Stroke is a clinical syndrome resulting from focal or generalized vascular injury to the brain that persists for more than 24 h or leads to death. The second major cause of mortality and the third highest cause of disability, according to the Global Burden of Disease, Injuries, and Risk Factors Study 2017. From 1990 to 2019, the prevalence, mortality and disability rate of stroke have all increased to some extent (1). Therefore, identifying risk factors for stroke and developing reasonable treatment and prevention guidelines are critical. Many diseases can cause stroke, including infections, such as bacterial, fungal, parasitic and a variety of viruses (2). Inflammation increases the risk of stroke by accelerating atherosclerosis, vasculitis, and vasculopathy (3). Infectious diseases triggered by severe acute respiratory coronavirus-2 (SARS-CoV-2) were identified as coronavirus disease 2019 (COVID-19). As it is highly contagious, the disease spread rapidly worldwide after its emergence, sparking a pandemic (4). COVID-19 affects several systems, leading to systemic inflammation and damage to the respiratory and nervous systems (5). Recently, there has been significant attention on the reported link between COVID-19 and ischemic stroke. There is some evidence that COVID-19 may contribute to ischemic strokes (6–8). In addition, there is still a lack of clear evidence-based medical consensus on the impact of reporting on the prognosis, mortality, and morbidity of ischemic stroke, the relationship between COVID-19 and TOAST typing of ischemic stroke, and the impact of COVID-19 on risk factors for ischemic stroke in patients. This review investigated whether COVID-19 affects the incidence, mortality, and prognosis of ischemic stroke.

Attention is gradually being drawn to the part COVID-19 plays in the incidence of cerebrovascular disease. Current studies suggest that COVID-19 may have some influence on the morbidity, mortality, and prognosis of ischemic stroke (4, 16–19); however, the evidence is not conclusive. In addition, in patients with COVID-19, hypertension, diabetes, dyslipidemia, coronary artery disease, and obesity raise the probability of ischemic stroke (20, 21). In this systematic review, the correlation between the occurrence of ischemic stroke in patients with COVID-19 and AF, chronic kidney disease, COPD, or heart failure was analyzed. Twenty-one studies with quality assurance and credible results were included.

After analyzing 21 studies, compared to those without COVID-19, patients with COVID-19 were at increased likelihood of developing an ischemic stroke. Based on certain research, patients with COVID-19 have a 1–1.5% chance of having an ischemic stroke (5, 14), which is consistent with our results. In addition, we found that the incidence of patients aged≥65 was higher than that of patients aged<65. This may be related to the differences in the burden of comorbidities and clinical management between the two groups. Our study revealed that the in-hospital mortality rate in patients with COVID-19 and ischemic stroke was markedly elevated in comparison to patients with ischemic stroke but without COVID-19 (10, 13, 14, 22–29). In addition, the mortality rate in patients with ischemic stroke at 3 months after the onset of ischemic stroke was significantly higher than that in patients with ischemic stroke but without COVID-19 (11, 29–31), suggesting that there is an elevated risk of in-hospital mortality in patients with ischemic stroke after a 3-month onset period, with the potential for the presence of the COVID-19 to be a contributing factor. These outcomes align with those of previous research studies (20, 32). Patients with COVID-19 experience respiratory distress, multi-organ failure, elevated levels of serum inflammatory markers, and fibrin activation, which increases incidence and mortality rates in those with ischemic stroke (20, 21, 33, 34). Patients with COVID-19 and ischemic stroke are discharged with a poor functional status, suggesting that a major factor in deciding the prognosis of these patients is COVID-19. In contrast, following 3 months of illness, there was little variation in the mRS score between patients with COVID-19 and ischemic stroke and those without COVID-19 but with ischemic stroke. Patients who have both COVID-19 and an ischemic stroke are more likely to have poor outcomes since COVID-19 affects nearly all organ systems (35). In our study, patients with ischemic stroke and COVID-19 stayed 0.13 days longer in the hospital than did patients without COVID-19. This can be attributed to the fact that patients with COVID-19 and ischemic stroke have a poor overall clinical status. In addition, we found that the hospital stays of the group aged < 65 was longer than that of the group aged ≥ 65. This may be related to the differences in clinical decision-making and medical resource allocation between the two groups. Compared to previous studies (36, 37), the length of hospital stay observed in our study was lower. This discrepancy can be ascribed to the varying severity of patients’ conditions when hospitalized. The incidence of large-artery atherosclerosis and small-vessel disease phenotype of ischemic stroke was higher in patients with COVID-19 and ischemic stroke compared to those without COVID-19. However, there was little variation in the incidence of cardioembolic, other determined etiologies and cryptogenic phenotype. Common risk factors for the onset of ischemic stroke in patients with COVID-19 were hypertension, diabetes, smoking, obesity, dyslipidemia, chronic renal disease, coronary artery disease, and COPD, with no significant correlation with age. Although many COVID-19 comorbidities, such as myocardial infarction, heart failure, and chronic kidney disease, may increase the occurrence of ischemic stroke (38–41), the primary risk factors remain those typically associated with ischemic stroke.

