Background Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite score of T2 biomarkers (fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin) with a standardised symptom-risk-based algorithm (control). MethodsWe did a single-blind, parallel group, randomised controlled trial in adults (18-80 years of age) with severe asthma (at treatment steps 4 and 5 of the Global Initiative for Asthma) and FENO of less than 45 parts per billion at 12 specialist severe asthma centres across England, Scotland, and Northern Ireland. Patients were randomly assigned (4:1) to either the biomarker strategy group or the control group by an online electronic case-report form, in blocks of ten, stratified by asthma control and use of rescue systemic steroids in the previous year. Patients were masked to study group allocation throughout the entirety of the study. Patients attended clinic every 8 weeks, with treatment adjustment following automated treatment-group-specific algorithms: those in the biomarker strategy group received a default advisory to maintain treatment and those in the control group had their treatment adjusted according to the steps indicated by the trial algorithm. The primary outcome was the proportion of patients with corticosteroid dose reduction at week 48, in the intention-to-treat (ITT) population. Secondary outcomes were inhaled corticosteroid (ICS) dose at the end of the study; cumulative dose of ICS during the study; proportion of patients on maintenance oral corticosteroids (OCS) at study end; rate of protocol-defined severe exacerbations per patient year; time to first severe exacerbation; number of hospital admissions for asthma; changes in lung function, Asthma Control Questionnaire-7 score, Asthma Quality of Life Questionnaire score, and T2 biomarkers from baseline to week 48; and whether patients declined to progress to OCS. A secondary aim of our study was to establish the proportion of patients with severe asthma in whom T2 biomarkers remained low when corticosteroid therapy was decreased to a minimum ICS dose. This study is registered with ClinicalTrials.gov, NCT02717689 and has been completed. FindingsPatients were recruited from Jan 8, 2016, to July 12, 2018. Of 549 patients assessed, 301 patients were included in the ITT population and were randomly assigned to the biomarker strategy group (n=240) or to the control group (n=61). 28•4% of patients in the biomarker strategy group were on a lower corticosteroid dose at week 48 compared with 18•5% of patients in the control group (adjusted odds ratio [aOR] 1•71 [95% CI 0•80-3•63]; p=0•17). In the per-protoco...

Background: Whether blood eosinophil counts and exhaled nitric oxide (FeNO) are associated with important outcomes in mild asthma is unclear. Methods: This question was explored in a pre-specified analysis of a 52week, open-label, randomized, parallel-group trial in patients with mild asthma receiving only reliever inhalers, comparing salbutamol 200µg asneeded, maintenance budesonide 200µg twice-daily with salbutamol as needed, and budesonide/formoterol 200/6µg as-needed. Outcomes were compared between patients with blood eosinophils of <0.15, 0.15-<0.3 and ≥0.3x109/L; FeNO of <20, 20-50 and >50ppb; and a composite score based on both. Results: The proportion of patients randomised to as-needed salbutamol having a severe exacerbation increased progressively with increasing blood eosinophil sub-group (4.1%, 6.5% and 19.5%; p=0.014). There were no significant interactions between either biomarker and the effect of as-needed budesonide/formoterol compared with as-needed salbutamol for either exacerbations or severe exacerbations. However, there were significant interactions between blood eosinophil sub-groups and the effect of maintenance budesonide compared with as needed salbutamol for exacerbations (p<0.001) and severe exacerbations (p<0.001). Maintenance budesonide was more effective than as-needed salbutamol in patients with eosinophils ≥0.3x109/L for exacerbations (odds ratio 0.13; 95% CI 0.05-0.33) and severe exacerbations (0.11; 0.03-0.45). This was not the case for eosinophils <0.15x109/L (odds ratio for exacerbations 1.15; 0.51-1.28 and severe exacerbations 5.72; 0.97-33.6). There was no consistent interaction between treatment response and FeNO or the composite score. Conclusions: In patients with mild asthma the effects of as-needed budesonide/formoterol on exacerbations are independent of biomarker profile, whereas the benefits of maintenance inhaled budesonide are greater in patients with high blood eosinophil counts.

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 CD8CRTH2 (Tc2) cells are enriched in blood and airways in severe eosinophilic asthma. Concentrations of prostaglandin D (PGD) and cysteinyl leukotriene E (LTE) are also increased in the airways of the same group of patients. In vitro PGD and LTE 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.

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