Prolonged increased neutrophil-to-lymphocyte ratio is associated with mortality after successful revascularization for treatment of acute ischemic stroke

Endovascular treatment (EVT) has become the gold standard for the treatment of large vessel occlusion in patients with acute ischemic stroke [1]; however, patients undergoing this therapy are still at high risk of a poor prognosis, including mortality as high as 15.3% [2]. The inflammatory mechanism of stroke has been widely researched [3]. A systemic inflammatory response is rapidly induced shortly after ischemia reperfusion injury, and neutrophils in the blood enter ischemic or infarcted tissue through the injured blood-brain barrier and transmit inflammatory factors [4, 5]. Through a variety of mechanisms, inflammatory mediators such as oxygen free radicals and matrix metalloproteinase-9 cause damage to brain cells [6‐8]. However, the increased concentration of neutrophils in the peripheral blood is accompanied by a continuous decrease in lymphocytes because of the engagement of T cells and platelets through P-selectin [9]. The activated platelets can prevent bleeding transformation and play a role in hemostasis [10].

Previous studies have shown that the neutrophil-to-lymphocyte ratio (NLR) in the early poststroke period may reflect the state of inflammation and which plays an important role in ischemia-reperfusion injury [11‐15], thus NLR is served as an inexpensive and reliable biological indicator [16‐19]. However, the correlation between NLR and death after ischemia reperfusion is still controversial [20, 21], and the relationship between dynamic NLR during hospitalization and death in stroke patients with successful revascularization is still unclear.

To address these uncertainties, we collected data on stroke patients undergone successful revascularization for anterior circulation large vessel occlusion stroke, and sought to assess the potential relationship between dynamic NLR during hospitalization and mortality at 1 month, in the hope that a proven correlation would help physicians make treatment decisions.

In this study, we assessed dynamic NLR in patients who underwent EVT for ischemic stroke with acute large artery occlusion and found that increased NLR in the early stage within 3 days after treatment was associated with an increased risk of mortality at 1 month. Within 1 month after EVT, the NLR of survivors had decreased more than that of nonsurvivors, even after adjustments were made for confounders. These results suggest that increased NLR over time are associated with a higher risk of mortality. This study further expands the impact of dynamic NLR on mortality in stroke patients.

Inflammation plays an important role in the process of ischemic stroke initiation, progression, and recovery [30]. In the acute stage of stroke, blood flow stagnation at the distal end of the thrombus may cause the arterial endothelium to release adhesion molecules, cytokines, and chemokines and to recruit white blood cells, mainly neutrophils, by occluding the distal cortical pial collateral vessels [5]. These white blood cells collect in ischemic cerebral vessels. Neutrophils in the blood enter ischemic or infarcted tissue through the damaged blood-brain barrier and transmit inflammatory factors. The local release of oxygen free radicals and matrix metalloproteinase-9 and inflammatory mediators such as cytokines (eg, interleukin-1β, TNF, and interleukin-6) further increases the risk of blood-brain barrier injury and reperfusion injury, malignant edema, and/or hemorrhagic transformation [7, 8]. However, the ability of T lymphocytes to bind platelets through P-selectin may play a key role in preventing hemorrhagic transformation after acute ischemic stroke [9, 10]. In the subacute phase of acute ischemic stroke (> 48 to 72 h), cerebral ischemic tissue may release cytokines and neurotransmitters and activate immune regulation systems such as the hypothalamus-pituitary axis and sympathetic nervous system, which can lead to down-regulation of systemic immune function and stroke-induced immunosuppression) [31, 32]. This in turn leads to a decrease in lymphocytes (especially T cells and natural killer cells), systemic immunosuppression, and an increased risk of infection [30]. Acute ischemic stroke causes distal organ damage and is associated with a high risk of non-neurological complications, including respiratory failure, cardiovascular dysfunction, liver and kidney damage, and altered immune and endocrine function [33]. These complications can affect prognosis and may have serious short-term and long-term adverse consequences. Thus, assessing the state of inflammation in the early poststroke period may provide clinicians with additional information about potential outcomes.

