Sex differences in the risk factor distribution, severity, and outcomes of ischemic stroke are multifactorial and related to genetics, environmental factors, and social influences [21–23]. Previous studies have revealed that older women with higher stroke severity at stroke onset have higher platelet counts, higher prevalence of cardioembolism, and more unfavorable clinical outcomes. Similar results were observed in the present study. Furthermore, we found that women had higher SII and PLR, as well as higher rates of cancer history, elevated troponin I level, and in-hospital complications. No differences in NLR and NC were observed between male and female patients, possibly due to absence of platelet count in these markers. Recent studies have revealed that risk of stroke not only increases after a new cancer diagnosis but also increases with time in almost all cancer survivors [24, 25]. Cancer and related therapies may cause coagulopathies, such as nonbacterial thrombotic endocarditis, alterations in platelet and endothelial function, and radiation-induced atherosclerosis. Elevated troponin I level during acute stroke is a strong independent predictor for both unfavorable outcomes and in-hospital mortality. The mechanisms of elevated troponin I level during acute stroke include ischemic myocardial injury, neurogenic heart syndrome through increased sympathetic activity causing cardiomyopathy, and other systemic conditions such as infection, sepsis, renal failure, and pulmonary embolism [5].
Atherosclerosis is the primary underlying pathological process in coronary and cerebral arterial diseases; it is considered as a chronic inflammation that causes large and medium arterial thromboses [26]. The innate and adaptive immune mechanisms are both involved in the prothrombotic progression of atherosclerotic change. When acute ischemic stroke occurs during arterial occlusion, the inflammatory response following the release of danger signals from damaged brain tissue leads to an activation of immune system. Innate immunity, including neutrophils, monocytes, macrophages, platelet, and dendritic cells, is rapidly activated with the production of various cytokines. This is followed by activation of the adaptive immunity, namely lymphocytes, which exerts an immunosuppressive effect that promotes intercurrent infections (i.e., stroke-induced immunodepression) [7]. These immunological changes may last for weeks and may increase the risk of respiratory or urinary tract infections, particular among patients with severe stroke, thus affecting clinical outcomes [27]. Neutrophils, which are secretory and phagocytic cells, migrate to the intraparenchymal perivascular areas within several hours after cerebral ischemia and participate in the early destruction of the blood–brain barrier [28]. Higher NC indicates a larger area of ischemia and more severe brain damage. Lymphocytes, which mainly comprise humoral immune response B cells and cellular immunity T cells, accumulate in the brain 3–6 days after stroke and are considered as having a regulatory function by inducing neuroprotection. Persistent lymphopenia after stroke, caused by the redistribution of lymphocytes to the lymphatic organs and increased catecholamine and cortisol levels, indicates prolonged brain damage with a higher stress response, and this is associated with unfavorable long-term prognosis [29]. In addition to promoting the progression of atherosclerosis, platelets release mediators to boost inflammation after stroke and result in the release of neutrophils and lymphocytes into the vessel wall. For patients with cancer, neutrophils and platelets have also been observed to promote cancer cell proliferation, invasion, immune evasion, and metastasis through multiple mechanisms. Therefore, elevated levels of inflammatory markers are considered to indicate a substantial tumor burden and an ongoing chronic inflammatory process [30].
In the present study we found that all four immuno-inflammatory markers were positively correlated with age, glucose level, creatinine level, NIHSS on admission, LOS in hospital, and mRS at discharge. Patients whose immuno-inflammatory markers were higher than the cutoff values for unfavorable outcomes also exhibited higher rates of uremia, elevated troponin I level, and in-hospital complications. Higher NLR and PLR have been reported in patients with type 2 diabetes mellitus and hyperglycemia, respectively [31, 32]. Although previous studies have suggested that these immuno-inflammatory markers were increased among patients with various cancers, we did not identify any differences among stroke patients with and without a history of cancer, possibly because these cancers were inactive or cured. Cholesterol level had an inverse correlation with age and immuno-inflammatory markers, and it was lower in patients with unfavorable outcomes. This result was similar to that revealed by Fang et al., who identified that high total cholesterol was significantly and independently predictive of lower NIHSS and less severe stroke [13]. Older adults tending to have diets with low lipid content or experiencing malnutrition due to chewing disorders may explain this finding. Higher immuno-inflammatory markers indicated a higher severity of stroke and a less favorable immune status, which resulted in more in-hospital complications, such as pneumonia and urinary tract infections, and prolonged LOS in hospital. The levels of immuno-inflammatory markers varied between the etiologies of stroke according to TOAST classification. Patients with TIA and small-vessel disease had the lowest levels of these markers; this was due to the minor level of stroke severity and the small extent of brain tissue damage from small-artery occlusion. Notably, patients with other determined etiology of stroke, who tended to be younger and have minor degrees of stroke severity relative to those with large-artery atherosclerosis and cardioembolism, exhibited the highest levels of immuno-inflammatory markers. These results differ slightly from those of Gökhan et al., who revealed that NLR was lowest among patients with TIA and highest among those with large-artery occlusion [29]. Other determined etiology in the TOAST classification was classified as rare stroke type in the study by Gökhan et al., and no patient was assigned to the rare stroke subtype. In the present study, 43 patients were assigned to the other determined etiology group. Most of these patients had prominent immunological, hematological, or systemic disorders associated with acute stroke. Therefore, immuno-inflammatory markers were considerably higher in these patients.
Several concomitant comorbidities, clinical features, and laboratory parameters were associated with unfavorable short-term outcomes during univariate analyses. Significant predictors of unfavorable outcomes in the multivariate analyses were NIHSS on admission ≥ 5, age > 75 years, diabetes mellitus, elevated troponin I level, female sex, heart disease, prior stroke, and the four immuno-inflammatory markers (SII > 724, NLR > 3.5, PLR > 143, and NC > 6 × 103/mL). Among these, NIHSS on admission ≥ 5 had the highest OR for unfavorable outcomes (13.4–14.2), followed by age > 75 years (2.5–2.8), and the four immuno-inflammatory markers (1.6–1.8). The predictive performance for unfavorable outcomes was similar when using SII, NLR, and PLR, whereas the performance of NC was slightly weaker. Because the four markers were derived from white blood cell counts with or without platelet counts, which are essential laboratory data during acute stroke and common routine examinations, we can choose one as a reference marker for the prediction of unfavorable outcomes. SII > 724 is the most appropriate marker because this provided the optimal predictive performance of 0.864 when combined with the other seven predictors.
This study had several limitations. First, this was a retrospective study. We did not have sufficient sequential data during hospitalization for a dynamic comparison of immuno-inflammatory markers. A dynamic increase in NLR has been reported to predict 3-month mortality or major disability among patients receiving intravenous thrombolytic treatment [33]. Second, we did not investigate the association between infarct volume and the immuno-inflammatory markers. However, the TOAST classifications may partly reflect the infarct size. Third, because we did not perform a follow-up study after discharge, only short-term outcomes at discharge were available. A prospective study with serial immuno-inflammatory markers and long-term outcomes may provide more prognostic relevance for acute ischemic stroke. Notwithstanding these limitations, the results extend the current understanding of the implications of immuno-inflammatory markers among patients with acute ischemic stroke.