Le Infezioni in Medicina, n. 2, 140-150, 2023

doi: 10.53854/liim-3102-2

REVIEWS

Cerebrovascular disease in COVID-19: a systematic review and meta-analysis

Ritesh G. Menezes1, Tamim Omar Alabduladhem2, Ahmed Kamal Siddiqi3, Muhammad Talha Maniya3, Abdulaziz Mazen Al Dahlawi4, Mohammed Waleed Abdulaziz Almulhim4, Hadeel Waleed Almulhim4, Yasmeen Abdulwahab Ali Saeed5, Moath Saad Alotaibi4, Sarah Saud Alarifi4, Abdulrahman Mohammed Alkathiry4, Talal Almas6

1Department of Pathology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia;

2College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia;

3Department of Medicine, Ziauddin University, Karachi, Pakistan;

4College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia;

5College of Medicine, King Khalid University, Abha, Saudi Arabia;

6RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland

Article received 20 January 2023, accepted 23 April 2023

Corresponding author

Muhammad Talha Maniya

Email: talhamaniya@hotmail.com

SummaRY

Background: The association between COVID-19 and acute cerebrovascular disease (CVD) has not been explored extensively. New data has come to light which may change previous results.

Methods: We queried the PubMed electronic database from its inception until February 2022 for studies evaluating the incidence of stroke in COVID-19 patients. Results of the analysis were pooled using a random-effects model and presented as odds ratios (ORs) with 95% confidence intervals (95% CIs).

Results: 37 studies consisting of 294,249 patients were included in our analysis. Pooled results show that the incidence of acute CVD events in COVID-19 positive patients is 2.6% (95% CI: 2.0-3.3; P<0.001). Cardioembolic (OR=14.15, 95% CI: 11.01 to 18.19, P<0.00001) and cryptogenic (OR=2.87, 95% CI: 1.91 to 4.32, P<0.00001) etiologies were associated with COVID-19 positivity. Risk factors for CVD events in patients with COVID-19 were atrial fibrillation (OR=2.60, 95% CI: 1.15 to 5.87, P=0.02), coronary artery disease (OR=2.24, 95% CI: 1.38 to 3.61, P=0.0010), diabetes (OR=2.46, 95% CI: 1.36 to 4.44, P=0.003) and hypertension (OR=3.65, 95% CI: 1.69 to 7.90, P=0.005).

Conclusion: COVID-19 infection is associated with an increased risk for acute CVD and is associated with cardioembolic and cryptogenic etiologies and the risk factors of atrial fibrillation, coronary artery disease, diabetes and hypertension in COVID-19 positive patients.

Keywords: Stroke, COVID-19, SARS-CoV-2, acute cerebrovascular disease, CVD.

INTRODUCTION

COVID-19, also known as SARS-CoV-2, is a single-stranded positive-sense RNA virus that was discovered in the Chinese province of Wuhan. It has since spread throughout the world to pandemic levels due to its extremely high infection rate, incubation period, and proclivity for recombination and rapid mutation [1-4].

While the SARS coronavirus (CoV) primarily affects the respiratory system, it is also known to increase the risk of cardiovascular disease and has also been shown to increase the risk of acute cerebrovascular disease (CVD). Multiple of studies on the effects of this novel coronavirus infection of the brain have been completed, with Nannoni et al. publishing a meta-analysis in 2021 highlighting the association between Covid-19 incidence and CVD [5, 6]. Given that new data to this end has emerged over time, we felt it was necessary to update this study. This is particularly true considering that a number of recent high-powered studies, including those conducted by Ramos-Araque et al., and Katsoularis et al. found that COVID-19 positivity was not a significant risk factor for CVD incidence, a finding that contradicts Nannoni et al. [6-8]. As a result, we believed that these new studies could significantly alter the previous findings. This is substantial because, in the midst of a global pandemic, it is critical to identify groups at higher risk of infection-related complications and modify treatment and prophylaxis guidelines accordingly.

