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The ability of human tissue to reorganize and restore its existing structure underlies tissue homeostasis in the healthy airways, but in disease can persist without normal resolution, leading to an altered airway structure. Eosinophils play a cardinal role in airway remodeling both in health and disease, driving epithelial homeostasis and extracellular matrix turnover. Physiological consequences associated with eosinophil-driven remodeling include impaired lung function and reduced bronchodilator reversibility in asthma, and obstructed airflow in chronic rhinosinusitis with nasal polyps (CRSwNP). Given the contribution of airway remodeling to the development and persistence of symptoms in airways disease, targeting remodeling is an important therapeutic consideration. Indeed, there is early evidence that eosinophil attenuation may reduce remodeling and disease progression in asthma. This review provides an overview of tissue remodeling in both health and airway disease with a particular focus on eosinophilic asthma and CRSwNP, as well as the role of eosinophils in these processes and the implications for therapeutic interventions. Areas for future research are also noted, to help improve our understanding of the homeostatic and pathological roles of eosinophils in tissue remodeling, which should aid the development of targeted and effective treatments for eosinophilic diseases of the airways.

Hitasha Rupani,1 Wei Chern Gavin Fong,2,3 Aref Kyyaly,2,3 Ramesh J Kurukulaaratchy1– 4 1Department of Respiratory Medicine, University Hospitals Southampton NHS Foundation Trust, Southampton, UK; 2Clinical and Experimental Sciences, University of Southampton, Southampton, UK; 3David Hide Asthma and Allergy Research Centre, Isle of Wight NHS Trust, Isle of Wight, UK; 4NIHR Biomedical Research Centre, University Hospitals Southampton NHS Foundation Trust, Southampton, UKCorrespondence: Ramesh J KurukulaaratchyClinical Experimental Sciences, University of Southampton, Southampton, UKTel +44 238120 5232Email R.J.Kurukulaaratchy@soton.ac.ukWei Chern Gavin FongClinical and Experimental Sciences, University of Southampton, Southampton, UKTel +44 2381205232Email W.C.Fong@soton.ac.ukAbstract: The present prevailing inflammatory paradigm in asthma is of T2-high inflammation orchestrated by key inflammatory cells like Type 2 helper lymphocytes, innate lymphoid cells group 2 and associated cytokines. Eosinophils are key components of this T2 inflammatory pathway and have become key therapeutic targets. Real-world evidence on the predominant T2-high nature of severe asthma is emerging. Various inflammatory biomarkers have been adopted in clinical practice to aid asthma characterization including airway measures such as bronchoscopic biopsy and lavage, induced sputum analysis, and fractional exhaled nitric oxide. Blood measures like eosinophil counts have also gained widespread usage and multicomponent algorithms combining different parameters are now appearing. There is also growing interest in potential future biomarkers including exhaled volatile organic compounds, micro RNAs and urinary biomarkers. Additionally, there is a growing realisation that asthma is a heterogeneous state with numerous phenotypes and associated treatable traits. These may show particular inflammatory patterns and merit-specific management approaches that could improve asthma patient outcomes. Inhaled corticosteroids (ICS) remain the mainstay of asthma management but their use earlier in the course of disease is being advocated. Recent evidence suggests potential roles for ICS in combination with long-acting beta-agonists (LABA) for as needed use in mild asthma whilst maintenance and reliever therapy regimes have gained widespread acceptance. Other anti-inflammatory strategies including ultra-fine particle ICS, leukotriene receptor antagonists and macrolide antibiotics may show efficacy in particular phenotypes too. Monoclonal antibody biologic therapies have recently entered clinical practice with significant impacts on asthma outcomes. Understanding of the efficacy and use of those agents is becoming clearer with a growing body of real-world evidence as is their potential applicability to other treatable comorbid traits. In conclusion, the evolving understanding of T2 driven inflammation alongside a treatable traits disease model is enhancing therapeutic approaches to address inflammation in asthma.Keywords: asthma, biologics, monitoring, respiratory disease, T2 inflammation, treatable traits

