated mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: Severe asthma has a poor response to hormone therapy and a poor level of control, so the discovery of new pathogenetic mechanisms is important for diagnosing and treating severe asthma. IL-35 may play a protective role in autoimmune diseases by directly or indirectly inhibiting the secretion of IL-17, which is an important proinflammatory factor involved in the occurrence and development of autoimmune diseases. The autologous serum skin test (ASST) is a good sensitivity and specificity screening test for autoimmune functional autoantibodies. We compared the levels of IL-35 and IL-17 in serum samples, the positive rate of ASST, the level of exhaled nitric oxide (FeNO), and the atopic constitution in patients with severe asthma to those with mild-to-moderate asthma so as to explore the possible autoimmune pathogenesis of severe asthma. Methods: Patients with mild-to-moderate and severe asthma were enrolled. Their age, gender, smoking history, family history of asthma, history of allergic rhinitis, positive allergen results, serum total IgE (TlgE), allergen-specific IgE (slgE), routine blood, ASST results, and FeNO test results were compared and analyzed. The IL-35 and IL-17 levels in serum samples from both groups were measured by enzyme-linked immunosorbent assay for comparison and analysis. The SPSS 22.0 software package was used for statistical analysis. Results: A total of 50 patients with mild-to-moderate asthma and 31 patients with severe asthma were included in this study. The proportion of patients with a history of smoking and a family history of asthma was significantly higher in the severe asthma group compared to the mild-to-moderate asthma group (all p < 0.05); the number of positive allergen tests was significantly lower in patients with severe asthma compared to those with mild-to-moderate asthma (p < 0.001). The rate of positive ASST was significantly higher in patients with severe asthma than in patients with mild-to-moderate asthma (p < 0.05). Serum IL-17 levels were significantly higher in patients with severe asthma than in patients with mild-to-moderate asthma (p < 0.05), but serum IL-35 level between the two group was not significantly different (p = 0.113). ASST-positive patients had a statistically significant increase in the risk of developing severe asthma, while patients with allergen positive were less likely to develop severe asthma (positive ASST: OR = 5.277, p = 0.024; allergen positivity: OR = 0.123, p = 0.001). Conclusions: IL-35 has a weaker inhibitory effect on high IL-17 expression in patients with severe asthma, and the rate of positive ASST was significantly higher in patients with severe asthma, which all suggested the possibility of autoimmune pathogenesis in patients with severe asthma. [ABSTRACT FROM AUTHOR]

Objective: To discuss the differentially expressed genes in severe bronchial asthma [severe asthma (SA)] by bioinformatics methods and analyze their mechanisms, and to screen the traditional Chinese medicines and their active components with potential therapeutic effects. Methods: The GSE136587 and GSE158752 datasets were selected from the Gene Expression Omnibus (GEO)Database; R software was used for the differential analysis to obtain the differentially expressed gene; the proteinprotein interaction (PPI)network analysis was used to screen the core genes, and the key pathways and hub genes were identified. The core genes were uploaded to the Coremine Database to screen for the traditional Chinese medicines with the potential therapeutic effects, and the relevant Chinese herbal prescriptions were searched in Chinese Medical Dictionary. Results: A total of 466 differentially expressed genes were screened. The PPI network constructed through the STRING platform led to the selection of synaptosomal associated protein 25 kDa (SNAP25), glutamate ionotropic receptor AMPA type subunit 2 (GRIA2), neurexin 1 (NRXN1), potassium voltage-gated channel subfamily a member 1 (KCNA1), synaptotagmin 1 (SYT1), and chromogranin A (CHGA). The Gene Ontology (GO) functional enrichment analysis results showed that the biological processes of SA were significantly related to the cellular chemotaxis and leukocyte migration. The Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways enrichment mainly involve bone marrow leukocyte migration, leukocyte chemotaxis, cell chemotaxis, leukocyte migaration, up-regulation of outside stimulus, and bone marrow leukocyte activation signaling pathways. Network pharmacology was applied to screen for 367 traditional Chinese medicines with potential therapeutic effects based on the core targets. Among them, ginseng, water buffalo horn, scorpio, and astragalus, which involve multiple core targets, were highly related to SA. A total of 17 potential Chinese herbal prescriptions with therapeutic effects were retrieved from Chinese Medical Dictionary. Conclusion: The bioinformatics screening of potential biomarkers and traditional Chinese medicines with therapeutic effects for SA provides the new targets for the early diagnosis and research on the pathogenesis of SA, and offers new insights into the development of herbal prescriptions for its treatment. [ABSTRACT FROM AUTHOR]

Objective To compare the clinical characteristics, peripheral blood inflammatory cells and levels of oxidative stress indicators between severe asthma and non-severe asthma patients, analyze the effects of neutrophils and oxidative stress molecules on the severity of asthma, and build a biological model for early prediction of severe asthma. Methods From Aug 2018 to Jul 2019, 67 adult patients with stable asthma in our hospital were enrolled in this study. The clinical characteristics, peripheral blood inflammatory cells and levels of oxidative stress indicators of severe asthma group and non-severe asthma group were compared. Single factor Logistic regression analysis was conducted on severe asthma to screen out the most important five variables. Multifactor Logistic regression analysis was further conducted to establish a prediction model for severe asthma. Results There were 25 severe asthma patients in this cohort, who had a longer course of disease, more frequent acute attacks, poorer asthma control, higher peripheral neutrophils, more severe obstructive ventilation dysfunction, lower myeloperoxidase (MPO) level and higher superoxide dismutase (SOD) than non-severe asthma patients. The patients with higher peripheral blood neutrophil count or proportion were more likely to show severe asthma, more frequent acute attacks, and more obvious reduction of pulmonary ventilation function. A panel of biomarkers, centered on peripheral blood neutrophil count and oxidative stress indicators SOD, human 8-epiprostaglandin F2α (8-iso-PGF2α), could build a model to predict severe asthma. Conclusion There are significant differences in clinical characteristics, peripheral blood inflammatory cells, and oxidative stress index levels between severe asthma patients and non-severe asthma patients. In stable asthma patients, levels of neutrophils and oxidative stress indicators such as SOD had an impact on the severity of asthma. The prediction model of severe asthma established on this basis provides a new idea for early recognition of severe asthma. [ABSTRACT FROM AUTHOR]

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Cost-effectiveness studies evaluate health technologies and help choose treatments. The current study compared dupilumab to omalizumab, mepolizumab, and benralizumab in Colombian adults with severe uncontrolled type 2 asthma. Over a 5-year period, a Markov model was utilized to assess the costs of biological treatments and management of exacerbations, comparing various doses of exacerbations, comparing various doses of dupilumab, omalizumab, mepolizumab, and benralizumab as add-on treatments. It included a 5% annual discount rate per local HTA, and set willingness-to-pay at three times GDP per capita per quality-adjusted life year (QALY) in Colombia. Dupilumab (200 mg) exhibited greater QALYs and reduced overall costs compared to mepolizumab (100 mg), benralizumab (30 mg), and omalizumab (450 mg and 600 mg), with the incremental cost-effectiveness ratio (ICER) per QALYgained being -$5.429, -$6.269, -$196.567 and -$991.007, respectively. Dupilumab had greater QALYs and costs versus omalizumab 300 mg (ICERof $200.653 per QALY, above the willingness-to-pay threshold of 3 × GDP per capita). Sensitivity analyses were consistent with base case results. Dupilumab 200 mg was strongly dominant versus omalizumab 450 mg and 600 mg, mepolizumab 100 mg, and benralizumab 30 mg; however, cost-effectiveness was not demonstrated versus omalizumab 300 mg. These results could assist healthcare professionals in choosing an appropriate biologic for treating severe type 2 asthma. [ABSTRACT FROM AUTHOR]

Abstract Background Dupilumab has been shown to be an effective treatment in moderate‐to‐severe atopic dermatitis (AD) and severe asthma (SA). However, comparative real‐world analyses of adverse events (AE), particularly dupilumab‐associated ocular surface disease (DAOSD), are lacking. Objective This is the first real‐world study to provide insight into the prevalence of AEs associated with dupilumab in AD compared with SA. Secondary objectives were to assess the prevalence, onset and therapeutic strategies of DAOSD and evaluate dupilumab discontinuation rates. Methods Data from two daily practice registries including AD and SA patients receiving dupilumab treatment were analyzed. Adverse events, including DAOSD, were evaluated. Results In total, 322 AD and 148 SA patients were included. Headaches (23.6%), injection site reactions (10.1%), and influenza‐like symptoms (13.5%) were more prevalent in SA patients. Interestingly, ocular AEs were significantly more prevalent in AD patients (62.1%, p

BackgroundSevere eosinophilic asthma (SEA) is often linked to a dysregulation in the Interleukin-(IL)-5 axis. Mepolizumab, a humanized monoclonal antibody, reduces eosinophils by directly binging to IL-5, potentially restoring homeostatic eosinophil biology, with a significant impact on quality of life, acute exacerbations and oral corticosteroids (OCS) elimination in SEA patients. While its short- and middle-term effects are well described, no study has so far investigated its long-lasting effects in SEA patients. The aim of our study was therefore to explore the effects of a long-term, six-year continuous treatment with mepolizumab on clinical control and clinical remission in a cohort of SEA patients.MethodsWe conducted a retrospective review of clinical records of patients who were prescribed mepolizumab between June 2017 and April 2018. We collected demographical, functional, and clinical data from visits performed at baseline and then at the specified timepoints and checked if patients had reached clinical remission after 6 years. We assessed asthma control test (ACT), exacerbation rate, and OCS elimination dose at 6 years. Clinical Remission (CR) was defined on the basis of the elimination of OCS and the contemporary presence of all the following: 1) stable lung function; 2) no exacerbation in the previous 12 months; 3) acceptable symptom control (ACT ≥ 20).ResultsOf 86 patients screened, 62 were included in the final analysis. Our study suggests that mepolizumab is effective and well tolerated after a six-year course of continuous treatment in patients with SEA. We reported a prevalence of 28 (46.8%) patients who reached complete CR at 72 months from the treatment start. 75% of patients eliminated the maintenance OCS already after 1 year of treatment; this proportion reached the 87% within the sixth year of treatment.ConclusionMepolizumab proved to be effective in real-life after 6 years of treatment, inducing a complete clinical remission in the 46.8% of patients, with sustained improvements in quality of life, exacerbation rate, OCS intake and lung function.