The purpose of this study is to investigate the incidence of CVD in Covid-19 positive patients, as well as the risk factors and specific aetiology and characteristics of Covid-associated stroke, as well as to compare the likelihood of developing acute CVD events in patients positive and negative for COVID-19 infection.

METHODOLOGY

Data sources and search strategy

This systematic review and meta-analysis was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines [9]. Based on MEDLINE and Embase databases with no language restrictions, an extensive electronic literature search was collected from December 2019 - February 2022 by two researchers (AKS and MTM) independently, for all relevant studies having acute cerebrovascular disease (CVD) incidences in COVID-19 patients. For purpose to making sure that all important publications were included, the snowballing approach was used and hand searches of all reference lists of eligible articles were conducted. Duplications were identified and removed from all retrieved articles using Endnote X7 (Clarivate Analytics, PA). To avoid overlapping, the meta-analysis of the respective outcome only included the latest study from the studies reported by the same author or institution and conducted in the same period with the same outcomes. The search string used was: (((Covid-19) OR (Covid19) OR (2019-nCoV) OR (SARS CoV-2) OR (SARS-CoV-2) OR (SARS-CoV) OR (2019 novel coronavirus)) AND ((Stroke) OR (Acute cerebrovascular disease) OR (cerebral thrombosis) OR (brain infarction) OR (intracranial hemorrhage) OR (ischemic stroke) OR (hemorrhagic stroke))).

Study selection

This meta-analysis is included and merged retrospective cohort studies, case-control studies, and case-series accounting incidence of acute cerebrovascular disease (CVD) events in patients with COVID-19 infection, risk factors of stroke incidence in COVID-19 patients, and stroke etiology in stroke patients with and without COVID-19. Inclusion criteria contained the studies included at least five cases of COVID-19 patients developing acute CVD. All animal studies, case reports, editorials, studies having less than five cases, and studies without full-text available were excluded.

Data Extraction and Quality Assessment

Based on the titles and abstracts, two researchers (AKS and MTM) filtered studies based on titles and abstracts, depending on the inclusion criteria. Studies that met the inclusion criteria were reviewed and analyzed thoroughly. The data was extracted and cross-checked by the two researchers and for each study, the following set of data was extracted: General information (the first author’s last name, publication year, study setting, sample size, participant’s sex and age), study design, outcomes and aims of meta analysis. Lastly, publication bias was assessed by using funnel plots statistically and visually, where it was considered significant if the p-value was less than 0.05. To evaluate the quality of included studies, The Newcastle-Ottawa scale (NOS) was used [10]. Two researchers (AMAD and MWAA) performed the quality assessment for included studies. In cases of disagreement, a third researcher (HWA), was consulted for a final decision.

Statistical Analysis

Review manager, version 5.4 (Nordic Cochrane Center Copenhagen, Denmark) and OpenMetaAnalyst was used for statistical analysis [11]. Frequencies of patients with the Incident of acute CVD among COVID-19 patients were calculated and was presented as a proportion by dividing the patient with acute CVD by the total number of COVID-19 patients. Odds ratio (OR) estimates with 95% confidence intervals (CIs) was used to represent other dichotomous outcomes i.e risk factors for stroke incidence in COVID-19 patients with and without acute CVD and stroke etiologies among COVID-19 patients with stroke and non-COVID-19 patients with stroke. The results were pooled using random effects model [12]. Forest plots were created to visually assess the result of pooling. The Higgins Ι2 statistic was analyzed to assess heterogeneity and a value of less than 50% was acceptable. A visual inspection of Funnel Plot was conducted to evaluate potential publication bias. A p-value of less than 0.05 was considered significant in all cases.

RESULTS

Study selection, trial characteristics and quality assessment

Initial search of PubMed/Medline database yielded a total of 5,877 unique hits. The first round of screening using title and abstract resulted in the identification of 74 relevant studies. After the duplicates were removed, further assessment of the full-text lead to the inclusion of 37 unique relevant studies in our meta-analysis [13-49]. Studies with at least five patients reporting the incidence of acute CVD in COVID-19 patients with relevant outcomes were included in our analysis. The PRISMA flowchart summarizing the study selection process is provided in Figure 1. The total number of patients included in our analysis were 294,249. The studies comprised of case-series, case-control and retrospective cohort studies. The baseline study characteristics are summarized in Table 1. The results of quality assessment are provided in Supplementary Table S1. All studies were of reasonably high methodological quality. Symmetry in the funnel plot (Figure S1) suggests no small study or publication bias.

