With almost 6 million deaths and more than 10% of all mortality every year, stroke has become one of the predominant threats to human health (1). There are two types of strokes, one is ischemic stroke, which accounts for 85% of all acute stroke, and the other is hemorrhagic stroke. According to previous reports, about 40% of all stroke deaths are attributable to hemorrhagic stroke (2). Currently, the major treatment for acute ischemic stroke is reperfusion therapy, which includes intravenous tissue plasminogen activator and endovascular therapy (EVT) (3). Exploring the key factors that affect the prognosis of stroke patients is crucial for clinicians to design appropriate treatments to improve the clinical efficacy and prognosis to stroke patients.

As we all know, there are two important pathophysiological mechanisms of stroke including oxidative stress and inflammation. After stroke, the inflammatory response is activated and plays a significant role in secondary brain injury (4). In recent years, the immunity has emerged as a new breakthrough target in the treatment strategy for acute stroke. Meanwhile, it is non-displaceable in predicting a poor prognosis (5). However, it is a complex process that can induce the activation and immunosuppression of a variety of inflammatory cells. Previous studies have found the different roles of neutrophils and lymphocytes in the progression and prognosis after stroke. Neutrophils could re-infiltrate the ischemic site in the first few hours after stroke, and then release chemical mediators related to increased tissue damage and poor neurological prognosis (6). At the same time, stroke could trigger a special immunosuppressive state (4), such as the activation of neutrophils, which leads to a decrease in lymphocytes (7), and certain types of lymphocytes are considered to be important brain protective immune regulators; the decrease of these lymphocytes may lead to deterioration of nerve function (8). Recently, the neutrophil-to-lymphocyte ratio (NLR) has become a powerful predictor of death in patients with cardiovascular disease or peripheral arterial occlusive disease. Previous studies reported a correlation between stroke severity and NLR determined at admission. Several studies suggested that the initial NLR was associated with mortality and infarct size in ischemic stroke patients.

However, the value of NLR in predicting the poor prognosis of stroke patients is still controversial. Some studies showed that NLR had no obvious effect on mortality (9, 10), while some studies demonstrated that a high NLR was an independent predictor of poor clinical outcomes in patients with stroke (11, 12). Thus, the aim of this study was to perform a meta-analysis to clear the relationship between NLR and the prognosis in patients with stroke.

Stroke is one of the important diseases that seriously threaten human health, which has high mortality and morbidity (50). Despite its high incidence, there are few effective treatments to improve the quality of life of patients. Therefore, it is of great clinical significance to find simple and accurate serum biomarkers to assess the degree of early neurological damage and prognosis of stroke patients. The purpose of this meta-analysis was to evaluate the prognostic of NLR in patients with stroke. Inflammation is considered to be the secondary damage mechanism of stroke. We carried out the meta-analysis including 41 articles based on criterion with 27,124 individuals, and the result revealed that NLR was independently associated with prognosis in patients with stroke.

In recent years, inflammation has shown to have a strong relationship with the occurrence of stroke (51). Post-stroke inflammation has a harmful effect on brain injury, but it may play a protective role in tissue restoration and regeneration, and its role changes over time (52). As the marker of systemic inflammation, white blood cell counts were significantly increased after stroke (53) and related to the poor prognosis of stroke patients (54, 55). As we all know, different subtypes of WBC may have different effects on the inflammatory response of damaged tissues. Neutrophils are the major subtype of white blood cells that can respond earlier after stroke and show an active inflammatory response (52). Neutrophils first accumulate in the cerebral blood vessels within a few hours, which may cause the expansion of the infarction and block the microvessels (56). On the other hand, neutrophils increase the expression of matrix metalloprotein 9, which directly destroys the blood–brain barrier, causing secondary brain injury or hemorrhagic transformation (57, 58). Previous studies have confirmed that early leukocytosis and neutrophilia are related to the infarct volume assessed by DWI in the early stage of ischemic stroke (59). Neutrophils are recruited to the ischemic area of brain tissue and may release some proteolytic enzymes or free oxygen free radicals and other inflammatory mediators into the damaged area (5). It has recently been reported that when patients with acute cerebral infarction are admitted to the hospital, a higher total number of white blood cells and neutrophil counts are associated with the severity of stroke (60). Similar with cerebral infarction, some studies showed that elevated neutrophil level was related to hematoma volume and outcomes in ICH patients. Moreover, studies revealed that in a rat autologous blood model, neutrophils penetrated in and around the hematoma, which reached a peak at 2–3 days (61). Activated neutrophils can release a variety of proteolytic enzymes and pro-inflammatory proteases, which can damage the brain tissue directly.

Subpopulations of lymphocytes, especially T lymphocytes, may have regulatory functions in inflammation-induced neuroprotection (62). Lymphocytes in ischemic brain tissue rise later than neutrophils. Lymphocytes have been found to play an important role in healing or repairing inflammation (63). However, the role of lymphocytes in the pathogenesis of stroke remains controversial. It has been reported that other subtypes of T cells (pro-inflammatory lymphocytes) are the main source of cytotoxic substances and have a negative effect on ischemic brain tissue (64). Then, there is also experimental evidence that certain subtypes of lymphocytes (mainly regulatory T cells and B cells) have regulatory functions, and these cells are responsible for the reduction of ischemic tissue volume in ischemic stroke and the improvement of function after neurological deficit (65). Early studies indicated that a higher level of lymphocytes could upregulate the anti-inflammatory cytokine interleukin (IL)-10 and suppress inflammatory cytokines including tumor necrosis factor (TNF)-α and IL-6, which can play an anti-inflammatory effect (66). In addition, clinical evidence shows that lower lymphocyte count is associated with poor early neurological function improvement and poor long-term functional prognosis (67).

