Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with a range of multisystem complications, including acute cerebrovascular diseases. Although COVID-19 primarily affects the respiratory system, previous studies have established its ability to cause endothelial dysfunction, hypercoagulability, and systemic inflammation, all of which are key contributors to thromboembolic events, such as acute ischemic stroke (1). Several large cohort studies have shown that patients with both COVID-19 and ischemic stroke have significantly worse clinical outcomes than do stroke patients without COVID-19. For example, data from the U. S. National Inpatient Sample demonstrated higher in-hospital mortality in acute ischemic stroke patients with COVID-19 (16.9%) than in those without COVID-19 (4.1%) (2). This group exhibited a marked increase in mechanical ventilation usage, with elevated rates of acute venous thromboembolism, acute myocardial infarction, septic shock, cardiac arrest, and acute kidney injury and increased hospital stay durations and average total hospitalization costs (2). Similarly, Yaghi et al. reported that stroke patients with COVID-19 had greater stroke severity and D-dimer levels, increased rates of cryptogenic stroke and mortality, and worse functional outcomes than non-COVID-19 stroke patients did (3). A recent meta-analysis involving 43 studies and over 165,000 patients confirmed these findings, showing that patients with both acute ischemic stroke and COVID-19 had nearly fourfold higher mortality risk and worse functional outcomes than non-COVID-19 acute ischemic stroke patients did (4).

Emerging evidence also suggests that a prior history of stroke increases the risk of death in COVID-19-infected individuals, indicating a bidirectional relationship between cerebrovascular disease and SARS-CoV-2 infection (5). Several reports from the Middle East, such as a young Saudi who developed ischemic stroke following COVID-19 infection without any cerebrovascular risk factors (6), suggest unique regional characteristics that warrant further investigation. Previously, we reported that common comorbidities, such as hypertension, diabetes, and dyslipidemia, were more common in ischemic stroke patients with COVID-19 aged ≥65 years than in those aged <65 years and that pneumonia and dementia significantly predict mortality (7). However, these studies were limited by either a single-center design or cohorts that focused solely on age group differences in ischemic stroke patients with COVID-19, which may have introduced confounding factors due to baseline differences in age, sex, and comorbidities.

To address these limitations, advanced statistical methods, such as propensity score matching (PSM), are essential for balancing baseline characteristics and minimizing bias. PSM mimics the effects of randomization by matching participants on key covariates, allowing for a more accurate estimation of disease impact (8). This methodology has been effectively employed in stroke COVID-19 studies to provide more accurate comparisons between groups. For example, Harrison et al. used a large, matched cohort of ischemic stroke patients with and without COVID-19 and reported a significantly lower survival rate in the COVID-19 group and an adjusted 60-day mortality odds ratio of 2.51 (95% CI: 1.88–3.34) after PSM (9). Similarly, a global multicenter observational study by Ntaios et al. confirmed that ischemic stroke patients with COVID-19 had higher mortality and worse disability outcomes than did matched controls without COVID-19, even after adjusting for demographics and vascular risk factors via PSM (10). However, similar analyses remain scarce in the Saudi and Middle Eastern contexts, where demographic and health system factors may influence outcomes.

Therefore, this study aims to use a PSM design to compare the clinical outcomes and mortality rates between ischemic stroke patients with and without COVID-19 comprehensively. We hypothesized that, after adjusting for baseline comorbidities using propensity score matching, COVID-19 infection would remain independently associated with increased in-hospital mortality and complications in ischemic stroke patients.

This multicenter propensity score–matched study provides the first evidence from Saudi Arabia that COVID-19 significantly worsens in-hospital outcomes among patients with acute ischemic stroke. After controlling for major comorbidities, stroke patients with COVID-19 experienced longer hospitalizations and markedly higher rates of pneumonia, cognitive impairment, and mortality compared to those without COVID-19. These associations remained significant after matching, indicating that COVID-19 has an independent effect on stroke outcomes. Our findings are consistent with earlier reports showing that stroke patients who contract SARS-CoV-2 tend to experience higher rates of complications and mortality (11–14).

In the present analysis, pneumonia occurred far more frequently among stroke patients with COVID-19 than among those without it (54.1% versus 10.6%, respectively) (p < 0.001). This striking difference illustrates the combined impact of respiratory compromise and cerebrovascular injury. The inflammatory and endothelial disturbances triggered by COVID-19, along with weakened immune defenses, likely contribute to the increased risk of respiratory infections in this group (15–17). The strong association between pneumonia and COVID-19 observed in our conditional logistic regression model (OR = 10.88) underscores the need for vigilant monitoring of pulmonary function and for early preventive measures in patients at risk.

