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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: We have previously developed Core Outcome Measures sets for Severe Asthma (COMSA) by multi-stakeholder consensus. There are no patient-centred tools to quantify response to biologics for severe asthma. We aimed to develop paediatric and adult CompOsite iNdexes For Response in asthMa (CONFiRM) incorporating clinical parameters and patient-reported quality of life (QoL)., Methods: International expert healthcare professionals (HCPs) and patients with severe asthma were invited to: 1) develop consensus levels of clinically relevant changes for each outcome measure within COMSA; 2) use multicriteria decision analysis to develop the CONFiRM scores and 3) assess their internal validity. A separate group of HCPs evaluated CONFiRM's external validity., Results: Five levels of change for each COMSA outcome were agreed. Severe exacerbations and maintenance oral corticosteroids use were rated as most important in determining both paediatric and adult CONFiRM scores. There was strong agreement between HCPs and patients, although patients assigned greater importance to QoL. The CONFiRM score quantified response to a biological from -31 (deterioration) to 69 (best possible response). Paediatric and adult CONFiRMs had good discriminative ability for a sufficient (AUC≥0.92) and a substantial (AUC≥0.95) response to biologics. Both CONFiRMs demonstrated excellent external validity (Spearman correlation coefficients 0.9 and 0.8 for paediatric and adult respectively (p<0.0001))., Conclusions: We have developed novel patient-centred paediatric and adult CONFiRMs which include QoL measures. CONFiRMs should allow a more holistic understanding of response for the patient and a standardised assessment of the effectiveness of biologics between studies. Further research is needed to prospectively validate CONFiRM scores., (Copyright ©The authors 2024.)

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

Background: Type 2 low-severe asthma phenotype is often a result of corticosteroid-overtreated type 2 disease owing to persistent symptoms, often unrelated to asthma and unlikely to respond to high-dose corticosteroid treatment., Objective: This study aimed to characterize patients with severe asthma with low eosinophil counts (<300 cells/μL) and describe their disease burden and treatment across health care settings in the United Kingdom., Methods: A retrospective cohort study of patients with severe asthma using linked Clinical Practice Research Datalink (CPRD) Aurum-Hospital Episode Statistics (HES) and UK Severe Asthma Registry (UKSAR) data indexed patients according to the latest blood eosinophil count (BEC). Clinical characteristics, treatment patterns, outcomes, and health care resource use were described by baseline BEC (≤150 and >150 to <300 cells/μL)., Results: Analysis included 701 (CPRD-HES) and 1,546 (UKSAR) patients; 60.5% and 59.4% had BECs 150 cells/μL or less at baseline, respectively. Across BEC groups, the proportion with uncontrolled asthma (two or more exacerbations) at follow-up (12 months after the index) was 5.4% in CPRD-HES and 45.2% in UKSAR. Maintenance oral corticosteroid use remained high across BEC groups (CPRD-HES: 29.4%; UKSAR: 51.7%), symptom control remained poor (>200 μg short-acting β 2 agonist or >500 μg terbutaline/d in CPRD-HES: 48.8%; median Asthma Control Questionnaire-6 score in UKSAR: 2.0 [range, 1.0-3.3]). Health care resource use was similar across BEC groups., Conclusions: Most patients managed in primary care experienced infrequent exacerbations, whereas UKSAR patients had frequent exacerbations. Large proportions of both patient groups had poor symptom control and continued to receive high levels of maintenance oral corticosteroids, increasing the risk of corticosteroid-induced morbidity. These data highlight the need for rigorous assessment of underlying disease pathology to guide appropriate treatment., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Benralizumab has been reported to lead to clinical remission of severe eosinophilic asthma (SEA) at 1 year in some patients. However, whether this is maintained over a longer term remains unclear. Additionally, the impact of pulmonary and extrapulmonary comorbidities on the ability to meet remission is poorly understood., Methods: Clinical outcomes including remission of SEA with benralizumab at 1 and 2 years were assessed retrospectively in a real-world