The mechanism of action of COVID-19 in ischemic stroke remains unclear. Our study suggests several possible mechanisms. In 20–55% of hospitalized patients with COVID-19, elevated D-dimer levels of more than twice the normal value, a slightly prolonged prothrombin time (1–3 s above normal), and mild thrombocytopenia have been observed (42). These changes can lead to the development of sepsis-induced coagulation disorder, which is a precursor for disseminated intravascular coagulation (43), which in turn can increase the risk of thrombosis and ischemic stroke. In addition, antiphospholipid antibodies are present in severely ill patients with COVID-19 and multiple cerebral infarctions. These antibodies can increase the risk of thrombosis by promoting cellular activation, inhibiting the natural anticoagulant and fibrinolytic systems, and triggering the complement system (44). Lung cells in the alveolar lining express angiotensin-converting enzyme 2 (ACE2) receptors, which SARS-CoV-2 uses to infect the host and inflict lung injury. In addition to the lungs, endothelial cells also have high levels of expression for ACE2 receptors (45), and the infection of these cells can elicit an inflammatory response (46), which is considered one of the precursors for COVID-19-related thrombotic complication. An essential function of ACE2 is to control the renin-angiotensin system (47), and ACE2-induced angiotensin 1–7 production promotes angiogenesis, oxidative stress inhibition, and neuroinflammatory resistance in brain tissues and improves cerebral blood flow (48). Through the induction of receptor endocytosis, SARS-CoV-2 depletes ACE2 (43). This process causes endothelial dysfunction in the heart and brain, which raises sympathetic activity, impairs blood pressure autoregulation, causes vasoconstriction, and ultimately causes ischemia in the affected organs (49). Viral infection causes sustained uncontrolled activation of the immune system with an over-release of cytokines (50), resulting in a cytokine storm that leads to systemic symptoms, systemic inflammation, and multi-organ dysfunction, and, if not properly treated, multi-organ failure and coagulation disorders (51). SARS-CoV-2 directly invades vascular endothelial cells through angiotensin-converting enzyme 2 (ACE2) receptor, triggering the continuous activation of the NF-κB signaling pathway (52, 53), leading to the massive release of pro-inflammatory cytokines such as IL-6 and TNF-α. This “cytokine storm” not only aggravates the inflammatory infiltration in the plaque, promotes the activation of macrophages and the secretion of matrix metalloproteinases (MMP-2/9), but also causes the detachment of endothelial glycocalyx, exposing the procoagulant surface of the vessel wall and accelerating platelet adhesion. Second, virus-induced monocyte activation promotes the overexpression of tissue factor (TF), which initiates the exogenous coagulation pathway. Meanwhile, extracellular traps (NETs) released by neutrophils provide scaffolds for thrombus formation and enhance fibrin deposition (54, 55). Together, these changes lead to large-artery atherosclerosis phenotype of ischemic stroke. After virus invasion of brain microvascular endothelial cells, the activation of MMP-9 mediated by Spike protein leads to the degradation of tight junction proteins and increases the permeability of the blood–brain barrier (56). At the same time, excessive activation of the complement system, especially the C5a-C5aR1 axis, drives platelet microaggregation and fibrin deposition in small vessels (57). In addition, hypoxia-induced up-regulation of