Notably, cognitive impairment was also more common among stroke patients with COVID-19, at 11.9%, than among non-COVID-19 patients, at 2.8% (p = 0.001). This pattern suggests that SARS-CoV-2 infection may aggravate poststroke neurological dysfunction. Mechanistically, systemic inflammation, coagulation abnormalities, and potential direct neurotropic effects of the virus may intensify ischemic injury and interfere with neuronal recovery (18–20). These observations align with prior studies that reported an increased occurrence of delirium, encephalopathy, and long-term cognitive decline among stroke patients infected with COVID-19 (21, 22).

In-hospital mortality was also substantially higher in the COVID-19 group, reaching 23.9% compared with 10.1% among noninfected stroke patients (p = 0.001). This finding mirrors international data showing a two- to fourfold increase in mortality rates among stroke patients with concurrent COVID-19 (21, 22). The odds ratio of 2.98 for in-hospital death reflects the profound effect of COVID-19 on clinical outcomes and highlights the urgency of tailoring management approaches to reduce fatality rates. Importantly, these differences persisted even after adjusting for baseline characteristics and comorbidities, implying that the infection itself plays a direct pathogenic role. Supporting studies have also linked the severity of COVID-19 and prolonged hospitalization with inflammatory and biochemical disturbances, such as elevated neutrophil counts and altered renal parameters, that may worsen neurological outcomes (23).

While no significant postmatching differences were detected in deep vein thrombosis, hemorrhagic transformation, or stroke recurrence, prematching comparisons suggested a higher rate of DVT in the COVID-19 group, which was consistent with the hypercoagulable state induced by the infection (24). The application of propensity score matching in our analysis was therefore essential to minimize confounding factors such as age, comorbidities, and baseline stroke severity and to provide a clearer understanding of how COVID-19 independently influences stroke prognosis.

Collectively, these findings have important clinical implications. Stroke patients who contract COVID-19 should be closely monitored for respiratory complications and cognitive decline, with early interventions aimed at reducing these risks. Clinicians should also consider enhanced supportive and multidisciplinary care strategies to improve survival and neurological recovery. Finally, our results reinforce the importance of preventive measures, including vaccination and infection control, among individuals at high risk for cerebrovascular disease, particularly older adults and those with multiple chronic conditions.

This study has several key limitations. First, the retrospective design may introduce selection bias and residual confounding, even when propensity score matching is applied. Second, electronic medical records were obtained from three hospitals and may therefore exhibit variability in documentation practices, stroke management guidelines, and COVID-19 testing protocols. Third, the study accounted for only in-hospital outcomes and did not assess long-term functional recovery, disability, or postdischarge mortality. Additionally, COVID-19 severity and treatment data (e.g., use of antiviral agents, corticosteroids, or the need for ventilatory support) were not uniformly reported and therefore could not be incorporated into the analysis. The centers employed varying clinical indicators for COVID-19 severity (e.g., based on oxygen requirements or respiratory symptoms), but no uniform scale was used. While precise mild/moderate/severe classification is not possible retrospectively, the hospitalization requirement and high rates of complications (e.g., pneumonia in 54.1%) suggest the COVID-19 stroke group predominantly represented moderate-to-severe cases, which may limit direct comparisons with series including milder infections. Vaccination status was not addressed. The stroke subtype classification (using the TOAST criteria) was not available. We lacked imaging-based severity or perfusion data to explore differences in stroke mechanisms. While a larger cohort would enhance the robustness of our observations, the present study captured all consecutive eligible patients across three hospitals during the specified period, representing the totality of available cases in our setting at that time. The findings should thus be interpreted in the context of this real-world consecutive sample. Finally, cognitive impairment was determined by clinical reports rather than by standardized neuropsychological testing, which may limit its reliability. This assessment occurred in the acute stroke setting, where confounding factors such as pneumonia and other infections, medication side effects, altered sleep cycles, and delirium could contribute to transient cognitive changes, potentially reducing the accuracy and specificity of the diagnosis. Future research should investigate the long-term neurocognitive effects of COVID-19 in stroke patients, incorporate biomarker profiling, and examine whether vaccination or antiviral therapy affects outcomes.

This multicenter propensity score–matched study demonstrated that COVID-19 independently worsens in-hospital outcomes among patients with acute ischemic stroke in Saudi Arabia. Even after controlling for major confounders, COVID-19 was significantly associated with increased risks of pneumonia, cognitive impairment, prolonged hospitalization, and in-hospital mortality. These findings underscore the compounding effect of SARS-CoV-2 infection on cerebrovascular disease, highlighting the importance of early respiratory management, cognitive monitoring, and comprehensive multidisciplinary care in this high-risk population. Future multicenter, longitudinal studies integrating stroke subtype analysis, biomarker profiling, and vaccination data are warranted to elucidate the biological mechanisms underlying these poor outcomes and to guide the development of preventive and therapeutic strategies tailored for stroke patients in infectious disease settings.