Rahul Shrimanker

Interleukin-5 Inhibitors for Severe Asthma: Rationale and Future Outlook

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.

A new approach to the classification and management of airways diseases: identification of treatable traits

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.

Emerging Biologics in Severe Asthma

Asthma is a heterogeneous disease that can be classified into different clinical endotypes, depending on the type of airway inflammation, clinical severity, and response to treatment. This article focuses on the eosinophilic endotype of asthma, which is defined by the central role that eosinophils play in the pathophysiology of the condition. It is characterized by persistently elevated sputum and/or blood eosinophils and by a significant response to treatments that suppress eosinophilia. Eosinophil activity in the airway may be more important than their numbers and this needs to be investigated. Transcriplomic or Metabolomic signatures may also be useful to identify this endotype.

Type-2 CD8+ T lymphocytes responsive to PGD2 and LTE4 in severe eosinophilic asthma

The functions and in vivo roles of type-2 CD8+ T cells in humans have not been well defined and this cell type has been largely overlooked in models of 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 D2 (PGD2) and cysteinyl leukotriene E4 (LTE4) are also increased in the airways of the same group of patients. In vitro PGD2 and LTE4 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.

Synergistic activation of pro-inflammatory type-2 CD8 + T lymphocytes by lipid mediators in severe eosinophilic asthma

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 D2 (PGD2) and cysteinyl leukotriene E4 (LTE4) are also increased in the airways of the same group of patients. In vitro PGD2 and LTE4 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.

P187 Seasonality of eosinophilic and non-eosinophilic exacerbations of copd

Background Patients presenting with an acute exacerbation of COPD (AECOPD) and a peripheral blood eosinophil count≥=2% of the total white cell count have a better response to oral cortico-steroids, suggesting that stratification by this biomarker identifies a pathologically distinct phenotype and has clinical value.1 We have tested the hypothesis that the eosinophilic and non-eosinophilic exacerbations of COPD have different seasonality using a dataset of patents admitted to an inner London teaching hospital with AECOPD over 9 years. Methods All admissions with AECOPD were recorded between 2004 and 2012. We recorded the first blood test result within 24 hours of admission. The month of admission was recorded. Seasons were defined as per figure 1 and the distribution of eosinophilic (blood eosinophil count≥=2%) and non-eosinophilic events compared. Abstract P187 Figure 1 Results 2793 admissions with AECOPD were recorded, of which 2416 (86.5%) had a FBC result available and 750 (31.0%) were eosinophilic. The mean age of the entire population was 70 with 44.3% female. Eosinophilic admissions had a median age 69.3 of which 40.5% were female. Non-eosinophilic admissions had a median age 70.9 of which 46.9% were female. There were no significant differences between the number of eosinophilic exacerbations across seasons. In contrast, non-eosinophilic exacerbations occurred more commonly in winter compared to summer. The proportion of eosinophilic events was 36.5 vs 28.1% in summer and winter respectively (mean difference 9%; 95% CI 4%–14%; p=0.003). Figure 1 – Admissions via A and E for patients with Acute Exacerbations of COPD between 2004 and 2012 stratified by season and peripheral blood eosinophil percentage. Discussion Exacerbations of COPD associated with a higher blood eosinophil count do not vary according to season whereas non-eosinophilic exacerbations occur more commonly in winter and account for a significantly higher proportion of winter events. Reference Bafadhel M, McKenna S, Terry S, et al. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: A randomised placebo-controlled trial. Am J Respir Crit Care Med2012;186(1):48–55. doi:10.1164/rccm.201108-1553OC

P234 Sputum cytokines and clinical biomarkers in severe asthma

Introduction Emerging treatments for type-2 high asthma such as anti-IL-5 (mepolizumab) and anti-IL-4 and IL-13 (dupilumab) target specific cytokine pathways resulting in type-2 inflammation. Whether patients with type 2 inflammation respond equally to both treatment or have distinct IL-13 and IL-5 profiles is currently unclear. We have tested the hypothesis that these pathways may function independently of each other and that simple biomarkers can help differentiate IL-13 and IL-5 high patients. Methods Patients with well characterised, severe asthma were evaluated with the blood eosinophil count and fractional exhaled nitric oxide (FeNO). Patients also had paired measurements of type-2 cytokines in induced sputum samples. Sputum cytokines were measured using a Luminex assay. Results We found that there was no relationship between the blood eosinophil count and FeNO. There was a positive correlation between FeNO and sputum IL-13 (r = 0.51, p < 0.01) and blood eosinophils and sputum IL-5 (r = 0.47, p < 0.01). Conclusions These findings suggest that readily available, non-invasive biomarkers may be able to differentiate sub-phenotypes in type-2 high asthma. Post-hoc analysis of clinical trial data of anti-IL-5 and anti-IL-4 and IL-13 treatments based on the predominant clinical biomarker would be of interest to see if these predict response to treatment. Simple biomarkers may be of use in deciding which of the emerging biological treatments to use in severe, type-2 high asthma.