key: cord-0966329-mivoa67y
authors: Mbonde, Amir A.; O’Carroll, Cumara B.; Grill, Marie F.; Zhang, Nan; Butterfield, Richard; Demaerschalk, Bart M.
title: Stroke Features, Risk Factors and Pathophysiology in SARS-CoV-2 infected Patients
date: 2022-01-21
journal: Mayo Clin Proc Innov Qual Outcomes
DOI: 10.1016/j.mayocpiqo.2022.01.003
sha: 431185c7b2e633ec304fa13a03ab7d01de9fc6c6
doc_id: 966329
cord_uid: mivoa67y

Objectives To provide a comprehensive description of stroke characteristics, risk factors, laboratory parameters and treatment in a series of SARS-CoV-2 infected patients admitted to Mayo Clinic hospitals in Rochester MN, Jacksonville FL, Phoenix AZ, and the Mayo Clinic Health System. Patients and methods We retrospectively identified hospitalized patients in whom stroke and SARS-CoV-2 infection were diagnosed within the same 3-month interval between the period of September 2019 and December 2020, and extracted data on all available variables of interest. We further incorporated our findings into the existing body of basic science research to present a schematic model illustrating the proposed pathogenesis of ischemic stroke in SARS-CoV-2 infected patients. Results We identified 30 cases during the study period yielding a 0.5% stroke rate across 6381 SARS-CoV-2 infected hospitalized patients. Strokes were ischemic in 26/30 cases and hemorrhagic in 4/30. Traditional risk factors were common including hypertension (24/30), hyperlipidemia (18/30), smoking history (13/30), diabetes (11/30) and atrial fibrillation (8/30). The most common ischemic stroke mechanisms were cardioembolism (9/26) and cryptogenic (9/26). Intravenous alteplase and mechanical thrombectomy were administered in 2/26 and 1/26 respectively. Serum C-reactive protein median (IQR) 66 (21-210) mg/dl, interleukin-6 116 (8-400) pg/ml, D-dimer 1267 (556-4510) ng/ml , fibrinogen 711 (263-772) mg/dl and ferritin 407 (170-757) were elevated in those with available results. Conclusion The high prevalence of vascular risk factors and concurrent elevation of pro-inflammatory and pro-coagulation biomarkers suggests that there is an interplay between both factors in the pathogenesis of stroke in SARS-CoV-2 infected patients.

In March 2020, the World Health Organization declared the Coronavirus disease 2019 (COVID-19) a global pandemic, and since then millions of cases and fatalities have been reported globally. 1 primarily affects the respiratory system. Individuals can present with dry cough, fever, dyspnea, hypoxia, acute respiratory distress syndrome, and respiratory failure. 1, 3 Neurologic involvement has been reported in 30-50% of all individuals with SARS-CoV-2 infection 4, 5, 6 and nearly half of these cases are attributable to stroke. 5, 7 SARS CoV-2 viral infection has been shown to significantly increase one's risk of stroke and this is thought to result from a dysregulated host immune response to the virus, thus triggering endothelial cell dysfunction, platelet activation, activation of the coagulation cascade and a perturbation of the renin angiotensin aldosterone system (RAAS) 9 (figure 1). Data on the role of traditional vascular risk factors such as hypertension, hyperlipidemia and diabetes on stroke pathogenesis have been mixed, with some studies demonstrating an association 10,11 and others not. 12, 13 Furthermore, the temporal relationship between SARS-CoV-2 infection and stroke is unclear. Most case series have described the acute stroke characteristics in those with simultaneous J o u r n a l P r e -p r o o f SARS-CoV-2 infection even though the dysregulated immune response in COVID-19 is likely to persist for several months, thus leading to various post-infectious neurologic manifestations including the COVID-19 long hauler syndrome. 6, 14 In this work, we aimed to provide a comprehensive description of vascular risk factors, laboratory parameters, timing of disease onset, and treatment delivery in a series of SARS CoV-2 infected patients admitted to Mayo Clinic hospitals in Rochester Minnesota, Jacksonville Florida, Phoenix Arizona, and the Mayo Clinic Health System in the same 3-month interval between September 2019 and December 2020.