Background: Aging implies changes in terms of lung function, immune system, and respiratory and extra-respiratory comorbidities. Few studies have specifically addressed the relevance of age on severe asthma burden and control. We aimed to evaluate whether age acts as an independent determinant of asthma severity, in terms of clinical, functional, and inflammatory profile, and to explore potential cofactors that contribute to a more difficult disease control in different age groups. Methods: Patients from Severe Asthma Network Italy (SANI) registry were retrospectively divided in subgroups according to their age. Cutoffs for age were established according to quartiles in order to obtain a comparable number of patients for each group, and then rounded for the sake of simplicity. Results: Overall, 1805 severe asthma patients were analyzed. Lung function represented the most important age-related variable. On the opposite the level of asthma control was not differently distributed among age ranges. In young people the presence of atopy-related comorbidities (allergic rhinitis, atopic dermatitis) predominated, whilst systemic-metabolic and degenerative comorbidities such as diabetes, cardiovascular diseases, anxious-depressive syndrome, and osteoporosis prevailed in elderly. Bronchiectasis and sleep disturbances were significantly associated with age. Conclusions: Despite that it cannot be considered a treatable trait, our study suggests that age should be evaluated within a personalized approach to severe asthma patients, in order to provide a better clinical profiling and a more tailored treatment strategy.

Background: Severe asthma pathology encompasses a wide range of pulmonary and extrapulmonary treatable traits with a high prevalence of comorbidities. Although asthma-specific health-related quality-of-life measures are most sensitive to changes in asthma control, generic measures, such as EQ-5D-5L (EuroQol 5-Dimension 5-Level questionnaire), are potentially better for capturing the impact of comorbidities. Objective: We sought to examine the impact of pulmonary and extrapulmonary treatable traits on quality of life at initial severe asthma assessment, and to compare the characteristics of those patients whose quality of life does and does not improve during follow-up at severe asthma centers. Methods: Patients’ characteristics at baseline assessment within the UK Severe Asthma Registry were compared by EQ-5D-5L utility index quartile. Patients with follow-up review data were stratified by change in EQ-5D-5L utility index from baseline to follow-up, and characteristics similarly examined. Results: Patients in the quartiles with worst dysutility at baseline were observed to exhibit more treatable traits and in particular extrapulmonary traits associated with cumulative systemic corticosteroids, including obesity, anxiety/depression, and osteoporosis. In those patients whose quality of life improved over follow-up, a reduction in exacerbations, uncontrolled symptoms, and requirement for maintenance oral corticosteroids were observed. Conclusions: Both pulmonary and extrapulmonary treatable traits are important determinants of quality of life in severe asthma. Comorbidities associated with cumulative systemic corticosteroid exposure are particularly associated with worse quality of life, emphasizing the importance of early identification and management of severe asthma before comorbidities develop.

Introduction and purpose Air pollution, stemming from natural occurrences and human activities, significantly threatens global health, particularly impacting respiratory conditions like asthma. Air pollution substantially influences asthma exacerbation in athletes, a group particularly vulnerable due to their high physical activity levels and increased respiratory demands. Key pollutants, including particulate matter (PM), ground-level ozone (O3), sulfur dioxide (SO2), and nitrogen dioxide (NO2), play critical roles in asthma development and exacerbation. The State of Knowledge Asthma, a chronic inflammatory disease influenced by genetic predisposition and environmental factors like air pollution, is characterized by airway hyperresponsiveness, obstruction, and chronic inflammation, leading to symptoms such as shortness of breath, coughing, wheezing, and chest tightness. Research highlights the link between air pollution exposure and asthma development, with PM2.5 exposure associated with increased asthma risk and pollutants exacerbating symptoms, especially in children. Athletes inhaling air pollutants during exercise face increased airway inflammation, mucus production, and bronchospasm, worsening asthma symptoms like wheezing and shortness of breath. Chronic exposure decreases lung function, increasing reliance on medication and limiting outdoor training on polluted days. Summary Effective asthma management amidst air pollution requires personal, community, and governmental measures. Patients should minimize exposure by wearing N95 masks and choosing low-traffic routes. Governments must monitor pollution, inform the public, and control emissions through alternative fuels and technologies. Adhering to WHO air quality guidelines could prevent many new asthma cases, emphasizing comprehensive air quality management's importance, especially among vulnerable populations like children.