NLR stands for an easily available, non-invasive, and inexpensive marker that can be routinely used to evaluate systemic inflammation in clinical work. The mechanism behind the clinical significance of NLR in stroke is that inflammation plays a central role in all types of stroke, from the occurrence and development of injury to recovery (68). The underlying mechanism of elevated NLR and poor prognosis may be related to excessive activation of inflammation and immunosuppression (69). First, after an ischemic stroke, the damaged brain tissue will produce a strong inflammatory response and, consequently, produce inflammatory biomarkers (69). Although inflammation is necessary for early repair after stroke, excessive activation of inflammation can cause damage to the brain tissue, leading to deterioration of neurological function and brain edema (70, 71). Second, the theories about immunosuppression suggest that after a stroke, catecholamines are released into the blood through over-activated sympathetic nerves, which may reduce circulating lymphocyte level and increase the risk of infection (71). Recently, NLR has been proposed as an independent predictor of severity and mortality to predict coronary syndrome (72).

Application prognostic biomarkers may enhance risk stratification, help design individual treatment, and determine follow-up schedules. In the stage of customized treatment strategy, NLR may be a key sticking point in the risk stratification of acute stroke patients. Moreover, neurologists can develop more frequent and stricter follow-up strategies for patients who may have a poor prognosis. In short, in the different stages of diagnosis, treatment, and follow-up, the application of these preoperative lymphocyte-related systemic inflammation biomarkers may improve the accuracy of current prognostic models and help make clinical decisions.

This meta-analysis adopted strict inclusion and exclusion criteria, and covered 41 medium-to-high-quality studies, including retrospective studies and prospective studies, and successively explored the relationship between NLR and the prognosis of ischemic stroke and hemorrhagic stroke. Our meta-analysis found that high NLR has a predictive effect on the prognosis in stroke patients, mainly in terms of mortality, poor prognosis, and hemorrhagic transformation. Meanwhile, NLR has a stronger predictive effect on ischemic stroke than hemorrhagic stroke. Many studies also support that NLR is an independent risk factor for predicting short-term outcomes in both ischemic and hemorrhagic stroke. Zhang et al. (11) reported that NLR was the best independent predictor associated with mortality and poor outcome in AIS patients. Ying et al. (14) suggested that NLR could predict the HT and outcome in AIS patients with r-tPA treatment. Switonska et al. (15) indicated that NLR is an inexpensive tool that could identify the increased risk of early symptomatic hemorrhage after recanalization in AIS. Giede-Jeppe et al. (38) proved that in aSAH patients, NLR represents an independent parameter associated with unfavorable functional outcome. For NLR and AIS, the results of meta-analysis show that NLR has a significant correlation with the two. In the AHS patients, although the meta-analysis results suggest that patients with higher NLR have a poorer prognosis, the heterogeneity between the studies is high, and no single article that can significantly reduce the heterogeneity was found in the sensitivity analysis. In the subsequent subgroup analysis, the source of heterogeneity was deeply explored, and the stability of the results was further proved. Furthermore, we found that a high NLR is more closely related to the prognosis of AIS patients after endovascular treatment. Therefore, as a potential prognostic biomarker, NLR will help to more accurately determine the prognosis of stroke patients.

There are also some limitations in this study: First, the inflammatory process is relatively complex. We use a relatively simple ratio of neutrophils to lymphocytes to show the effect of inflammation on the prognosis of patients with stroke. It only reflects the general trend, not the full picture of the inflammatory process. Second, the results of some subgroup analysis suggest that there is a high degree of heterogeneity among the studies, and there may be potential selection bias or other confounding factors. Third, the ORs obtained by this meta-analysis are small; this requires clinicians to use it with caution and explain carefully. It is necessary to combine the patient's own situation to predict the prognosis of acute stroke patients. Moreover, there were few studies with negative results in this meta-analysis, which might lead to potential publication bias. Besides, only two subarachnoid hemorrhage cases were included in this meta-analysis that might result in an inaccuracy of the results. We look forward to more researches to deeply discuss this relationship. Finally, the optimal cutoff values of NLR remain undetermined. In this study, the NLR cutoff values of each article are different, and different NLR cutoff values may cause higher heterogeneity, which may interfere with the accuracy of our analysis results. Therefore, the establishment of a standard NLR cutoff value will promote in-depth research on its prognostic value.

In summary, our research refers that a high NLR value is closely related to the prognosis of stroke patients. High NLR is associated with a 1.1- to 1.3-fold increased risk of poor outcomes of AIS/AHS patients. Elevated NLR can predict the mortality, poor prognosis, and the occurrence of spontaneous cerebral hemorrhage in stroke patients, and our subgroup analysis suggests that a high NLR is more closely related to the prognosis of AIS patients after endovascular treatment. This low-cost and easy-to-obtain biomarker will play a greater and more profound role in clinical work in the future. Future studies need to combine with TOAST classification, OCSB classification, and other indicators in order to better predict the prognosis of stroke patients.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

WL and MH conceived the presented idea and designed the research. ZD and XL searched databases and performed data analysis and statistical analysis. WL, MH, YS, and XL were responsible for writing the manuscript. All authors critically revised the article for important intellectual content and approved the final manuscript.

This work was supported by the Key Research and Development Program, Science and Technology Department of Shanxi Province (grant number 201703D421018), Selected Program for Science and Technology Activities of Overseas Students, Science and Technology Department of Shanxi Province (grant number 2018-1059-13), Scientific Research Program for Returned Overseas Students, Science and Technology Department of Shanxi Province (grant number HGKY2019096), and Talent introduces research launches of Shanxi Bethune Hospital (grant number 2020RC007).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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