Figure 1 - PRISMA flowchart summarizing results of the literature search.

Table 1 - Baseline characteristics of the included studies.

Table S1 - Quality assessment of the observational studies included in the meta-analysis based on the Newcastle-Ottawa scale.

Figure S1 - Funnel plot.

Results of meta-analysis

Detailed forest plots showing results of this meta-analysis are provided in the online supplementary data (supporting information Figure S2 - S12; online supplementary data).

Figure S2 - Forest plot of single-arm analysis of CVD incidence in COVID-19 patients.

Figure S3 - Forest plot of dual-arm analysis of CVD incidence.

Figure S4 - Diabetes.

Figure S5 - Hypertension.

Figure S6 - Coronary artery disease.

Figure S7 - Atrial fibrillation.

Figure S8 - Female sex.

Figure S9 - Kidney injury (acute/chronic).

Figure S10 - Chronic obstructive pulmonary disease (COPD).

Figure S11 - Smoking.

Figure S12 - Forest plot of stroke etiologies among stroke patients with and without COVID-19.

Incidence of acute CVD in COVID-19 patients (single arm analysis): Out of the 37 selected studies, all the studies reported incidence of acute CVD in COVID-19 patients (total, 294,249; events, 1963). Our pooled analysis demonstrates that the incidence of acute CVD in COVID-19 patients is 2.6% (95% CI: 2.0-3.3; P<0.001; Figure 2).

Figure 2 - Forest plot of single-arm analysis of CVD incidence in COVID-19 patients.

Incidence of acute CVD in COVID-19 patients (double arm analysis): 3 selected studies reported incidence of acute CVD in COVID-19 patients (total cases, 166,493; events, 280) with a dual-arm analysis (total controls, 1,749,344; events, 6,772). Our pooled analysis demonstrates that the incidence of acute CVD in COVID-19 vs non-COVID-19 patients is 1.16 (95% CI: 0.43-3.14; P=0.77; Figure 3).

Figure 3 - Forest plot of dual-arm analysis of CVD incidence.

Risk factors for stroke incidence in COVID-19 patients: seven studies were available to compare clinical characteristics of COVID-19 patients with CVD (n= 456) and without CVD (n= 22076), (Figure 4).

Figure 4 - Summary plot of risk factors for stroke incidence in COVID-19 patients.

Diabetes: Out of the 7 studies, all the studies reported for diabetes in COVID-19 patients with CVD (total, 309; events, 135) and without CVD (total, 21782; events, 4474). Our pooled analysis demonstrates that COVID-19 patients with CVD were significantly associated with greater likelihood of having diabetes than COVID-19 patients without CVD (OR=2.46, 95% CI: 1.36 to 4.44, P=0.003; Figure S4).

Hypertension: Out of the 7 studies, all the studies reported for hypertension in COVID-19 patients with CVD (total, 309; events, 214) and without CVD (total, 21782; events, 7214). Our pooled analysis demonstrates that COVID-19 patients with CVD were significantly associated with greater likelihood of having hypertension than COVID-19 patients without CVD (OR = 3.65, 95% CI: 1.69 to 7.90, P=0.005; Figure S5).

Coronary artery disease: Out of the 7 studies, 5 studies reported for coronary artery disease in COVID-19 patients with CVD (total, 234; events, 48) and without CVD (total, 12280; events, 1340). Our pooled analysis demonstrates that COVID-19 patients with CVD were significantly associated with greater likelihood of having coronary artery disease than COVID-19 patients without CVD (OR=2.24, 95% CI: 1.38 to 3.61, P=0.0010; Figure S6).