Background: Children with severe asthma suffer from recurrent symptoms and impaired quality of life despite advanced treatment. Underlying causes of severe asthma are not completely understood, although genetic mechanisms are known to be important. Objective: The aim of this study was to identify gene regulatory enhancers in leukocytes, to describe the role of these enhancers in regulating genes related to severe and mild asthma in children, and to identify known asthma-related SNPs situated in proximity to enhancers. Methods: Gene enhancers were identified and expression of enhancers and genes were measured by Cap Analysis Gene Expression (CAGE) data from peripheral blood leukocytes from children with severe asthma (n = 13), mild asthma (n = 15), and age-matched controls (n = 9). Results: From a comprehensive set of 8,289 identified enhancers, we further defined a robust sub-set of the high-confidence and most highly expressed 4,738 enhancers. Known single nucleotide polymorphisms, SNPs, related to asthma coincided with enhancers in general as well as with specific enhancer-gene interactions. Blocks of enhancer clusters were associated with genes including TGF-beta, PPAR and IL-11 signaling as well as genes related to vitamin A and D metabolism. A signature of 91 enhancers distinguished between children with severe and mild asthma as well as controls. Conclusions: Gene regulatory enhancers were identified in leukocytes with potential roles related to severe and mild asthma in children. Enhancers hosting known SNPs give the opportunity to formulate mechanistic hypotheses about the functions of these SNPs.

This article describes two clinical observations of the use of mepolizumab in patients with severe uncontrolled asthma with a mixed granulocytic pattern of inflammation in the bronchi and comorbid pathology. The mixed granulocytic form of severe asthma is characterized by a combination of T2 endotype and non-T2 endotype. The most common mixed granulocytic pattern of severe asthma occurs in comorbid pathology, in particular, when it is combined with chronic obstructive pulmonary disease (COPD) or bronchiectasis.In the presented observations, both patients had an experience of smoking, a late manifestation of bronchial asthma with the development of centrilobular emphysema and an irreversible decrease in the FEV/FVC ratio as part of the development of COPD. A feature of one of the cases was the presence of cylindrical bronchiectasis in both lungs. The choice of mepolizumab as an additional maintenance agent at GINA stage 5 in both cases was justified by the uncontrolled course of asthma despite the use of a high dose of glucocorticosteroids in combination with other basic drugs and the need for the use of systemic corticosteroids > 50 % of the time per year, a history of recurrent exacerbations in previous 12 months, the presence of persistent blood eosinophilia (>150 cells/μl), as well as a combination of asthma with polypous rhinosinusitis in one of the patients.Overall, the use of mepolizumab 100 mg subcutaneously every four weeks in addition to regular maximum optimized maintenance therapy was characterized by rapid, signifi cant and sustained effi cacy, which was expressed in early achievement of asthma control within the fi rst 16 weeks of therapy.

Biologics targeting IgE, IL-5, IL-4/IL-13, and TSLP are crucial in severe asthma treatment. Research, including randomized controlled trials and real-world studies, has been conducted to assess their efficacy and identify patient characteristics that may predict positive responses. The effectiveness of switching biologics, especially given overlaps in treatment eligibility, and the clinical outcomes post-cessation are critical areas of investigation. This work reviews the effects of switching between these biologics and the indicators of treatment success or failure. Insights are primarily derived from real-world experiences, focusing on patients transitioning from one monoclonal antibody to another. Moreover, this review aims to provide insights into the effectiveness, safety, and broader implications of switching biologics, enhancing understanding for clinicians to optimize severe asthma management. The article underlines the importance of a patient-centered approach, biomarker assessment, and the evolving nature of asthma treatment in making informed decisions about biologic therapy.

Abstract Background Severe asthma places a large burden on patients and society. The characteristics of patients with severe asthma in the Chinese population remain unclear. Methods A retrospective review was conducted in patients with severe asthma. Demographic and clinical data were collected. Patients were grouped according to phenotypes in terms of exacerbations, body mass index (BMI) and fixed airway obstruction (FAO) status, and the characteristics of different groups were compared. Comorbidities, factors that influence asthma phenotypes, were also analyzed in the study. Results A total of 228 patients with severe asthma were included in our study. They were more likely to be overweight or obese. A total of 41.7% of the patients received GINA step 5 therapy, and 43.4% had a history of receiving regular or intermittent oral corticosteroids (OCS). Severe asthmatic patients with comorbidities were prone to have more asthma symptoms and decreased quality of life than patients without comorbidities. Patients with exacerbations were characterized by longer duration of asthma, poorer lung function, and worse asthma control. Overweight or obese patients tended to have more asthma symptoms, poorer lung function and more asthma-related comorbidities. Compared to patients without FAO, those in the FAO group were older, with longer duration of asthma and more exacerbations. Conclusion The existence of comorbidities in patients with severe asthma could result in more asthma symptoms and decreased quality of life. Patients with exacerbations or with overweight or obese phenotypes were characterized by poorer lung function and worse asthma control. Patients with FAO phenotype tended to have more exacerbations.