UK multi-centre severe asthma cohort. The presence of clinically relevant pulmonary and extrapulmonary comorbidities associated with respiratory symptoms was recorded. Analyses to identify factors associated with the ability to meet remission were performed., Results: In total, 276 patients with SEA treated with benralizumab including 113 patients who had switched from a previous biologic to benralizumab were included. Overall, clinical remission was met in 17% (n = 31/186) and 32% (n = 43/133) of patients at 1 and 2 years, respectively. This increased to 28% at 1 year and 49% at 2 years once patients with pulmonary and/or extrapulmonary comorbidities were excluded. Body mass index (BMI) and maintenance OCS (mOCS) use demonstrated a negative association with clinical remission at 1 (BMI: OR: 0.89, 95% CI: 0.82-0.96, p < 0.01; mOCS: OR: 0.94, 95% CI: 0.89-0.99, p < 0.05) and 2 years (BMI: OR: 0.93, 95% CI: 0.87-0.99, p < 0.05; mOCS: OR: 0.95, 95% CI: 0.89-0.99, p < 0.05)., Conclusions: In this long-term, real-world study, patients with SEA demonstrated the ability to meet and sustain clinical remission when treated with benralizumab. The presence of comorbidities including obesity, which are known to be independently associated with respiratory symptoms, reduced the likelihood of meeting clinical remission., (© 2024 The Author(s). Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Uncontrolled asthma is associated with an increased risk of adverse perinatal outcomes. Asthma biologics reduce exacerbation frequency, are steroid sparing, and improve quality of life in people with severe asthma. However, evidence for the use and safety of asthma biologics during pregnancy is scarce, largely because pregnant women were excluded from clinical trials. To help to support clinical teams, we conducted an international modified Delphi study. 141 panellists from 32 countries who were involved in the care of people with severe asthma completed two rounds of online surveys covering key areas surrounding the use of asthma biologics in pregnancy. The results from this international Delphi study emphasise risk versus benefit discussions and shared clinical decision making, with consensus among panellists that asthma biologics can be used during conception and throughout pregnancy, initiated during pregnancy in line with prescribing criteria for non-pregnant people, and initiated or continued during breastfeeding. Collating data through international registries remains essential to inform clinical guidelines., Competing Interests: Declaration of interests JN and MC declare no competing interests. DJJ has received advisory board and speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, and Sanofi and research grant funding to his institution from AstraZeneca. GdA has received grants from AstraZeneca, GSK, and Chiesi; consulting fees and payment for educational events from AstraZeneca, GSK, Sanofi, and Chiesi; and support to attend meetings from Chiesi and Sanofi. LGH has received research grant funding to his institution from GSK, AstraZeneca, and Roche/Genentech; lectures fees from AstraZeneca, Novartis, Roche, Genentech, Sanofi, Circassia, GSK, Chiesi, and Teva; and travel funding from AstraZeneca and GSK. LGH has sat on Novartis, Roche/Genentech, GSK, Teva, and Celltrion monitoring and advisory boards. PD has received advisory board fees, speaker fees, and congress travel support from AstraZeneca, GSK, Chiesi, and Sanofi. AB has received research grant funding to his institution from AstraZeneca and lecture fees from Chiesi. HR has received advisory board and speaker fees from GSK, Chiesi, AstraZeneca, Sanofi, and Boehringer Ingelheim; conference support from AstraZeneca; and grant funding to her institution from AstraZeneca and GSK., (Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

