The impacts of the EOS-B and EOS-S on the longitudinal clinical manifestation of asthma were examined in this present study. High eosinophilic cases were likely to have lower lung function and poorer asthma control at the baseline but to show a greater improvement in these outcomes over time compared with the low eosinophilic patients. The EOS-S revealed a higher impact on the time-dependent %FEV1 predicted but not on the ACT score compared with the EOS-B. The magnitude of the impact increased linearly with the elevation of the cut-off level for the EOS-B but remained stable or reduced for the EOS-S classification. A phenotype involving both a high EOS-B and high EOS-S was associated with a higher increment in the %FEV1 predicted and ACT over time. Neither the EOS-S nor EOS-B showed a significant impact on exacerbation.
Concerns about using the EOS-B as a surrogate for the EOS-S have been raised in previous studies [12–14]. Our present data confirmed in this regard that the relationship between both parameters is relatively weak. The combination of blood and sputum EOS as a classification approach revealed a relatively high percentage discrepancy (40% of the participants were assigned to a so-called “grey zone” with a high EOS-B but low EOS-S, and vice versa). It has been demonstrated previously that blood eosinophilia is not only related to airway inflammation but to various infectious and non-infectious illnesses [18]. An elevation in the EOS-B, therefore, may not always be accompanied by an increase in the EOS-S. On the other hand, persistent airway eosinophilia has been reported to occur in many asthmatic patients, particularly in severe asthmatics, even though high-dose corticosteroid treatments are being used [19]. We thus speculated that the EOS-B and EOS-S may have different impacts on the clinical manifestations of asthma.
Studies to date on the association between blood eosinophilia and lung function in asthmatic patients have produced inconsistent results. A prior meta-analysis on four Caucasian cohorts reported that an elevated blood eosinophil count in asthmatic patients (≥ 300 cells per µL) was associated with a lower lung function at the baseline and its accelerated declination over time [20]. However, among four cohorts, a significant association between EOS-B and a reduced FEV1 was evident in one, which raised the question of whether an improvement in lung function among the high eosinophilic subjects was caused by treatment responses [20]. In contrast, another previous study did not report this association [21]. A consistent tendency was found in our present data in which the baseline lung function was lower but improved more strongly in the high eosinophilic groups, both with the EOS-B and EOS-S classifications. This finding may be partly explained by the fact that asthma patients with a high EOS-B and/or EOS-S tend to respond better to corticosteroid therapy [22]. Interestingly, we found although the magnitude of this association was higher for the EOS-S classification, it remained stable over the cut-off levels. Meanwhile, a higher threshold for the EOS-B was associated with higher impacts. These results suggested that, while using lung function as an outcome, the EOS-S seems to be a better predictor, and that a higher threshold is needed for the EOS-B. Indeed, higher EOS-B cut-off levels have been found previously to improve the prediction of sputum eosinophilia [12]. The integration of EOS-B and EOS-S identified a good clinical improvement phenotype that was characterized by the elevation of both blood and sputum eosinophils. This phenotype had a significantly higher slope of change in the %FEV1 predicted than others in our subgroup analysis. The better clinical manifestation of this phenotype was likely induced by a good treatment response.
Evidence to date shows that the impact of EOS-S on asthma control is higher than that of EOS-B [15]. In our current study, the effects of the EOS-B and EOS-S on asthma control were found to be identical. However, as with the observed tendencies for lung function, we found a linear positive relationship between the cut-off levels and the impact of the predictors with the EOS-B but not the EOS-S classification, and that the phenotype involving an elevation of both the EOS-B and EOS-S was associated with asthma control improvement over time. This finding once again emphasized the fact that the EOS-B and EOS-S should be considered independent predictors and that their combination is a better approach to eosinophil-based phenotyping. The relationship between eosinophil and asthma exacerbation has been the subject of some debate [5, 23, 24]. A prior meta-analysis confirmed the association between EOS-B and exacerbation but found that this effect varied substantially across different study methods (cohort versus cross-sectional) and with the definition of exacerbation (hospitalization versus emergency visit) [5]. In our present study, an exacerbation of asthmatic symptoms was defined by integrating information from outpatient visits, emergency visits, and elevations in the treatment level. Furthermore, a one-year follow-up seemed to be relatively short for accurately examining the risk of exacerbation. We found no significant association between a high eosinophil count and exacerbation, both in the EOS-B and EOS-S classifications. Although our subgroup analysis for exacerbation found no statistically significant relationship, an interesting trend did emerge from our analyses. The risk of exacerbation increased sharply at 3 months from baseline among the participants with a high EOS-S and those with a low EOS-S but high EOS-B. However, this risk appeared to be stable over the follow-up period among the patients having both a high EOS-B and EOS-S. The good improvement in lung function and asthma control with this phenotype may be a reasonable explanation for this finding. The molecular basis of this phenotype should however be investigated further.
The trends for our current findings were confirmed by sensitivity analysis of the data set including the participants with available baseline EOS-B and EOS-S data. Although the effect and difference in the magnitude of the EOS-B and EOS-S on lung function and asthma control remained, the interaction between the cut-off level and the impact of the EOS-B was found to be attenuated. Meanwhile, the EOS-B and EOS-S data sets differed in terms of smoking, atopy, and control conditions. Although these factors did not interact significantly with the impact of the eosinophil count on lung function and asthma control, they may influence the effect of using a different cut-off value. Thus, future comparisons between the EOS-B and EOS-S should take into account of these confounding factors.
To our knowledge, our present study is the first attempt to compare the impact of the EOS-B and EOS-S measures on time-dependent clinical outcomes in a large multicenter cohort of asthmatic adults. The interaction of other confounding factors, including the cut-off values used and treatments, were examined and the results were confirmed by sensitivity analyses. However, our analyses had several notable limitations. First, because missing data was a critical issue with the COREA cohort, and analyses of these patients were performed as a real-life study, the results, therefore, may have potential selection bias. Second, due to the missing data issue, we included only follow-up data within one year. Because asthma is a chronic illness that results in a gradual decline in lung function, further investigations with a longer follow-up should be considered. Third, the year of the baseline visit varied largely among our included participants, from 2005 to 2021, during which time the prevalence and pattern of asthma have changed dramatically [25]. The associations between risk factors and outcome, therefore, may alter accordingly. Finally, the difference in the association between the variation of the EOS-B and EOS-S during follow-up and the clinical outcomes was not investigated and should be the objective of a future study.
In conclusion, the baseline EOS-B and EOS-S contribute differently to the change in lung function and asthma control over time and should be taken into account independently as part of the clinical management of asthma patients. The integration of these two markers to assess eosinophil-based phenotypes may be a promising approach for individualized asthma care.