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Eosinophilic asthma is characterized by frequent exacerbations, poor symptom control and accelerated lung function decline. It is now recognized that the immune response underlying eosinophilic asthma involves a complex network of interconnected pathways from both the adaptive and innate immune systems. Within this response, interleukin‐5 (IL‐5) plays a central role in eosinophil differentiation, activation and survival and has emerged as a key target for therapies treating severe asthma. The monoclonal antibodies mepolizumab and reslizumab target the ligand IL‐5, preventing its interaction with eosinophils; in contrast, benralizumab binds to the IL‐5 receptor (IL‐5R), preventing IL‐5 from binding and leading to substantially greater eosinophil reduction by enhanced antibody‐dependent cell‐mediated cytotoxicity. Although no direct head‐to‐head clinical trials of asthma have been published to formally evaluate the clinical significance of these different therapeutic approaches, the potential benefits of partial versus complete eosinophil depletion continue to remain an important area of study and debate. Here, we review the existing real‐world and clinical study data of anti‐IL‐5/anti‐IL‐5R therapies in severe eosinophilic asthma. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mepolizumab and benralizumab are monoclonal antibodies (mAb) directed against anti-IL-5 and anti-IL5R, respectively, and their use reduces exacerbation rate and maintenance oral corticosteroid (mOCS) requirements in severe eosinophilic asthma (SEA).1-4 We recently reported that a minority of patients treated with mepolizumab experience a sub-optimal response including those with a higher baseline ACQ and mOCS requirement.1 It remains unclear if such patients may improve following a switch to benralizumab which provides a more complete depletion of airway eosinophils.5,6 We retrospectively assessed patients with SEA treated at our specialist centre, who were switched from mepolizumab to benralizumab following a sub-optimal response defined as failing to achieve either: >=50% reduction in mOCS dose; >=50% reduction in annualized exacerbation rate (AER);and an ongoing requirement of >=7.5 mg prednisolone/day or an AER of >=3. In essence this notion is no different from the reality that within severe eosinophilic asthma, some patients require low dose maintenance oral steroids, whilst others require a higher dose to adequately suppress their airways inflammation. Our results appear to support this possibility and suggest that a more profound depletion in airway eosinophilia as occurs with benralizumab may offer additional clinical benefit in patients with particularly severe eosinophilic asthma. Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone-dependent severe asthma. [Extracted from the article]

Background Methods Results Conclusions Severe refractory, neutrophilic asthma remains an unsolved clinical problem. STING agonists induce a neutrophilic response in the airways, suggesting that STING activation may contribute to the triggering of neutrophilic exacerbations. We aim to determine whether STING‐induced neutrophilic lung inflammation mimics severe asthma.We developed new models of neutrophilic lung inflammation induced by house dust mite (HDM) plus STING agonists diamidobenzimidazole (diABZI) or cGAMP in wild‐type, and conditional‐STING‐deficient mice. We measured DNA damage, cell death, NETs, cGAS/STING pathway activation by immunoblots, N1/N2 balance by flow cytometry, lung function by plethysmography, and Th1/Th2 cytokines by multiplex. We evaluated diABZI effects on human airway epithelial cells from healthy or patients with asthma, and validated the results by transcriptomic analyses of rhinovirus infected healthy controls vs patients with asthma.DiABZI administration during HDM challenge increased airway hyperresponsiveness, neutrophil recruitment with prominent NOS2+ARG1− type 1 neutrophils, protein extravasation, cell death by PANoptosis, NETs formation, extracellular dsDNA release, DNA sensors activation, IFNγ, IL‐6 and CXCL10 release. Functionally, STING agonists exacerbated airway hyperresponsiveness. DiABZI caused DNA and epithelial barrier damage, STING pathway activation in human airway epithelial cells exposed to HDM, in line with DNA‐sensing and PANoptosis pathways upregulation and tight‐junction downregulation induced by rhinovirus challenge in patients with asthma.Our study identifies that triggering STING in the context of asthma induces cell death by PANoptosis, fueling the flame of inflammation through a mixed Th1/Th2 immune response recapitulating the features of severe asthma with a prognostic signature of type 1 neutrophils. [ABSTRACT FROM AUTHOR]

The prevalence of many chronic noncommunicable diseases has been steadily rising over the past six decades. During this time, over 350,000 new chemical substances have been introduced to the lives of humans. In recent years, the epithelial barrier theory came to light explaining the growing prevalence and exacerbations of these diseases worldwide. It attributes their onset to a functionally impaired epithelial barrier triggered by the toxicity of the exposed substances, associated with microbial dysbiosis, immune system activation, and inflammation. Diseases encompassed by the epithelial barrier theory share common features such as an increased prevalence after the 1960s or 2000s that cannot (solely) be accounted for by the emergence of improved diagnostic methods. Other common traits include epithelial barrier defects, microbial dysbiosis with loss of commensals and colonization of opportunistic pathogens, and circulating inflammatory cells and cytokines. In addition, practically unrelated diseases that fulfill these criteria have started to emerge as multimorbidities during the last decades. Here, we provide a comprehensive overview of diseases encompassed by the epithelial barrier theory and discuss evidence and similarities for their epidemiology, genetic susceptibility, epithelial barrier dysfunction, microbial dysbiosis, and tissue inflammation., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma., Methods: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV 1 ) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV 1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day., Results: 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV 1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria., Conclusions: Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)