Cases were identified retrospectively from the Mayo Clinic enterprise-wide and universally adopted electronic medical record (EMR). We identified adult patients ≥ 18 years of age , with CT and/or MRI confirmed acute ischemic or hemorrhagic stroke and positive SARS-CoV-2 real-time reverse transcription polymerase chain reaction test who were admitted to any one of the Mayo Clinic hospitals in Arizona, Florida, Iowa, Minnesota, and Wisconsin. We used ICD-10 codes and test result codes to identify cases (Supplementary figure 1). 7 Mbonde our EMR system were included. We subsequently reviewed all identified cases resulting from this initial search and only included those with a confirmed new diagnosis of acute ischemic or hemorrhagic stroke. We excluded individuals with a history of stroke or those in whom the stroke imaging characteristics were consistent with a chronic infarct. For all included participants, we extracted data on socio-demographic characteristics, vascular risk factors, clinical presentation, timing of disease onset, laboratory markers, radiologic findings, and treatment strategies. Ischemic stroke features on imaging were summarized by anatomic location. We recorded the proposed stroke mechanism, as documented in the clinical notes, and data on mortality outcomes.

Data entry and Statistical analysis: All relevant Information was entered directly into a pre-tested REDCap database questionnaire hosted on the Mayo Clinic server.

Categorical data from all participants were summarized using proportions and percentages, whilst continuous data were summarized using medians and interquartile ranges (IQR). Mortality outcome was summarized using proportions and categorized by stroke types. Fisher's exact test was used to compare the risk of mortality between those with ischemic and hemorrhagic stroke. As an exploratory analysis, Fisher's exact test and Kruskal Wallis test were used, where appropriate, to compare demographic and clinical characteristics between cryptogenic ischemic stroke patients and all other ischemic stroke patients. Board. We excluded individuals who did not provide research authorization, as required by Minnesota state laws. Only de-identified data was extracted from patient charts and entered into REDCap. Those with cryptogenic ischemic stroke were significantly younger (median age 69 years vs. 79 years, p=0.0081) (Supplementary Table 2 ).

Participants were predominantly white (67%, 20/30), followed by black or African American individuals (13%, 4/30) and Asian Americans (7%, 2/30) ( Table 1) Stroke type, severity, mechanism, imaging characteristics and treatment: Strokes were ischemic in 87% (26/30) and hemorrhagic in 13% (4/30) of participants. The median (IQR) National Institutes of Stroke Scale score (NIHSS) was 6 (3,10). Anterior circulation was the most common ischemic stroke location, accounting for 80% (21/26) of cases. In terms of stroke mechanisms, cardioembolism (35%, 9/26) and cryptogenic (35%, 9/26) were the most documented (Supplementary Table 1 ).

Intravenous alteplase for acute stroke treatment was administered in only 7% (2/26) of ischemic stroke cases, and the most documented reasons for not treating with thrombolysis were presentation outside of the 4.5-hour-window and/or subacute infarct noted on head imaging (Table 1) . Only one patient underwent mechanical thrombectomy.

Hemorrhagic strokes were mostly lobar (75%, 3/4), with a median (IQR) hematoma volume of 33 cm 3 (21, 61) . Of those with hemorrhagic stroke, 33% (1/4) were on therapeutic doses of anticoagulation therapy.

COVID-19 disease severity, treatment strategies: Nearly half of the individuals had asymptomatic SARS-CoV-2 infection (53%, 16/30). Those with severe or critical disease were also common, collectively accounting for 30% (9/30) of all cases (Table 1) .

Remdesivir (47%, 14/30) and dexamethasone (33%, 10/30) were commonly administered to patients. Approximately one-third (30%, 9/30) of individuals were mechanically ventilated in the intensive care unit for acute respiratory failure.

Convalescent plasma was used in 10% (3/30) of cases (Table 1) . (Table 2 ). More than half of the individuals had a complete blood count, international normalized ratio, D-dimer, serum lipids, ferritin and troponins completed. Table 2 Mortality outcomes: Overall, 11/30 (37%) of individuals died; 9 with ischemic stroke (9/26, 34%) and 4 with hemorrhagic stroke (2/4, 50%). The difference in mortality rates was not statistically significant (p=0.611) although the event rate and sample size were low for this analysis.

There are several notable findings from our study. Firstly, we found a low prevalence (0.5%) of acute stroke amongst SARS-CoV-2 infected patients. Secondly, traditional stroke risk factors were highly prevalent in our cohort with more than 80% of individuals having had at least one documented risk factor such as hypertension, hyperlipidemia, smoking history, diabetes, or atrial fibrillation. Thirdly, serum biomarkers for inflammation and coagulation were elevated in individuals in whom these laboratory J o u r n a l P r e -p r o o f values were available. Fourthly, only a small minority of acute ischemic stroke cases were eligible for reperfusion therapy mostly due to late presentation. Lastly, in-hospital outcomes were very poor among our individuals with stroke and SARS-CoV-2 infection as evidenced by the high mortality rate. Our findings are relevant as they add to the mounting body of evidence that is aimed at helping to improve our understanding of the unique interaction between stroke and SARS-CoV-2 infection, thus providing avenues by which critical stroke prevention and treatment strategies can be derived.