Ramesh J Kurukulaaratchy,1–4 Hitasha Rupani,1 Wei Chern Gavin Fong,2,3 Aref Kyyaly2,3 1Department of Respiratory Medicine, University Hospitals Southampton NHS Foundation Trust, Southampton, UK; 2Clinical and Experimental Sciences, University of Southampton, Southampton, UK; 3David Hide Asthma and Allergy Research Centre, Isle of Wight NHS Trust, Isle of Wight, UK; 4NIHR Biomedical Research Centre, University Hospitals Southampton NHS Foundation Trust, Southampton, UKCorrespondence: Ramesh J KurukulaaratchyWei Chern Gavin Fong Clinical and Experimental Sciences, University of Southampton, Southampton, UKTel +44 238120 5232Email R.J.Kurukulaaratchy@soton.ac.uk; W.C.Fong@soton.ac.uk View the original paper by Dr Rupani and colleagues This is in response to the Letter to the Editor

Background: Disease heterogeneity in patients with severe asthma and its relationship to inflammatory mechanisms remain poorly understood.Objective: We aimed to identify and replicate clinicopathologic endotypes based on analysis of blood and sputum parameters in asthmatic patients.Methods: One hundred ninety-four asthmatic patients and 21 control subjects recruited from 2 separate centers underwent detailed clinical assessment, sputum induction, and phlebotomy. One hundred three clinical, physiologic, and inflammatory parameters were analyzed by using topological data analysis and Bayesian network analysis.Results: Severe asthma was associated with anxiety and depression, obesity, sinonasal symptoms, decreased quality of life, and inflammatory changes, including increased sputum chitinase 3–like protein 1 (YKL-40) and matrix metalloproteinase (MMP) 1, 3, 8, and 12 levels. Topological data analysis identified 6 clinicopathobiologic clusters replicated in both geographic cohorts: young, mild paucigranulocytic; older, sinonasal disease; obese, high MMP levels; steroid resistant TH2 mediated, eosinophilic; mixed granulocytic with severe obstruction; and neutrophilic, low periostin levels, severe obstruction. Sputum IL-5 levels were increased in patients with severe particularly eosinophilic forms, whereas IL-13 was suppressed and IL-17 levels did not differ between clusters. Bayesian network analysis separated clinical features from intricately connected inflammatory pathways. YKL-40 levels strongly correlated with neutrophilic asthma and levels of myeloperoxidase, IL-8, IL-6, and IL-6 soluble receptor. MMP1, MMP3, MMP8, and MMP12 levels were associated with severe asthma and were correlated positively with sputum IL-5 levels but negatively with IL-13 levels.Conclusion: In 2 distinct cohorts we have identified and replicated 6 clinicopathobiologic clusters based on blood and induced sputum measures. Our data underline a disconnect between clinical features and underlying inflammation, suggest IL-5 production is relatively steroid insensitive, and highlight the expression of YKL-40 in patients with neutrophilic inflammation and the expression of MMPs in patients with severe asthma.

Medical imaging has seen substantial and rapid technical advances during the past decade, including advances in image acquisition devices, processing and analysis software, and agents to enhance specificity. Traditionally, medical imaging has defined anatomy, but increasingly newer, more advanced, imaging technologies provide biochemical and physiologic information based on both static and dynamic modalities. These advanced technologies are important not only for detecting disease but for characterizing and assessing change of disease with time or therapy. Because of the rapidity of these advances, research to determine the utility of quantitative imaging in either clinical research or clinical practice has not had time to mature. Methods to appropriately develop, assess, regulate, and reimburse must be established for these advanced technologies. Efficient and methodical processes that meet the needs of stakeholders in the biomedical research community, therapeutics developers, and health care delivery enterprises will ultimately benefit individual patients. To help address this, the authors formed a collaborative program-the Quantitative Imaging Biomarker Alliance. This program draws from the very successful precedent set by the Integrating the Healthcare Enterprise effort but is adapted to the needs of imaging science. Strategic guidance supporting the development, qualification, and deployment of quantitative imaging biomarkers will lead to improved standardization of imaging tests, proof of imaging test performance, and greater use of imaging to predict the biologic behavior of tissue and monitor therapy response. These, in turn, confer value to corporate stakeholders, providing incentives to bring new and innovative products to market.