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., Competing Interests: Disclosure of potential conflict of interest: P. E. Pfeffer has attended advisory board for 10.13039/100004325AstraZeneca (AZ), 10.13039/100004330GlaxoSmithKline (GSK), and Sanofi; has given lectures/webinars at meetings with/without lecture honoraria supported by AZ, Chiesi, and GSK; has attended international conferences with AZ, GSK, 10.13039/100004336Novartis, and Sanofi; has taken part in clinical trials sponsored by AZ, GSK, Novartis, 10.13039/100009857Regeneron, and Sanofi; and is conducting research funded by GSK for which his institution receives remuneration. T. Brown has received speaker fees from GSK, AZ, Teva, Chiesi, and Sanofi; honoraria for advisory board meetings from AZ, Sanofi, and Teva; sponsorship to attend international scientific meetings from Chiesi, Teva, Novartis, and Sanofi; and fees as an external expert for the AZ Pathway Programme. R. Chaudhuri has received lecture fees from GSK, AZ, Teva, Chiesi, Sanofi, and Novartis; honoraria for advisory board meetings from GSK, AZ, and Celltrion; sponsorship to attend international scientific meetings from Chiesi, Sanofi, and GSK; and a research grant to her institute from AZ for a UK multicenter study. S. Faruqi has received speaker fees and sponsorship to attend specialty meetings from AZ, GSK, Chiesi, Novartis, and Sanofi. R. Gore has received lecture fees from GSK, Sanofi, AZ, and Novartis and sponsorship to attend national scientific meetings from Sanofi UK. L. Heaney has received grant funding, participated in advisory boards, and given lectures at meetings supported by Amgen, AZ, Boehringer Ingelheim, Chiesi, Circassia, Hoffmann la Roche, GSK, Novartis, Theravance, Evelo Biosciences, Sanofi, and Teva; has received grants from MedImmune, Novartis UK, Roche/Genentech, Inc, and GSK, Amgen, Genentech/Hoffman la Roche, AZ, MedImmune, Aerocrine, and Vitalograph; has received sponsorship for attending international scientific meetings from AZ, Boehringer Ingelheim, Chiesi, GSK, and Napp Pharmaceuticals; has also taken part in asthma clinical trials sponsored by AZ, Boehringer Ingelheim, Hoffmann la Roche, and GSK for which his institution received remuneration; is the Academic Lead for the 10.13039/501100000265Medical Research Council Stratified Medicine UK Consortium in Severe Asthma, which involves industrial partnerships with a number of pharmaceutical companies including Amgen, AZ, Boehringer Ingelheim, GSK, Hoffmann la Roche, and Janssen. A. H. Mansur has received funds personal and to institution from AZ, GSK, Novartis, Chiesi, Boehringer Ingelheim, and Sanofi for talks, advisory board meetings, educational grant, and sponsorships to attend conferences. T. Pantin has received advisory board honoraria from AZ, speaker fees from GSK, and sponsorship for attending conferences from GSK, Sanofi, and Chiesi. H. Rupani has received speaker fees from GSK, AZ, Chiesi, Sanofi, and Boehringer Ingelheim; conference support from AZ; grant funding to her institution from AZ and GSK; and has attended advisory boards for AZ and GSK. S. Siddiqui has received advisory board and/or speaker fees from GSK, AZ, Chiesi, Areteia Therapeutics, CSL Behring, ERT Medical, and Medscape; grant funding from AZ; and is a cofounder of Eupnoos Limited. J. Busby reports research grants from AZ and personal fees from Nuvoair. The rest of the authors declare that they have no relevant conflicts of interest., (© 2024 The Authors.)

Objectives: Diagnostic errors are the leading cause of preventable harm in clinical practice. Implementable tools to quantify and target this problem are needed. To address this gap, we aimed to generalize the Symptom-Disease Pair Analysis of Diagnostic Error (SPADE) framework by developing its computable phenotype and then demonstrated how that schema could be applied in multiple clinical contexts., Methods: We created an information model for the SPADE processes, then mapped data fields from electronic health records (EHR) and claims data in use to that model to create the SPADE information model (intention) and the SPADE computable phenotype (extension). Later we validated the computable phenotype and tested it in four case studies in three different health systems to demonstrate its utility., Results: We mapped and tested the SPADE computable phenotype in three different sites using four different case studies. We showed that data fields to compute an SPADE base measure are fully available in the EHR Data Warehouse for extraction and can operationalize the SPADE framework from provider and/or insurer perspective, and they could be implemented on numerous health systems for future work in monitor misdiagnosis-related harms., Conclusions: Data for the SPADE base measure is readily available in EHR and administrative claims. The method of data extraction is potentially universally applicable, and the data extracted is conveniently available within a network system. Further study is needed to validate the computable phenotype across different settings with different data infrastructures., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)