Atrial fibrillation: Out of the 7 studies, 5 studies reported atrial fibrillation in COVID-19 patients with CVD (total, 233; events, 52) and without CVD (total, 12064; events, 1356). Our pooled analysis demonstrates that COVID-19 patients with CVD were significantly associated with greater likelihood of having atrial fibrillation than COVID-19 patients without CVD (OR = 2.60, 95% CI: 1.15 to 5.87, P=0.02; Figure S7).

Female sex: Out of the 7 studies, all the studies reported female sex in COVID-19 patients with CVD (total, 309; events, 157) and without CVD (total, 21782; events, 11686). Our pooled analysis demonstrates no significant relation with regards to sex difference (OR=1.01, 95% CI: 0.80 to 1.27, P=0.93; Figure S8).

Kidney injury (acute/chronic): Out of the 7 studies, 6 studies reported kidney injury in COVID-19 patients with CVD (total, 297; events, 76) and without CVD (total, 21358; events, 3811). Our pooled analysis demonstrates no significant relation with kidney injury and the risk of stroke in COVID-19 patients (OR=1.48, 95% CI: 0.70 to 3.15, P=0.35; Figure S9).

Chronic obstructive pulmonary disease (COPD): Out of the 7 studies, 4 studies reported COPD in COVID-19 patients with CVD (total, 188; events, 12) and without CVD (total, 13672; events, 1905). Our pooled analysis demonstrates no significant relation with COPD and the risk of stroke in COVID-19 patients (OR=0.71, 95% CI: 0.31 to 1.67, P=0.40; Figure S10).

Smoking: Out of the 7 studies, 3 studies reported smoking in COVID-19 patients with CVD (total, 174; events, 34) and without CVD (total, 16980; events, 1210). Our pooled analysis demonstrates no significant relation with smoking and the risk of stroke in COVID-19 patients (OR=2.14, 95% CI: 0.63 to 7.26, P=0.28; Figure S11).

Stroke etiologies among stroke patients with and without COVID-19

Total stroke patients with COVID-19 were (n=1294), and total stroke patients without COVID-19 (n=17393), (Figure 5).

Figure 5 - Forest plot of stroke etiologies among stroke patients with and without COVID-19.

Atherosclerosis: Atherosclerosis in stroke patients with COVID-19 was (total, 186; events, 20) and in stroke patients without COVID-19 (total, 525; events, 96). Our pooled analysis demonstrates significantly higher odds of atherosclerotic events in stroke patients without COVID-19 (OR=0.54, 95% CI: 0.32 to 0.90, P=0.02).

Cardioembolic: Cardioembolism in stroke patients with COVID-19 was (total, 346; events, 103) and in stroke patients without COVID-19 (total, 13788; events, 401). Our pooled analysis demonstrates significantly higher odds of cardioembolic events in stroke patients with COVID-19 (OR=14.15, 95% CI: 11.01 to 18.19, P<0.00001).

Cryptogenic: Cryptogenic type in stroke patients with COVID-19 was (total, 146; events, 69) and in stroke patients without COVID-19 (total, 349; events, 83). Our pooled analysis demonstrates significantly higher odds of cryptogenic events in stroke patients with COVID-19 (OR=2.87, 95% CI: 1.91 to 4.32, P<0.00001).

Large vessel disease: Large vessel disease in stroke patients with COVID-19 was (total, 215; events, 47) and in stroke patients without COVID-19 (total, 1103; events, 211). Our pooled analysis demonstrates that the incidence of large vessel disease in stroke patients with and without COVID-19 was non-significant (OR=1.18, 95% CI: 0.83 to 1.69, P=0.36).

Small vessel disease: Small vessel disease in stroke patients with COVID-19 was (total, 401; events, 36) and in stroke patients without COVID-19 (total, 1628; events, 344). Our pooled analysis demonstrates significantly higher odds of small vessel disease events in stroke patients without COVID-19 (OR=0.37, 95% CI: 0.26 to 0.53, P<0.00001).

