LAUSR

Since their discovery by Paul Ehrlich in 1879, eosinophils have long been regarded to play a protective role against pathogens, especially during parasite infection. Contrary to other granulocytes, eosinophils contain four cationic and acid granule proteins: major basic protein, eosinophil cationic protein (ECP), eosinophilderived neurotoxin (EDN) and eosinophil peroxidase. In response to external stimuli, these granule proteins are released from eosinophils through piecemeal degranulation, exocytosis or cytolysis, along with proinflammatory chemokines and cytokines. When activated, eosinophils induce inflammation that leads to tissue injury and subsequent eosinophilinduced diseases. Of them, asthma is a common airway disease in which eosinophils serve as the key inflammatory cells. Total eosinophil count (TEC) in the blood is currently the most widely used biomarker for phenotyping asthma and initiating biological agents targeting T2 inflammation. Although higher TEC is related to greater treatment response to corticosteroids and T2targeting biologics, differences in the clinical course or treatment response among patients with similar levels of blood eosinophils have been noted. These findings suggest the heterogeneity in the functional properties of eosinophils in terms of the magnitude of activation and responsiveness to medical treatment, which cannot be assessed by solely counting the number of eosinophils. Therefore, researchers have attempted to identify clinically relevant biomarkers of asthma including eosinophil granule proteins. However, aside from fractional exhaled nitric oxide (FeNO) and sputum eosinophils, only few biomarkers that can aid the diagnosis of asthma or predict the disease course have been identified. In this issue of Thorax, Granger et al analysed the plasma levels of EDN and ECP in a large populationbased cohort in France, Epidemiological Study on the Genetics and Environment of Asthma (EGEA). The levels of both EDN and ECP were significantly higher in current asthmatics than in neverasthmatics. In particular, EDN was associated with asthma attacks, wheezing and breathlessness, while ECP was associated with elevated blood neutrophil count and chronic bronchitis. The authors also showed that high EDN was associated with persistent asthma and worse longterm asthma symptoms. Collectively, Granger et al highlighted the clinical relevance of EDN in asthmatic patients. In addition, the authors suggested a distinct role of EDN and ECP in asthma by showing their association with specific clinical and inflammatory phenotypes of asthma. Previously, we analysed 131 patients from a Korean asthma cohort and reported that serum EDN levels were significantly higher in patients with uncontrolled asthma than in those with controlled asthma. In addition, we had found that uncontrolled asthma could be more precisely predicted with EDN than with TEC; however, among patients with eosinophilic asthma, serum EDN levels did not show a significant difference according to the severity of asthma. Conversely, another study conducted in Korea reported that adult patients with severe asthma showed higher levels of serum EDN than those with nonsevere asthma. Meanwhile, Gon et al reported that serum EDN and persistent airflow limitation showed a significant association only in adult asthmatics sensitised to house dust mites. Although the clinical characteristics of asthmatic patients varied across the studies, increased EDN seems to be generally related to severe or uncontrolled forms of asthma. While Granger et al provided additional data regarding ECP and EDN in asthma, several issues need to be considered when interpreting the results. First, the presence of asthma was determined based on selfreported questionnaires rather than objective diagnostic criteria, which is an inherent limitation of populationbased studies; nevertheless, further validation is needed in patients with welldefined asthma. Second, the ‘current asthma’ group was largely composed of those with earlyonset asthma, as indicated by the mean onset age of 10 years (IQR 3–25). Considering the greater clinical importance of eosinophilic inflammation in lateonset asthma than in earlyonset asthma, an analysis in patients with lateonset asthma would be more informative. Lastly, there might have been potential confounders in the longitudinal analysis. Since the time interval between EGEA2 and 3 varied from 4 to 10 years, the clinical course of the patients could have been affected by asthma management, adherence to treatment and changes in lung function and comorbidities, which were not included in the present study. Although accumulating data implicate the clinical relevance of eosinophil granule proteins in asthma, it is still unclear how these results can be incorporated in clinical practice. Currently, there is no information regarding a clinically meaningful cutoff level of eosinophil granule proteins, which may be difficult to define due to the lack of standardised method for measuring blood EDN or ECP. In the literature, two different ELISA kits have been used to measure EDN, which reported somewhat different results in the analysis. 7 The question of whether to use plasma or serum EDN also remains unanswered. Moreover, the ranges of blood EDN and ECP levels overlap between asthmatic patients and healthy controls. Methodologically, eosinophils could be easily activated during the experimental process, which may further induce the release of granules. 5 Granger et al also suggested that EDN could be used as a biomarker for monitoring asthma. Blood EDN could be useful not only as a predictor of uncontrolled asthma, but also as a tool for monitoring treatment response to biological agents. 4 8 Measurement of EDN might be a more sensitive way of assessing activated eosinophils that tend to affect target organs and induce pathological changes. Further prospective studies are needed to confirm the role of EDN in the progression of asthma or deterioration of lung function. Another noteworthy finding of the present study is the distinct pathways related to EDN and ECP, which provides clues for better understanding the heterogeneity of eosinophils by assessing granule proteins and inflammatory markers in various medical scenarios. In addition, the significant correlation between eosinophil granule proteins and FeNO implies that EDN and ECP reflect both systemic and airway eosinophilic inflammation. Accordingly, new clinical parameters could be derived by proper combinations of the two variables in addition to TEC or FeNO, indicating specific characteristics or prognoses. Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea