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Eosinophils are key effector cells mediating airway inflammation and exacerbation in patients with severe eosinophilic asthma. They are present in increased numbers and activation states in the airway mucosa and lumen. Interleukin-5 (IL-5) is the key eosinophil growth factor that is thought to play a role in eosinophil priming and activation. However, the mechanism of these effects is still not fully understood. The anti-IL-5 antibody mepolizumab reduces eosinophil counts in the airway modestly but has a large beneficial effect on the frequency of exacerbations of severe eosinophilic asthma, suggesting that reduction in eosinophil priming and activation is of central mechanistic importance. In this study, we used the therapeutic effect of mepolizumab and single-cell ribonucleic acid sequencing to investigate the mechanism of eosinophil priming and activation by IL-5. We demonstrated that IL-5 is a dominant driver of eosinophil priming and plays multifaceted roles in eosinophil function. It enhances eosinophil responses to other stimulators of migration, survival, and activation by activating phosphatidylinositol-3-kinases, extracellular signal-regulated kinases, and p38 mitogen-activated protein kinases signaling pathways. It also enhances the pro-fibrotic roles of eosinophils in airway remodeling via transforming growth factor-β pathway. These findings provide a mechanistic understanding of eosinophil priming in severe eosinophilic asthma and the therapeutic effect of anti-IL-5 approaches in the disease., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Asthma exacerbations in people treated with mepolizumab result in less peak expiratory flow reduction than placebo but similar symptom scores. Symptoms recover slower, indicating these exacerbations may be less prednisolone responsive. https://bit.ly/3xQsFRB., Competing Interests: Conflict of interest: D.J. Bratton and S.W. Yancey are employees of GSK and hold stock/stock options in GSK. S.W. Yancey has since retired. I. Howell, G. Hynes and R. Shrimanker have no relevant competing interests to disclose. I.D. Pavord reports personal fees from AstraZeneca, GSK, Boehringer Ingelheim, Sanofi/Regeneron, Circassia, Merck, Novartis, Mundipharma, Teva and Knopp; and grants and personal fees from Chiesi and Afferent. L.G. Heaney reports personal fees or sponsorship from AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Roche/Genentech, Sanofi, Amgen, Aerocrine and Napp; and grants from AstraZeneca, Boehringer Ingelheim, GSK and Napp., (Copyright ©The authors 2024.)

Background: Mepolizumab inhibits IL-5 activity and reduces exacerbation frequency and maintenance oral corticosteroid (OCS) dosage in patients with severe eosinophilic asthma (SEA). Some patients remain dependent on OCS despite anti-IL-5 treatment, suggesting residual corticosteroid-responsive mechanisms., Objective: To determine the clinical and anti-inflammatory effects of OCS in patients with SEA on mepolizumab., Methods: We conducted a randomized, triple-blind, placebo-controlled crossover trial of prednisolone (0.5 mg/kg/d, maximum 40 mg/d, for 14 ± 2 days) in adults with SEA after 12 or more weeks of mepolizumab. We compared change in asthma symptoms, quality of life, lung function measured by spirometry and airwave oscillometry, fractional exhaled nitric oxide, and blood and sputum eosinophil cell count after prednisolone and placebo treatment., Results: A total of 27 patients completed the study. Prednisolone did not improve 5-item Asthma Control Questionnaire (mean difference in change for prednisolone vs placebo, -0.23; 95% CI, -0.58 to 0.11), mini-Asthma Quality of Life Questionnaire (0.03; 95% CI, -0.26 to 0.42), St. George's Respiratory Questionnaire (0.24; 95% CI, -3.20 to 3.69), or Visual Analogue Scale scores for overall asthma symptoms (0.11; 95% CI, -0.58 to 0.80). The mean difference for FEV 1 in favor of prednisolone was 105 mL (95% CI, -4 to 213 mL); forced expiratory flow at 25% and 75% 484 mL/s (95% CI, 151 to 816 mL/s); fractional exhaled nitric oxide reduction 41% (95% CI, 25% to 54%); blood eosinophil count reduction 49% (95% CI, 31% to 62%); and percentage of sputum eosinophil reduction 71% (95% CI, 26% to 89%)., Conclusions: OCS improved small-airway obstruction and reduced biomarkers of type 2 inflammation but had no significant effect on symptoms or quality of life in patients with SEA receiving treatment with mepolizumab., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Background: In T2-mediated severe asthma, biologic therapies, such as mepolizumab, are increasingly