HIF-1α further aggravates vasogenic edema and forms a vicious cycle of “inflammation and hypoxia” (58, 59). SARS-CoV-2 induces the small-vessel disease phenotype of ischemic stroke by causing the destruction of the blood–brain barrier and microcirculation disorders through this unique mechanism. The dominant distribution of large-artery atherosclerosis phenotype of ischemic stroke and small-vessel disease phenotype of ischemic stroke in patients with COVID-19 reflects the specific targeting of the virus to the vascular system, as compared with other TOAST subtypes such as cardioembolic phenotype of ischemic stroke. Cardioembolic phenotype of ischemic stroke usually requires structural heart disease, and although COVID-19 can induce atrial fibrillation, its incidence is relatively low (about 6–8%) and most of them are transient (60). In contrast, direct viral damage to the vascular endothelium and systemic inflammatory responses are more prevalent and persistent. Coagulation function tests showed that patients with COVID-19 presented with a special “bipolar” coagulation disorder, which manifested as a hypercoagulable state with significant increases in D-dimer and fibrinogen in the early stage, and could develop into consumption coagulopathy in the later stage. This dynamic change allows the risk of arterial thrombosis in situ to persist, while embolic events are relatively rare (61).

The results of this study can be used to guide clinical practice, particularly with regard to risk stratification and treatment strategies. A more accurate understanding of the impact of early COVID-19 on clinical outcomes in patients with ischemic stroke may provide insights for future prevention and treatment of ischemic stroke associated with the virus pandemic. In the management of COVID-19 patients, intensive ischemic stroke surveillance programmes should be implemented for groups of patients with specific risk factors, who should receive more intensive stroke screening and preventive anticoagulant therapy as appropriate for their condition. This high-risk group mainly includes three categories: first, patients with traditional vascular risk factors including hypertension, diabetes, hyperlipidemia and smoking history; Patients with cardiovascular disease, such as atrial fibrillation, coronary artery disease and chronic kidney disease; Third, patients with respiratory complications, especially chronic obstructive pulmonary disease. For hospitalized patients, daily systemic neurological evaluations are recommended by clinicians. When patients develop new neurological symptoms, head imaging should be initiated immediately. It is worth noting that for patients with severe disease requiring mechanical ventilation or patients with significant elevated inflammatory markers, such as D-dimer and CRP, it is still necessary to be highly vigilant against thromboembolic events even if traditional risk factors are lacking, and it is recommended to include them in the scope of intensive monitoring. In terms of anti-thrombotic treatment strategy, for patients without atrial fibrillation, if there is evidence of hypercoagulation, such as elevated D-dimer, low molecular weight heparin prophylactic anticoagulation can be considered. For patients with atrial fibrillation, it is necessary to ensure the continuity of anticoagulant therapy, prioritize direct oral anticoagulants, and closely monitor coagulation function. It is suggested that clinicians should adjust the prevention and treatment strategies in time according to the individual characteristics of patients and the dynamic monitoring results.