Abstract Background Mepolizumab, the first widely available anti-interleukin 5 biologic, targets eosinophilic inflammation and has been shown in clinical trials to reduce exacerbations, oral corticosteroid dependence, and healthcare utilization in patients with severe asthma. The impact of mepolizumab in a real-world, publicly funded healthcare setting is unknown. The objective of this study was to describe the demographics and clinical characteristics of real-world patients receiving mepolizumab, and to compare asthma-related outcomes and associated asthma-related costs before and during mepolizumab use. Methods This retrospective, observational study in Ontario, Canada, included patients initiating mepolizumab between February 2016 and March 2019. Patients were identified using the mepolizumab patient support program and linked to the Institute for Clinical Evaluative Sciences database of publicly accessed healthcare. Patient outcomes were obtained for 12 months pre- and post-mepolizumab initiation and compared. Results A total of 275 patients were enrolled in the overall patient support program cohort (mean [standard deviation] age 57.6 [13.5] years, mean [standard deviation] of the median per-patient eosinophil count 540.4 [491.9] cells/μL). Mepolizumab was associated with reductions in asthma exacerbations (46.1%, P < 0.001) and in the number of asthma-related visits to general practitioners (40.2%, P < 0.001), specialists (27.2%, P < 0.001), and emergency departments (52.1%, P < 0.001). Associated costs were significantly lower post- versus pre-mepolizumab for asthma-related general practitioner and specialist visits, and for all-cause emergency department visits and hospital admissions. Conclusions In a real-world population of Canadian patients with severe asthma with an eosinophilic phenotype, the use of mepolizumab within a patient support program reduced asthma exacerbations and decreased asthma-related healthcare resource utilization and associated costs.

In the Republic of Sakha (Yakutia), from 2001 to 2020, the incidence of asthma is increasing from 4.1 per 1000 population to 12.5 per 1000 population. Considering that currently one of the most effective modern methods of treating severe asthma is genetic engineering biological therapy, research on biologically active medications, as well as the lack of research on this problem in the Yakut population, our work seems relevant. The purpose of this study was to evaluate the effectiveness of treatment with genetic engineering biological drugs (GEBD) in patients with severe asthma in the Yakut population. The study included 17 patients suffering from severe asthma. In 5 patients with severe asthma, the effectiveness of the following GEBD was assessed: anti IL-4, IL-13 drug, in 6 patients – anti IL-5 drug, in 6 patients – anti IgE drug. The effectiveness of treatment was assessed using the ACQ-5 symptom control test, the number of exacerbations over the previous 12 months of asthma therapy, IgE levels, the absolute number of eosinophils, indicators of external respiratory function, and the need of patients for additional asthma therapy. Before initiation, 8 (47.10%) patients had exacerbations and sought medical help; 2 patients were hospitalized in the pulmonology department; after 6 and 12 months, no exacerbations or hospitalizations in specialized hospitals were registered. When using a GEBD for 12 months, the need for inhaled corticosteroids decreased in micrograms/day. Thus, treatment of severe asthma in the Yakut population with GEBD makes it possible to achieve control over its symptoms, reduce the risk of severe exacerbations and the number of hospitalizations, and prevent side effects from high doses of standard therapy.

