To the editor, Patients with severe eosinophilic asthma have a high risk of exacerbations requiring rescue oral corticosteroid treatment. Monoclonal antibody treatments inhibiting IL-5 directly or via the IL-5Rα or IL13/IL4 via the IL-4Rα reduce exacerbations of severe, eosinophilic asthma with evidence to type-2 inflammation as shown by a raised peripheral blood eosinophil count or fractional exhaled nitric oxide (FeNO) (1) (2). Both of these biomarkers have been associated with an increased risk of exacerbations (3).The key cytokine for the development of eosinophils is IL-5 whereas FENO is regulated by the IL-13 dependant inducible nitric oxide pathway (4) suggesting that their combination might provide additive prognostic and predictive information. We tested this hypothesis in a post-hoc analysis of a placebo controlled trial of anti-IL-5 (mepolizumab) in patients with severe asthma. MethodsWe undertook a post-hoc analysis of a phase 2b study of mepolizumab in patients with severe eosinophilic asthma (DREAM) (1). We selected this study as it was the only mepolizumab study to assess FeNO and blood eosinophils at baseline. DREAM evaluated placebo and 3 doses of mepolizumab (75 mg, 250 mg, 750 mg IV 4 weekly) for 52 weeks. Participants had a history of 2 or more exacerbations requiring oral corticosteroids in the previous year and evidence of eosinophilic inflammation as reflected by one of more of the following: a peripheral blood eosinophil count ≥300 cells/µL; a sputum eosinophil count ≥3%; FeNO ≥50ppb; and prompt deterioration of asthma control after a 25% or less reduction in regular maintenance inhaled or oral corticosteroids. As the DREAM study did not show a dose-related effect of active treatment or evidence of an interaction between dose and predictive value of biomarkers, our analysis is based on the combined effect of the different doses.

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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