Recent studies have shown that NLR is associated with the prognosis of hemorrhagic stroke and increased cerebral hemorrhage [34‐37]. Inflammation plays an important role in the mechanism of brain injury in hemorrhagic stroke. Therefore, by releasing cytotoxic mediators, increasing capillary permeability, and promoting disruption of the blood-brain barrier, neuro-inflammation plays a pivotal part in hematoma enlargement, brain cell death, brain edema formation and intracranial hypertension [38]. In the early stage of stroke, most of the white blood cells entering the brain come from peripheral blood, with neutrophils being the first hematopoietic cells to be recruited. Hence similar action mechanisms of inflammation in ischemic stroke and hemorrhagic stroke.

Previous studies have demonstrated a relationship between mortality and NLR at admission (OR = 1.19; 95% CI 1.03, 1.36; P = 0.02) [39]. Higher NLR (6.3 (IQR 4.4–10.8) vs 4.9 (IQR 3.1–7.4); P = 0.002) and greater temporal change in NLR (2.4 (IQR 1.1–7.6) vs 1.3 (IQR 0.1–3.7); P = 0.05) within 3 to 7 days after EVT were also associated with mortality at 90 days [40]. In the present study, we found that baseline NLR were not associated with mortality at 1 month (OR = 1.00; 95% CI: 0.86, 1.16; P = 0.971), but NLR obtained within 12 to 24 hours after EVT were associated with mortality at 1 month (OR = 1.18; 95% CI: 1.04, 1.33; P = 0.008). For every unit increase in NLR in the early stage, the risk of mortality increased by approximately 18%. Differences in findings between our study and previous research may be partially explained by differences in the enrolled populations (eg, more serious condition in patients requiring thrombectomy) and the stress reaction associated with undergoing EVT.

Our previous research has shown that increased NLR immediately after EVT is associated with an unfavorable prognosis (modified Rankin Scale score of 3–6) at 3 months for anterior circulation large vessel occlusion stroke (OR = 1.19; 95% CI: 1.07, 1.32; P = 0.002) [41], but in this study we did not find that increased NLR immediately after EVT was associated with death at 1 month(OR = 1.05; 95% CI: 0.94, 1.17; P = 0.422). Additionally, we found that NLR in patients still alive at 1 month decreased by an average of 0.29 daily than in nonsurvivors. To our knowledge, this is the first study to examine the association between persistent dynamic changes in NLR during hospitalization and mortality, thus extending previous research in several ways. First, we demonstrated the trends in dynamic NLR over time during hospitalization after successful revascularization. Second, we compared these trends in survivors and nonsurvivors to assess the association between dynamic NLR and mortality at 1 month after EVT. The NLR might be a biological marker of prognosis in patients undergoing EVT and could also sensitively reflect changes in the severity of a patient’s condition [12, 42]. Additionally, we found that the change in NLR over time was more informative regarding the risk of mortality than any individual NLR. Increased NLR over time should therefore prompt closer scrutiny of a patient’s condition. Because it is easy and inexpensive to obtain routine bloodwork results, performing this testing daily may help to elucidate disease progression and may assist clinicians with formulating more effective treatment measures. NLR-like inflammatory biomarkers, such as the systemic inflammatory response index (SIRI), have been shown to predict the prognosis of stroke patients who receive endovascular treatment and are successful recanalized [43]. However, even with complete or near complete recanalization, a higher admission SIRI increased the risk of a poor outcome at 3 months. Taken together, the advantage of these inflammatory markers is that they are easily available and accessible and cost-effective since they come from widely available laboratory variables that are typically collected in routine medical practices.

Our study had some limitations. First, this study was limited to patients who had experienced an anterior circulation stroke, and so the results cannot be extrapolated to the posterior circulation stroke population. Second, in order to study the mechanism of ischemia reperfusion injury, the enrolled patients had all undergone successful recanalization after thrombectomy; patients in whom revascularization was not successful were not included in the analysis. Third, some repeated measurements of NLR were missing for study patients. However, we used a generalized additive model and a generalized additive mixed model to analyze all collected data, and these models have been found to be useful when some data are missing. Finally, although we adjusted for multiple confounding factors, other potential confounding factors may have been missed in these analyses.

We demonstrated the pathophysiological changes of dynamic NLR on stroke and the persistent effect of inflammation on ischemia-reperfusion injury. Because NLR can be easily obtained repeatedly, these measurements can be used to assess the changes in disease progress over time. These results suggest that physicians should be aware of the potential harm associated with persistently high NLR in patients who have undergone successful revascularization for anterior circulation large vessel occlusion stroke.