Background anti-IgE (Omalizumab) is one of the targeted therapies for severe bronchial asthma. Its real-life safety is still under scrutiny.The aim of the study was to evaluate the persistent efficacy and safety of Omalizumab as a long-term treatment of severe bronchial asthma. Patients and methods A prospective cohort study was conducted on 74 patients who had severe bronchial asthma eligible for Omalizumab subcutaneous treatment with a long-term regular follow-up to evaluate the long-term safety and efficacy of Omalizumab. Results This study was conducted on 74 patients who had severe bronchial asthma: 33 patients (44.6%) were males with a mean±SD (37.2 ± 4), and 41 females (55.4%) with a mean±SD (35.9 ± 6). Those patients were eligible for Omalizumab treatment with a long-term regular follow-up (from 7 to 10 years) to assess the long-term safety of Omalizumab. Omalizumab treatment has a significant improvement in the clinical condition of severe bronchial asthma as it decreased the number of patients who used oral steroids from 63 patients (before starting treatment) to 6 patients after 6 months of treatment, and 2 patients after 12 months of the dose. The use of tiotropium bromide had a significant decrease because the number of patients fell from 61 patients (before the start of treatment) to 13 patients after 6 months. It also reduced the number of acute exacerbations of bronchial asthma from 7 times per year (before the start of treatment) to 3 times after 6 months, and 2 times after 12 months of treatment. Patients’ pulmonary functions (FEV1, FEV1/ FVC, PEFR) improved significantly from (43.7 ± 9, 52.3 ± 11, 51.1 ± 4) before starting Omalizumab treatment to (64.1 ± 11,71.3 ± 13, 68.2 ± 7) after 6 months of usage; and to (69.4 ± 12, 73.3 ± 14, 72.1 ± 6) after 12 months of treatment. Long-term use of Omalizumab has less severe side effects as 70% of patients had injection site reactions in the form of local tenderness and swelling, 24.3% had a headache, 12% had nausea, 9.4% had myalgia, and 17.5% had a fever while the serious side effects as cancer, anaphylaxis or myocardial infarction has not recorded. All the side effects occurred in the first year of treatment. Conclusion Long term use of Omalizumab in severe bronchial asthma management has persistent efficacy and no serious side effects such as cancer, myocardial infarction or anaphylaxis and has only minimal side effects that occurred mostly in the first year of Omalizumab treatment, meaning that the physician cannot stop giving patients the medication.

Abstract Introduction Poor sleep health is associated with increased asthma morbidity and mortality. Accelerometers have been validated to assess sleep parameters though studies using this method in patients with asthma are sparse and none have compared mild to difficult-to-treat asthma populations. Methods We performed a retrospective analysis from two recent in-house trials comparing sleep metrics between patients with mild and difficult-to-treat asthma. Participants wore accelerometers for 24-hours/day for seven days. Results Of 124 participants (44 mild, 80 difficult-to-treat), no between-group differences were observed in sleep-window, sleep-time, sleep efficiency or wake time. Sleep-onset time was ~ 40 min later in the difficult-to-treat group (p = 0.019). Discussion Broadly, we observed no difference in accelerometer-derived sleep-metrics between mild and difficult-to-treat asthma. This is the largest analysis of accelerometer-derived sleep parameters in asthma and the first comparing groups by asthma severity. Sleep-onset initiation may be delayed in difficult-to-treat asthma but a dedicated study is needed to confirm.

Background: Increased blood/sputum neutrophil counts are related to poor clinical outcomes of severe asthma (SA), where we hypothesized that classical monocytes (CMs)/CM-derived macrophages (Mφ) are involved. We aimed to elucidate the mechanisms of how CMs/Mφ induce the activation of neutrophils/innate lymphoid cells (ILCs) in SA. Methods: Serum levels of monocyte chemoattractant protein-1 (MCP-1) and soluble suppression of tumorigenicity 2 (sST2) were measured from 39 patients with SA and 98 those with nonsevere asthma (NSA). CMs/Mφ were isolated from patients with SA (n = 19) and those with NSA (n = 18) and treated with LPS/interferon-gamma. Monocyte/M1Mφ extracellular traps (MoETs/M1ETs) were evaluated by western blotting, immunofluorescence, and PicoGreen assay. The effects of MoETs/M1ETs on neutrophils, airway epithelial cells (AECs), ILC1, and ILC3 were assessed in vitro and in vivo. Results: The SA group had significantly higher CM counts with increased migration as well as higher levels of serum MCP-1/sST2 than the NSA group. Moreover, the SA group had significantly greater production of MoETs/M1ETs (from CMs/M1Mφ) than the NSA group. The levels of MoETs/M1ETs were positively correlated with blood neutrophils and serum levels of MCP-1/sST2, but negatively correlated with FEV1%. In vitro/in vivo studies demonstrated that MoETs/M1ETs could activate AECs, neutrophils, ILC1, and ILC3 by increased migration as well as proinflammatory cytokine production. Conclusions: CM/Mφ-derived MoETs/M1ETs could contribute to asthma severity by enhancing neutrophilic airway inflammation in SA, where modulating CMs/Mφ may be a potential therapeutic option.

Bronchial asthma is a heterogeneous disease in which various cells of innate and adaptive immunity help define the endotype and clinical control. NK cells perform a defensive function against pathogens and contribute to the resolution of bronchial inflammation through proapoptotic action toward eosinophils. Dysfunction of NK responses has been shown in severe asthma. Benralizumab interacts with NK cells and induces their proliferation and maturation. This project will investigate the role of NK cells in predicting response to Benralizumab. We will prospectively enroll 25 patients with severe asthma. NK cells will be detected by cytometry at baseline and after 1, 6 and 12 months of Benralizumab therapy. Basal NK levels and their therapy-induced change will be correlated with clinical remission defined after 12 months of treatment. [ABSTRACT FROM AUTHOR]