used to control disease. Current biomarkers can indicate adequate suppression of T2 inflammation, but it is unclear whether they provide information about airway microbial composition. We investigated the relationships between current T2 biomarkers and microbial profiles, characteristics associated with a Proteobacteria HIGH microbial profile and the effects of mepolizumab on airway ecology., Methods: Microbiota sequencing was performed on sputum samples obtained at stable and exacerbation state from 140 subjects with severe asthma participating in two clinical trials. Inflammatory subgroups were compared on the basis of biomarkers, including FeNO and sputum and blood eosinophils. Proteobacteria HIGH subjects were identified by Proteobacteria to Firmicutes ratio ≥0.485. Where paired sputum from stable visits was available, we compared microbial composition at baseline and following ≥12 weeks of mepolizumab., Results: Microbial composition was not related to inflammatory subgroup based on sputum or blood eosinophils. FeNO ≥50 ppb when stable and at exacerbation indicated a group with less dispersed microbial profiles characterised by high alpha-diversity and low Proteobacteria. Proteobacteria HIGH subjects were neutrophilic and had a longer time from asthma diagnosis than Proteobacteria LOW subjects. In those studied, mepolizumab did not alter airway bacterial load or lead to increased Proteobacteria., Conclusion: High FeNO could indicate a subgroup of severe asthma less likely to benefit from antimicrobial strategies at exacerbation or in the context of poor control. Where FeNO is <50 ppb, biomarkers of microbial composition are required to identify those likely to respond to microbiome-directed strategies. We found no evidence that mepolizumab alters airway microbial composition., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: The most recognizable phenotype of severe asthma comprises people who are blood eosinophil and FeNO-high, driven by type 2 (T2) cytokine biology, which responds to targeted biological therapies. However, in many people with severe asthma, these T2 biomarkers are suppressed but poorly controlled asthma persists. The mechanisms driving asthma in the absence of T2 biology are poorly understood., Objectives: To explore airway pathology in T2 biomarker-high and -low severe asthma., Methods: T2 biomarker-high severe asthma (T2-high, n = 17) was compared with biomarker-intermediate (T2-intermediate, n = 21) and biomarker-low (T2-low, n = 20) severe asthma and healthy controls (n = 28). Bronchoscopy samples were processed for immunohistochemistry, and sputum for cytokines, PGD 2 and LTE 4 measurements., Results: Tissue eosinophil, neutrophil and mast cell counts were similar across severe asthma phenotypes and not increased when compared to healthy controls. In contrast, the remodelling features of airway smooth muscle mass and MUC5AC expression were increased in all asthma groups compared with health, but similar across asthma subgroups. Submucosal glands were increased in T2-intermediate and T2-low asthma. In spite of similar tissue cellular inflammation, sputum IL-4, IL-5 and CCL26 were increased in T2-high versus T2-low asthma, and several further T2-associated cytokines, PGD 2 and LTE 4 , were increased in T2-high and T2-intermediate asthma compared with healthy controls., Conclusions: Eosinophilic tissue inflammation within proximal airways is suppressed in T2 biomarker-high and T2-low severe asthma, but inflammatory and structural cell activation is present, with sputum T2-associated cytokines highest in T2 biomarker-high patients. Airway remodelling persists and may be important for residual disease expression beyond eosinophilic exacerbations. Registered at ClincialTrials.gov: NCT02883530., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Clinical trials with mepolizumab, a humanised monoclonal antibody against interleukin-5, show a 50% reduction in severe asthma exacerbations in people with severe eosinophilic asthma. Exacerbations in patients treated with mepolizumab seem to be different to exacerbations in those given placebo, as patients treated with mepolizumab report fewer symptoms, have a lower sputum eosinophil count, and smaller fall in peak expiratory flow. We aimed to investigate the inflammatory phenotype and physiological characteristics of exacerbation events in patients with severe eosinophilic asthma who were treated with mepolizumab., Methods: This multicentre, prospective, observational cohort study was carried out at four UK specialist severe asthma centres. Participants were aged 18-80 years, with