A limitation of our study is the high degree of heterogeneity in the results of most analyses. we conducted subgroup analyses based on age for the incidence of COVID-19 combined with ischemic stroke and hospital length of stay. For the high heterogeneity of in-hospital mortality in COVID-19 patients with ischemic stroke, we conducted subgroup analysis by age and sample size, but the heterogeneity still persisted. This suggests that, in addition to differences in demographic characteristics and study sizes, there may be key confounders that have not been quantified. On the basis of the pathophysiology of COVID-19, we speculate that COVID-19 severity may be a central source of heterogeneity. However, due to the general lack of uniform grading criteria in the included literature, this study could not be quantitatively combined for analysis. In addition, when analyzing risk factors, our study had limitations. First, we verified the effects of age on the effect size of each risk factor through meta-regression analysis, and the results showed that age may not be a significant confounding factor in this study. However, other potentially confounding variables, particularly disease severity for COVID-19, were not included in the analysis due to the lack of uniform standard reporting in the original study and the small sample size. This lack of data may lead to residual confounding bias, as severely ill patients tend to have both a higher underlying disease burden and poorer clinical outcomes. Second, our study found that hypertension, diabetes, hyperlipidemia, smoking, atrial fibrillation, coronary artery disease, and chronic kidney disease were independently associated with adverse COVID-19 outcomes. It should be emphasized, however, that these factors may have complex interactions. Although we attempted to explore this interaction through subgroup analysis, we were limited by the lack of interaction item reporting in the original data and were unable to draw definitive conclusions. Future large-scale collaborative studies are needed to systematically assess the combined effects of combinations of risk factors to guide precise treatment strategies. Only 3 studies reported the association between COVID-19 and mRS ≤ 2 in patients with ischemic stroke at 3 months after the onset of ischemic stroke. Although the observed trend in effect (odds ratio, 0.67; p = 0.086) suggested that COVID-19 infection may reduce the odds of a good functional recovery, the result lacked significance. This may be due to the included sample size N = 403, which may be too small to detect a true effect rather than a true no association. Further studies with larger sample sizes are needed to confirm this finding. In the included literature, only two studies (22, 26) stratified the outcome of ischemic stroke based on the severity of COVID-19 infection. However, these two studies have obvious limitations. First, the sample size was small and the statistical power was insufficient. Second, the criteria and levels of stratification of the severity of COVID-19 infection that were used in the two studies were significantly different. Because of these methodological heterogeneity, we were not able to perform further meta-analysis. This missing data limit the systematic assessment of the potential effect of the severity of COVID-19 infection on the incidence, mortality, and clinical outcomes of ischemic stroke. Of note, despite these limitations, the results of both these studies showed an association between severe COVID-19 infection and worse stroke outcomes. This finding suggests that the severity of COVID-19 infection may be an important factor in the outcome of ischemic stroke, but more studies with uniform standards and large samples are needed to confirm this finding. To analyze the relationship of COVID-19 with the incidence of ischemic stroke, in-hospital mortality in patients with ischemic stroke, incidence of large-artery atherosclerosis phenotype and small-vessel disease phenotype ischemic stroke, the number of articles included was≥10, and a publication bias analysis was conducted. The remaining analyses each had less than 10 articles, which may have led to biased results. Nevertheless, the results yielded by the meta-analysis were consistently positive and representative. This article analyzed the impact of COVID-19 on mortality and adverse outcomes after 3 months of ischemic stroke onset. However, patients with COVID-19 combined with ischemic stroke may be at risk of long-term adverse outcomes, such as recurrent ischemic stroke or bleeding. Further studies are needed to determine the long-term effects of COVID-19 on ischemic stroke patients and the clinical therapeutic interventions for these patients. Language limitation is a limitation of this study, which may introduce language bias and exclude relevant studies from non-English speaking regions. However, our initial search revealed that most of the core scientific results in the field of COVID-19 and ischemic stroke prognosis have been published in English-language journals. Nonetheless, we recognize that some geographically specific findings may have been overlooked because they were published in local journals, and the risk of publication bias for negative results may be amplified. We look forward to more literature on language systems in this area in the future to ensure a more comprehensive study. Additionally, as COVID-19 is a disease that has only emerged recently, findings regarding its effect on ischemic stroke may still be considered preliminary. As the body of literature exploring the relationship between COVID-19 and ischemic stroke continues to expand, there is a necessity for meta-analyses that encompass a wider range of studies and larger sample sizes.

COVID-19 was linked to the incidence, mortality, and prognosis of ischemic stroke. Additionally, COVID-19 correlated with an elevated frequency of large-artery atherosclerosis, small-vessel disease, and cardioembolic phenotype of ischemic stroke. Furthermore, patients with COVID-19 were more susceptible to ischemic stroke due to a history of smoking, hypertension, diabetes, hyperlipidemia, AF, chronic kidney disease, coronary artery disease, and COPD. This will offer new insights and ideas for the treating and preventing of ischemic stroke in the setting of COVID-19.