DISCUSSION

In this study, we analyze 37 studies which included 230,031 patients, and our results showed that there is a significant association between acute cerebrovascular disease (CVD) and Covid-19. We found that Covid-19 positive patients are at higher risk to develop CVD than negative patients. The incidence is 2.7% (95% CI: 2.1-3.5, P<0.001). The etiologies were associated with CVD in COVID-19 positive patients are cardioembolic and cryptogenic. While other etiologies such as atherosclerosis and small or large vessel diseases were not associated with COVID-19 positivity. The common risk factors found in COVID-19 positive patients that increase the likelihood of CVD were atrial fibrillation, coronary artery disease, diabetes, and hypertension. Although there is a relation between COVID-19 and CVD, it might be only a correlation not a causation. This is because that the studies, which were included, evaluate the outcomes that are only found in hospitalized COVID-19 patients, without including other milder cases or even asymptomatic patients outside the hospital.

As our novel finding indicates that COVID-19 positivity is significantly associated with CVD, there might be a biological plausibility of Coronavirus itself being an independent risk factor. Due to the fact that atherosclerosis and small vessel disease were not found as etiologies in COVID-19 patients with CVD, Coronavirus may have an underlying pathophysiology. The hypercoagulable state in the disease manifestation, which is presented as high levels of D-dimer, fibrinogen, factor VIII (FVIII), von Willebrand factor (vWF), and decreased antithrombin as well as low TEG test results [50-54]. Also, COVID-19 positive patients, as one study demonstrated, lack a clot lysis [55], with another study found that patients with Covid-associated pneumonia had higher levels of platelets than seen in cases of severe pneumonia [56]. Although the underlying pathophysiology is poorly understood currently, the results of Covid infection being a risk of thromboembolic events are consistent with our finding, that is, COVID-19 positive patients have higher risk for cardioembolic and cryptogenic stroke, with lower risk of developing CVD as a result of atherosclerosis and both large and small vessel disease.

One important finding in our study is the incidence of CVD that was higher than what was expected. The global pandemic is affecting millions and the difference may be limited to only 1-2% but at the same time the implications of the potential stroke complications alone would be assessed in the tens of thousands, internationally. Our findings also refined those who were previously infected with COVID-19 – associated CVD to evaluate other risk factors and to focus on individuals who are more prone to have complications. Our findings aimed to find Covid 19 as an independent risk factor for stoke in our analysis. Nannoni et al. [6] have worked previously on this concept although due to other risk factors and comorbidities, this might have been a product of confounding bias. Due to this, there are conflicts related to COVID-19 being causally associated with stroke.

Consequently, a greater attention should be shifted toward positively infected COVID-19 patients due to the fact of being at a high risk of developing CVD, specifically in healthcare sittings. In addition to the importance of observing any new development of neurological clinical features that should be immediately evaluated to prevent CVD events or further complications.

COVID-19 should be considered in patient who presents with acute CVD events until Covid 19- is being excluded from diagnosis. Till then all measures of precautions should be taken into consideration to reduce COVID-19 spread and the impact of CVD.

In our study, one main limitation was the high grade of results heterogeneity in most analysis. This is due to the use of different study designs between the studies in our analysis. The increase of heterogeneity is resulted from the variation of Sample sizes, study protocols and specific choice of controls, historical or current. In addition, since COVID-19 pandemic is still a recent phenomenon these findings may still be considered preliminary. The pathophysiology and effect of COVID-19 on the brain is still needing further study because the current knowledge regarding this topic isn’t enough to estimate an underlying causational basis for our results. We encourage conducting Future studies that comprehend the underlying mechanisms that makes COVID-19 infection associated with a high risk of developing CVD. More data is needed to know if our findings were correlational or whether it is a result of a causative relationship and to have more precise effect sizes for both the incidence of CVD in Covid patients and the resulted CVD risk from COVID-19 positivity.

CONCLUSION

COVID-19 infection is independently associated with high risk of developing stroke and presents with a higher incidence than demonstrated previously. Stroke is associated with cardioembolic and cryptogenic aetiologies and the risk factors of atrial fibrillation, coronary artery disease, diabetes, and hypertension in COVID-19 positive patients.

Funding

None

Conflicts of interest

None

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