severe eosinophilic asthma (Global Initiative for Asthma steps 4 and 5), and were eligible for mepolizumab therapy. All participants received mepolizumab 100 mg subcutaneously every 4 weeks, had a scheduled study visit when stable on mepolizumab (≥3 months on treatment), and measured daily peak flow and completed symptoms diaries throughout the course of the study. Participants attended their study centre for unscheduled exacerbation assessment when symptoms worsened outside of their normal daily variation and before commencing rescue treatment. If a participant was unable to attend their study centre for exacerbation or had initiated rescue treatment before the study visit, clinical details of the missed exacerbation were collected by clinical staff. In this exploratory study, the endpoint was 100 clinical assessments at exacerbation completed across all sites for participants on mepolizumab before initiation of rescue treatment. Characteristics of those who had exacerbations on mepolizumab were compared with those who did not, peak flow and symptoms diaries were compared for assessed versus missed exacerbations, and exacerbation phenotypes defined by sputum eosinophil cell count were compared. The utility of fractional exhaled nitric oxide (FeNO) and C-reactive protein in determining exacerbation phenotype on mepolizumab treatment were also assessed. This study is registered with ClinicalTrials.gov, NCT03324230., Findings: Between Nov 30, 2017, and May 29, 2019, 145 participants were enrolled and treated with mepolizumab, five were excluded from the analysis. 172 exacerbations occurred, with 96 (56%) assessed before commencing rescue treatment. Compared with patients who did not exacerbate, patients who exacerbated had a higher exacerbation rate and more emergency department attendances in the year before commencing mepolizumab. The change in peak expiratory flow at nadir in the assessed exacerbation group was mean -40·5 L/min (SD 76·3) versus mean -37·0 L/min (93·0; p=0·84) in the missed exacerbation group, and there was no difference in reported symptom burden. When comparing exacerbations with a high sputum eosinophil count (≥2%; SE HIGH ) with exacerbations with a low sputum eosinophil count (<2%; SE LOW ), the SE HIGH exacerbations were FeNO high (median difference 33 parts per billion [ppb; 95% CI 8 to 87]; p=0·0004), with lower FEV 1 percent predicted (mean difference -15·9% [-27·0 to -4·8]; p=0·0075), lower FEV 1 to forced vital capacity ratio (mean difference -10·3 [-17·0 to -3·6]; p=0·0043), and higher blood eosinophil counts (median difference 40 cells per μL [20 to 70]; p=0·0009). By contrast, SE LOW exacerbations had higher C-reactive protein concentrations (median difference 12·7 mg/L [3·5 to 18·5]; p<0·0001), higher sputum neutrophil counts (median difference 52·7% [34·5 to 59·2]; p<0·0001), and were more likely to be treated with antibiotics (p=0·031). FeNO (≤20 or ≥50 ppb) was the most useful discriminator of inflammatory phenotype at exacerbation. The most common adverse event was hospital admission due to asthma exacerbation (17 [50%] of 34 events), none of the adverse events were study procedure related., Interpretation: Exacerbations on mepolizumab are two distinct entities, which can largely be differentiated using FeNO: non-eosinophilic events are driven by infection with a low FeNO and high C-reactive protein concentration, whereas eosinophilic exacerbations are FeNO high. The results of the MEX study challenge the routine use of oral corticosteroids for the treatment of all asthma exacerbation events on mepolizumab, as well as the switching of biological therapies for treatment failure without profiling the inflammatory phenotype of ongoing asthma exacerbations. The results highlight clinically available tools to enable profiling of these residual exacerbations in patients treated with mepolizumab., Funding: UK Medical Research council., Competing Interests: Declaration of interests PJM has received speaker's fees from Glaxo Smith Kline, outside the submitted work. FY has received personal fees and non-financial support from AstraZeneca and non-financial support from GlaxoSmithKline, outside the submitted work. CEB has received grants and personal fees from GlaxoSmithKline, AstraZeneca, Sanofi, Novartis, Chiesi, Genentech, Gossamer, Mologic, and 4DPharma for services outside the submitted work. RC has received grants, personal fees, and non-financial support from AstraZeneca; personal fees from GlaxoSmithKline and Novartis; personal fees and non-financial support from Teva and Chiesi; and non-financial support from Napp Pharmaceuticals, all