Vitamin D enhances production of soluble ST2, inhibiting the action of IL-33

In our cohort of patients with severe asthma, the majority receiving very high doses of inhaled or systemic corticosteroids, a blood eosinophil count of greater than 0.45 3 10 cells/L can correctly predict sputum eosinophilia in 9 of 10 cases. We have included only patients with severe asthma in our study, and therefore we believe our results are important because these are the patients who will be considered for novel TH2-targeting biologic agents. The search for biomarkers of airway inflammation has been made more urgent by the advance of novel therapies that act specifically by targeting this inflammation. To this end, recent studies that aimed to investigate the potential benefit of mepolizumab in patients with eosinophilic asthma identified patients by using blood eosinophil cutoffs as low as 0.153 10 cells/L. As demonstrated both here and in the article from the Severe Asthma Research Program group, this cutoff would include many patients who in fact do not have contemporaneous sputum eosinophilia (more than half in this study) and therefore potentially would not be in the group of patients who could benefit from treatment. The consequence of this in a trial of a biologic agent is that the magnitude of benefit could be underestimated or even missed, as happened previously when mepolizumab was trialed in unselected patients. The other potential consequence of using blood eosinophil counts as a surrogate for sputum is the very high risk of false-negative results; from our data, approximately 1 in 5 patients without blood eosinophilia had airway eosinophilia and hence could be missed by using this selection method. Choosing a simple and universally available biomarker (blood eosinophil counts) is attractive, but in this case does not lead to a personalized medicine approach. In conclusion, we have shown that using a cutoff of 0.45 3 10 cells/L for blood eosinophilia can usefully predict airway eosinophilia in patients with severe asthma receiving high levels of treatment. However, we agree with Hastie et al that lower cutoffs are not useful. We would propose that study design for novel antieosinophil therapies could use this higher cutoff to investigate the effect of these therapies but that patients should also be included with airway but not blood eosinophilia, as previously described. In the meantime, more work needs to be done to develop useful minimally invasive and accurate surrogate markers for airway inflammation, including composite biomarkers comprising, for example, exhaled nitric oxide and serum periostin levels together with blood eosinophil counts. Stephen J. Fowler, MD Ga€ el Tavernier, PhD Robert Niven, MD