The low prevalence (0.5%) of stroke in our study is similar to findings from one prior study from New York that reported an ischemic stroke prevalence rate of 0.9%. 15 However, larger studies and meta-analyses have reported slightly higher prevalence rates of around 1.3-1.5% 8, 16 which is more than double the rates reported in our study. Several other studies have reported even higher stroke rates. One study from a large university health system in the United States which enrolled a significantly younger population than ours, most of whom were African Americans (68% black, mean age 59 years) reported a stroke prevalence rate of 2.5%, five times more than ours. 8 Further, a retrospective study conducted at the peak of the COVID-19 disease pandemic in China reported a high stroke prevalence rate of 5.7% among those with severe SARS-CoV-2 infection, therein supporting the theory that individuals with severe infection are at a heightened risk of stroke. 7 Therefore, the differences in prevalence Regarding stroke risk factors, we found that proinflammatory and pro-coagulation biomarkers were elevated amongst individuals in our cohort. This unsurprising finding can be corroborated by data from numerous prior studies reporting similar laboratory findings in SARS-CoV-2 infected patients with acute stroke. 8, [18] [19] [20] In addition, we also found that there was a concurrently high rate of traditional stroke risk factors in our cohort, also similar to what others have previously noted. 16, 21 In one U.S study, 95% of patients had a history of hypertension and 60% had diabetes mellitus. 21 In fact, both diabetes mellitus and hypertension have also been associated with increased COVID-19 disease severity, acute respiratory distress and poor outcomes. [22] [23] [24] Diabetes and hypertension are hypothesized to lead to severe SARS-CoV-2 infection through a number of mechanisms such as impaired glucose homeostasis, impaired immune response and activation of the renin-angiotensin-aldosterone system (RAAS). 25 26, 27 The infected host cells then release an initial set of cytokines and chemokines such as tumor necrosis factor (TNF), CRP, interleukin-1 (IL-1) and interleukin-6 (IL-6) which leads to the recruitment of macrophages and monocytes. These produce even more proinflammatory cytokines and eventually a cytokine storm. The resultant cytokine storm leads to activation of tissue factor located on neutrophils and other immune cells which in turn interacts with factor VII to stimulate the extrinsic coagulation cascade. 28, 29 The hyperinflammatory response also independently leads to direct platelet activation and endothelial cell (EC) damage which both contribute to thrombosis. 30 In addition, EC ubiquitously express ACE2 and TMPRSS2 thus making them a target for direct viral invasion, viral proliferation and eventually EC activation/damage (Figure 1 ). [31] [32] [33] Endothelial activation by itself is a major orchestrator of thrombosis and stroke occurrence, as it leads to a number of downstream deleterious effects as summarized in Figure 1 including: extensive release of inflammatory cytokines and chemokines further fuelling the cytokine storm, 31, 32, 34 release of von Willebrand factor which further promotes coagulopathy, decreased production of nitrous oxide through suppression of nitric oxide synthase (necessary for vasodilation), and the release of oxygen reactive species. 35, 36 Another negative consequence of EC damage is the resultant decrease in the amount of ACE2 available to counter the effects of the classical RAAS pathway leading to further endoleliopathy and end organ damage. 35 All the processes described above can either lead to de novo endotheliopathy (particularly in younger individuals without a J o u r n a l P r e -p r o o f history of pre-existing vascular risk factors) or endothelial damage in those with underlying atherosclerosis and comorbid vascular risk factors (Figure 1 ).

Another key finding in our study was the revelation that there was an extremely low rate of acute reperfusion therapies offered to stroke patients at the time of stroke diagnosis.

The most common documented reason for not treating with thrombolysis was presentation outside of the 4.5-hour treatment window. This is likely due to individuals being hesitant to go to the hospital in the midst of the COVID-19 pandemic, a phenomenon that has been seen across several regions of the world with a worldwide decline in stroke admissions during the COVID-19 pandemic observed. 37, 38 This likely contributes to the poor stroke outcomes in COVID-19 patients. Therefore, significant efforts are needed to combat hesitancy toward hospital presentation in order to improve the number of patients eligible for acute stroke therapy.

A major strength of our study lies in the fact that this study was conducted in one of the single largest North American academic medical centers focused on integrated health care, education, and research with hospitals in five states, all universally adopting a single EMR. We included all eligible hospitalized patients in whom stroke, and SARS-CoV-2 infection were diagnosed within a comorbidity window, facilitating more rapid study completion and timely dissemination of results. Data fields and analysis plans were pre-specified. J o u r n a l P r e -p r o o f 

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