outside the submitted work. IDP has received financial support for research from Sanofi and Regeneron Pharmaceuticals, and non-financial support from Excerpta Medica, during the conduct of the study. IDP has also received speaker's fees from Aerocrine AB; speaker's fees and consultant fees from Almirall and Novartis; speaker's fees, payments for organisation of educational events, consultant fees, and international scientific meeting scholarship from AstraZeneca, GlaxoSmithKline, Regeneron Pharmaceuticals, Sanofi, and Teva; speaker's fees, consultant fees, and international scientific meeting sponsorship from Boehringer Ingelheim; speaker's fees, consultant fees, international scientific meeting sponsorship, and a research grant from Chiesi; consultant fees from Circassia, Dey Pharma, Genentech, Knopp Biosciences, Merck, Merck Sharp & Dohme, RespiVert, and Schering-Plough; and consultant fees and international scientific meeting sponsorship from Napp Pharmaceuticals, all outside the submitted work. LGH has received non-financial support from GlaxoSmithKline during the conduct of the study; has received grants from Amgen, AstraZeneca, Medimmune, Janssen, Novartis, Roche/Genentech, GlaxoSmithKline, Boehringer Ingelheim, Aerocrine, and Vitalograph; is the lead for the UK MRC Consortium for Stratified Medicine in Severe Asthma in partnership with Novartis, Hoffman la Roche/Genentech, Evelo Biosciences, Sanofi, GlaxoSmithKline, AstraZeneca, Teva, Theravance, and Circassia; has received travel funding support for international respiratory meetings (institution remunerated) from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Napp Pharmaceutical; has received project grant funding from Medimmune, Novartis UK, Roche/Genentech, and GlaxoSmithKline; and has received funding for clinical trials (institution remunerated) from AstraZeneca, GlaxoSmithKline, Schering Plough, Synairgen, Novartis, and Roche/Genentech, all outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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Human type-2 CD8 + T cells are a cell population with potentially important roles in allergic disease. We investigated this in the context of severe asthma with persistent airway eosinophilia-a phenotype associated with high exacerbation risk and responsiveness to type-2 cytokine-targeted therapies. In two independent cohorts we show that, in contrast to Th2 cells, type-2 cytokine-secreting CD8 + CRTH2 + (Tc2) cells are enriched in blood and airways in severe eosinophilic asthma. Concentrations of prostaglandin D 2 (PGD 2 ) and cysteinyl leukotriene E 4 (LTE 4 ) are also increased in the airways of the same group of patients. In vitro PGD 2 and LTE 4 function synergistically to trigger Tc2 cell recruitment and activation in a TCR-independent manner. These lipids regulate diverse genes in Tc2 cells inducing type-2 cytokines and many other pro-inflammatory cytokines and chemokines, which could contribute to eosinophilia. These findings are consistent with an important innate-like role for human Tc2 cells in severe eosinophilic asthma and suggest a potential target for therapeutic intervention in this and other diseases.

This review outlines a new, personalized approach for the classification and management of airway diseases. The current approach to airways disease is, we believe, no longer fit for purpose. It is impractical, overgeneralizes complex and heterogeneous conditions and results in management that is imprecise and outcomes that are worse than they could be. Importantly, the assumptions we make when applying a diagnostic label have impeded new drug discovery and will continue to do so unless we change our approach. This review suggests a new mechanism-based approach where the emphasis is on identification of key causal mechanisms and targeted intervention with treatment based on possession of the relevant mechanism rather than an arbitrary label. We highlight several treatable traits and suggest how they can be identified and managed in different healthcare settings., (© 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.)

In this review, we outline the pathophysiology of severe asthma and discuss the role of anti-interleukin (IL)-5 inhibitors for the treatment of asthma. Anti-IL-5 treatments have shown efficacy in reducing the rate of severe asthma attacks in eosinophilic asthma. We review the history of the development of these agents, lessons learnt about severe asthma along the way and key clinical trials supporting efficacy of the three anti-IL-5 treatments that are clinically available or undergoing clinical trials in asthma.