Endovascular therapy is clinically effective and offers cost savings for patients with AIS compared with usual care alone. HT is a serious complication after endovascular therapy for ischemic stroke, which increases the risk of death at 3 months and the likelihood of poor functional outcome [8, 16, 17]. The present study was performed to assess the relationship between eosinophils, HT and functional outcome after mechanical thrombectomy in patients with AIS. And the present study showed that decreased eosinophil levels were associated with an increased risk of sICH/PH. In addition, there was an association between eosinophils and functional outcome, which is consistent with previous studies [13–15]. More importantly, this study showed an important role of sICH on this association.
Many risk factors such as neutrophils and neutrophil-to-lymphocyte ratio have been identified for sICH [8, 18, 19]. To our knowledge, no study has investigated the effect of eosinophils on sICH after mechanical thrombectomy. In the present study, a decrease in eosinophils was associated with an increase in sICH (OR, 0.00; 95% CI, 0.00-0.01; P = 0.0141). The mechanisms underlying these observations are not well established, but eosinophil-induced neuroprotection may play a critical regulatory role in the development of sICH. Eosinophils can secrete vascular endothelial growth factor and several chemokines [2–4]. IL-4 and IL-13 secreted by eosinophils can induce the activation of M2 phenotype microglia, which are neuroprotective by promoting the resolution of inflammation. In contrast, vascular endothelial growth factor may have neuroprotective effects by regulating angiogenesis [2–4]. Alternatively, a decrease in eosinophils may lead to reduced neuroprotection and more sICH, which in turn leads to a worse outcome (Supplementary Fig. 7 in the supplementary file).
Eosinophils are associated with both sICH and functional outcome. sICH partially mediates the relationship between decreased eosinophil levels and poor outcome. These data suggest that eosinophil-induced neuroprotection and subsequent complications of sICH may be one of the mechanisms underlying the association between eosinophils and functional outcome. Furthermore, we found a significant association of eosinophils with poor outcome independent of sICH in multivariate analysis (mRS: β, -5.00; 95% CI, -8.71-1.30; P = 0.0086; poor outcome: OR, 0.00; 95% CI, 0.00-0.09; P = 0.0086. Supplementary Table 11 in the supplementary file). These results suggest that eosinophils have additional prognostic value when considering sICH, and in addition to sICH, eosinophils may contribute to adverse outcomes such as stroke-associated pneumonia (Supplementary Fig. 6 in the supplementary file).
A previous study showed that ischemic stroke decreased the proportion of eosinophils in the lungs [20]. The altered eosinophils coincided with a marked reduction in the levels of multiple chemokines and cytokines in the lungs that are essential to "pre-condition" the lungs against bacterial infection or to promote bacterial clearance in the event of lung infection [1, 17]. These suggest that ischemic stroke creates an immunosuppressive environment in the lungs by reducing the production of multiple pro-inflammatory chemokines and cytokines. In addition, extracellular structures formed by mitochondrial DNA and granule proteins released by eosinophils are able to bind and kill bacteria, which contributes to antimicrobial defense [1, 20, 21]. Whereas our previous study found that lower eosinophil levels were associated with higher SAP, SAP plays an important mediating role in the association of eosinophils with adverse outcomes. Given the above, it is possible that a decrease in eosinophils could lead to more sICH and SAP, which in turn could lead to poor outcomes (Supplementary Fig. 7 in the supplementary file). To test our hypothesis, further animal studies are needed.
Although eosinophilia was also associated with PH (OR, 0.00; 95% CI, 0.00-0.05; P = 0.0174), no mediation effect of PH on the association between eosinophilia and poor outcome was found in the present study. The reason for this discrepancy may be related to the small sample size, which weakens the statistical strength of our conclusions. Another reason for the mediating effect of sICH rather than PH may be that poor outcome itself is a clinical definition. sICH reflects the degree of brain injury and clinical symptoms, whereas PH reflects only the degree of brain injury, which leads to a situation where sICH better reflects functional outcome. And we did find that eosinophils appeared to be more sensitive to sICH (OR, 0.00; 95% CI, 0.00-0.01; P = 0.0141) or sICH to poor outcome (OR, 9.06; 95% CI, 2.31–35.48; P = 0. 0015) than eosinophils to PH (OR, 0.00; 95% CI, 0.00-0.05; P = 0.0174) or the effect size of PH on poor outcomes (OR, 6.27; 95% CI, 2.39–16.46; P = 0.0002). And further studies from other larger samples of patients with AIS are needed to explore whether PH mediates the association between eosinophilia and poor outcomes.
The main strength of our study is that we provide a comprehensive study with the established model to assess the effect of sICH on the relationship between eosinophil and functional outcomes. However, this study also has some limitations. First, eosinophil levels were measured at only one point, and therefore, results may vary depending on the possible rapid changes in their values after the onset of symptoms [8, 22]. Second, we neither explored the mechanisms by which eosinophils affect immunosuppressive and neuroprotective pathways nor investigated which factors regulate changes in eosinophils after ischemic stroke in animal studies. These will be the focus of our next work, especially to explore the role of eosinophils in ischemic stroke and their mechanisms. Third, this is a retrospective single-center study with a small sample size. In addition, our cohort represents a subgroup of stroke patients who underwent thrombectomy; therefore, our results may not be generalizable to the entire stroke patient population and further studies from other samples of AIS patients are needed to validate our results. Fourth, our study was designed as a cross-sectional study; therefore, causality could not be determined. To compensate for this limitation, we performed a causal mediation analysis and suggested a possible association between eosinophilia, sICH, and functional outcome (Fig. 1; Supplementary Figs. 4–6 in the supplementary file). However, it is noteworthy that this is the first study to show a complex relationship between eosinophils, sICH, and functional outcome in patients with AIS experiencing MT. In this regard, attempts to maintain eosinophils have important implications for stroke prognosis, especially considering that clinical outcomes at 3 months remain unsatisfactory, with nearly half of patients successfully reperfused presenting with an unfavorable functional prognosis [23].