Severe asthma presents significant management challenges, requiring a highly personalized diagnostic and therapeutic approach. Our study aims to explore the potential of volatile organic compounds (VOCs) in exhaled air as biomarkers useful for endotyping severe asthma patients. Using a device for collecting VOCs from the alveolar portion of the exhaled breath and using advanced analytical approaches, we aim to identify possible distinctive metabolic patterns related to the severity of pathology and the response to different treatments. By integrating clinical and biological data with machine learning techniques, we aim to define disease phenotypes and develop predictive algorithms for increasingly personalized management of severe asthma. [ABSTRACT FROM AUTHOR]

This article discusses asthma-related death trends and the use of biologics for severe asthma in Japan, which is considered a super-aged society with a large population of individuals over 65 years old. The article highlights the gender disparity in asthma prevalence, with males being more affected until adolescence and females becoming more prevalent in adulthood. The highest number of adult patients with asthma in Japan was found among people in their 70s. The article also addresses the reasons for poor asthma control among older individuals and the initiatives taken by the Ministry of Health, Labour, and Welfare to improve treatment efficacy. It emphasizes the importance of addressing regional disparities in severe asthma management and rectifying specialist imbalances to reduce asthma-related deaths among older adults. [Extracted from the article]

Guimei Fan,1 Mo Yi,2 Xiangmin Qiu,1 Jinfang Zhao1 1Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 2School of Nursing, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Jinfang Zhao, Shandong Provincial Hospital Affiliated to Shandong First Medical University, &num;324 Jingwuweiqi Road, Huaiyin District, Jinan City, Shandong Province, 250021, People’s Republic of China, Email zjfcqt@qq.comPurpose: This study aims to explore the complicated decision-making dilemma and challenges confronted by parents of children suffering from severe asthma within the Pediatric Intensive Care Unit (PICU) when participating in the development of their children’s discharge care plans.Patients and Methods: Employing a phenomenological methodology, a purposive sampling was performed to engage with 17 parents who participated in in-depth and semi-structured interviews between October 2022 and February 2023. The transcripts of these interviews were transcribed into textual data, which was then subjected to Colaizzi’s seven-step analysis for meticulous coding and comprehensive thematic elucidation.Results: The comprehensive analysis of the factors involved in the intricate decision-making dilemmas faced by parents of children with severe asthma during the process of crafting discharge care plans in the PICU revealed five themes and eight sub-themes: 1) Complexity of asthma-related information; 2) Insufficient provision of comprehensive decision-making support; 3) Encountering negative emotions and wavering confidence; 4) Navigating realistic constraints impacting both parents and HCPs; 5) Balancing the advantages and disadvantages of various plans.Conclusion: Parents of children with severe asthma in the PICU encounter intricate and multifaceted decision-making dilemmas while engaging in the formulation of discharge care plans. These complexities significantly dampen their decision-making enthusiasm and introduce potential risks to the children’s prognosis and recovery. In the future, it is imperative to leverage the guidance provided by healthcare professionals (HCPs) in the decision-making process, develop tailored decision support tools specifically designed for the formulation of discharge care plans for children with severe asthma in the PICU.Keywords: severe asthma, parents, discharge care plan, decision-making dilemma, phenomenological study

Abstract Background A 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. Methods A 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. Results Childhood-onset asthma, bronchiectasis, poor symptom control (ACT below 19), severe airway obstruction (

Abstract Background Increased airway NLRP3 inflammasome-mediated IL-1β responses may underpin severe neutrophilic asthma. However, whether increased inflammasome activation is unique to severe asthma, is a common feature of immune cells in all inflammatory types of severe asthma, and whether inflammasome activation can be therapeutically targeted in patients, remains unknown. Objective To investigate the activation and inhibition of inflammasome-mediated IL-1β responses in immune cells from patients with asthma. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from patients with non-severe (n = 59) and severe (n = 36 stable, n = 17 exacerbating) asthma and healthy subjects (n = 39). PBMCs were stimulated with nigericin or lipopolysaccharide (LPS) alone, or in combination (LPS + nigericin), with or without the NLRP3 inhibitor MCC950, and the effects on IL-1β release were assessed. Results PBMCs from patients with non-severe or severe asthma produced more IL-1β in response to nigericin than those from healthy subjects. PBMCs from patients with severe asthma released more IL-1β in response to LPS + nigericin than those from non-severe asthma. Inflammasome-induced IL-1β release from PBMCs from patients with severe asthma was not increased during exacerbation compared to when stable. Inflammasome-induced IL-1β release was not different between male and female, or obese and non-obese patients and correlated with eosinophil and neutrophil numbers in the airways. MCC950 effectively suppressed LPS-, nigericin-, and LPS + nigericin-induced IL-1β release from PBMCs from all groups. Conclusion An increased ability for inflammasome priming and/or activation is a common feature of systemic immune cells in both severe and non-severe asthma, highlighting inflammasome inhibition as a universal therapy for different subtypes of disease.

Background: Severe asthma places a large burden on patients and society. The characteristics of patients with severe asthma in the Chinese population remain unclear. Methods: A retrospective review was conducted in patients with severe asthma. Demographic and clinical data were collected. Patients were grouped according to phenotypes in terms of exacerbations, body mass index (BMI) and fixed airway obstruction (FAO) status, and the characteristics of different groups were compared. Comorbidities, factors that influence asthma phenotypes, were also analyzed in the study. Results: A total of 228 patients with severe asthma were included in our study. They were more likely to be overweight or obese. A total of 41.7% of the patients received GINA step 5 therapy, and 43.4% had a history of receiving regular or intermittent oral corticosteroids (OCS). Severe asthmatic patients with comorbidities were prone to have more asthma symptoms and decreased quality of life than patients without comorbidities. Patients with exacerbations were characterized by longer duration of asthma, poorer lung function, and worse asthma control. Overweight or obese patients tended to have more asthma symptoms, poorer lung function and more asthma-related comorbidities. Compared to patients without FAO, those in the FAO group were older, with longer duration of asthma and more exacerbations. Conclusion: The existence of comorbidities in patients with severe asthma could result in more asthma symptoms and decreased quality of life. Patients with exacerbations or with overweight or obese phenotypes were characterized by poorer lung function and worse asthma control. Patients with FAO phenotype tended to have more exacerbations. [ABSTRACT FROM AUTHOR]

Background: Mepolizumab, the first widely available anti-interleukin 5 biologic, targets eosinophilic inflammation and has been shown in clinical trials to reduce exacerbations, oral corticosteroid dependence, and healthcare utilization in patients with severe asthma. The impact of mepolizumab in a real-world, publicly funded healthcare setting is unknown. The objective of this study was to describe the demographics and clinical characteristics of real-world patients receiving mepolizumab, and to compare asthma-related outcomes and associated asthma-related costs before and during mepolizumab use. Methods: This retrospective, observational study in Ontario, Canada, included patients initiating mepolizumab between February 2016 and March 2019. Patients were identified using the mepolizumab patient support program and linked to the Institute for Clinical Evaluative Sciences database of publicly accessed healthcare. Patient outcomes were obtained for 12 months pre- and post-mepolizumab initiation and compared. Results: A total of 275 patients were enrolled in the overall patient support program cohort (mean [standard deviation] age 57.6 [13.5] years, mean [standard deviation] of the median per-patient eosinophil count 540.4 [491.9] cells/μL). Mepolizumab was associated with reductions in asthma exacerbations (46.1%, P < 0.001) and in the number of asthma-related visits to general practitioners (40.2%, P < 0.001), specialists (27.2%, P < 0.001), and emergency departments (52.1%, P < 0.001). Associated costs were significantly lower post- versus pre-mepolizumab for asthma-related general practitioner and specialist visits, and for all-cause emergency department visits and hospital admissions. Conclusions: In a real-world population of Canadian patients with severe asthma with an eosinophilic phenotype, the use of mepolizumab within a patient support program reduced asthma exacerbations and decreased asthma-related healthcare resource utilization and associated costs. [ABSTRACT FROM AUTHOR]

Introduction: Clinical remission (CliR) achievement has been recognized as a new potential outcome in severe asthma. Nevertheless, we still lack a detailed profile of what features could better identify patients undergoing clinical remission. In this study, we aim to address this issue, tracing a possible identikit of patients fulfilling remission criteria. Methods: We enrolled 266 patients with severe eosinophilic asthma (SEA) treated with a 12-month course of anti-IL5/IL5 receptor (IL5r) monoclonal antibodies. Patients with no exacerbation, OCS withdrawal, ACT ≥ 20 and FEV1 ≥ 80% after 1 year of biologic treatment were classified as in clinical remission. Results: 30.5% of the enrolled patients achieved remission after biologic administration. CliR group showed a lower number of baseline asthma exacerbations and better lung function parameters, with a trend for higher ACT scores and a less frequent history of a positive skin prick test. CliR achievement was unlikely in presence of a higher BMI, a positive skin prick test, an increased number of asthma exacerbations before biologic treatment, anti-muscarinic administration, and a previous diagnosis of EGPA, bronchiectasis or osteoporosis. In contrast, a better lung function, an increased blood eosinophilic count, the presence of chronic rhinosinusitis with nasal polyps and a more frequent use of reliever therapy predicts remission development. Changes in exacerbations number, OCS use, ACT scores and FEV1% between remittent and non-remittent patients arise at specific follow up timepoints and are positively associated with CliR achievement. Discussion: anti-IL5/IL5r biologics can induce CliR in a proportion of patients with SEA. Patients achieving remission demonstrate specific clinical, functional and inflammatory features, as well as a specific moment of improvement in all the CliR items. [ABSTRACT FROM AUTHOR]