SARS-CoV-2 and Stroke Characteristics

A Report From the Multinational COVID-19 Stroke Study Group

Shima Shahjouei, MD, MPH; Georgios Tsivgoulis, MD, PhD, MSc; Ghasem Farahmand, MD; Eric Koza, MD Candidate; Ashkan Mowla, MD; Alireza Vafaei Sadr, PhD; Arash Kia, MD; Alaleh Vaghefi Far, MD; Stefania Mondello, MD, PhD, MPH; Achille Cernigliaro, PhD, MPH; Annemarei Ranta, MD, PhD; Martin Punter, PhD, MBChB; Faezeh Khodadadi, PharmD; Soheil Naderi, MD; Mirna Sabra, PhD; Mahtab Ramezani, MD; Ali Amini Harandi, MD; Oluwaseyi Olulana, MS; Durgesh Chaudhary, MBBS; Aicha Lyoubi, MD; Bruce C.V. Campbell, MD; Juan F. Arenillas, MD; Daniel Bock, MD; Joan Montaner, MD; Saeideh Aghayari Sheikh Neshin, MD; Diana Aguiar de Sousa, MD, PhD; Matthew S. Tenser, MD; Ana Aires, MD; Mercedes de Lera Alfonso, MD; Orkhan Alizada, MD; Elsa Azevedo, MD, PhD; Nitin Goyal, MD; Zabihollah Babaeepour, MD; Gelareh Banihashemi, MD; Leo H. Bonati, MD; Carlo W. Cereda, MD; Jason J. Chang, MD; Miljenko Crnjakovic, MD; Gian Marco De Marchis, MD; Massimo Del Sette, MD; Seyed Amir Ebrahimzadeh, MD, MPH; Mehdi Farhoudi, MD; Ilaria Gandoglia, MD; Bruno Gonçalves, MD; Christoph J. Griessenauer, MD; Mehmet Murat Hancı, MD; Aristeidis H. Katsanos, MD; Christos Krogias, MD; Ronen R. Leker, MD; Lev Lotman, MD; Jeffrey Mai, MD; Shailesh Male, MD; Konark Malhotra, MD; Branko Malojcic, MD, PhD; Teresa Mesquita, MD; Asadollah Mir Ghasemi, MD; Hany Mohamed Aref, MD; Zeinab Mohseni Afshar, MD; Jusun Moon, MD; Mika Niemelä, MD, PhD; Behnam Rezai Jahromi, MD; Lawrence Nolan, DO; Abhi Pandhi, MD; Jong-Ho Park, MD; João Pedro Marto, MD; Francisco Purroy, MD, PhD; Sakineh Ranji-Burachaloo, MD; Nuno Reis Carreira, MD; Manuel Requena, MD; Marta Rubiera, MD; Seyed Aidin Sajedi, MD; João Sargento-Freitas, MD; Vijay K. Sharma, MD; Thorsten Steiner, MD; Kristi Tempro, MD; Guillaume Turc, MD, PhD; Yasaman Ahmadzadeh, MD; Mostafa Almasi-Dooghaee, MD; Farhad Assarzadegan, MD; Arefeh Babazadeh, MD, MPH; Humain Baharvahdat, MD; Fabricio Buchadid Cardoso, MD, MPH; Apoorva Dev, PhD; Mohammad Ghorbani, MD; Ava Hamidi, MD; Zeynab Sadat Hasheminejad, MD; Sahar Hojjat-Anasri Komachali, MD; Fariborz Khorvash, MD; Firas Kobeissy, PhD; Hamidreza Mirkarimi, MD; Elahe Mohammadi-Vosough, MD; Debdipto Misra, MS; Ali Reza Noorian, MD; Peyman Nowrouzi-Sohrabi, PhD; Sepideh Paybast, MD; Leila Poorsaadat, MD; Mehrdad Roozbeh, MD; Behnam Sabayan, MD, PhD; Saeideh Salehizadeh, MD; Alia Saberi, MD; Mercedeh Sepehrnia, MD; Fahimeh Vahabizad, MD; Thomas Alexandre Yasuda, MD; Mojdeh Ghabaee, MD; Nasrin Rahimian, MD, MPH; Mohammad Hossein Harirchian, MD; Afshin Borhani-Haghighi, MD; Mahmoud Reza Azarpazhooh, MD; Rohan Arora, MD; Saeed Ansari, MD; Venkatesh Avula, MS; Jiang Li, MD, MPH; Vida Abedi, PhD; Ramin Zand, MD, MPH

Disclosures

Stroke. 2021;52(5):e117-e130. 

In This Article

Methods

Study Design

The details of the study design are available in Document I in the Data Supplement. The authors declare that all supporting data are available within the article. Additional data that support the findings of this study are available from the corresponding author upon reasonable request. This multicenter, multinational prospective and observational study was conducted and reported according to the Strengthening the Reporting of Observational Studies in Epidemiology,[14] and Enhancing the Quality and Transparency of Health Research guidelines.[15] The study protocol was designed by the investigators at the Neuroscience Institute of Geisinger Health System, Pennsylvania, and received approval by the Institutional Review Board of Geisinger Health System and other participating institutions. Investigators from 6 continents including North America (Canada, 6 states of the United States, and Mexico), South America (Brazil), Europe (Belgium, Croatia, Czech Republic, Finland, France, Germany, Greece, Ireland, Italy, Norway, Portugal, Spain, Sweden, and Switzerland), Asia (India, Iran, Iraq, Israel, Lebanon, Singapore, South Korea, Turkey, and the United Arab Emirates), Oceania (Australia and New Zealand), and Africa (Egypt, Nigeria, and Uganda) responded to our invitation. The centers were included by nonprobability sampling, and data were included until June 10, 2020.

Participants. We included consecutive SARS-CoV-2–infected adult patients who had imaging-confirmed subsequent stroke[16]—AIS, intracerebral hemorrhage, subarachnoid hemorrhage (SAH), and CVST. The preferred diagnostic criteria for SARS-CoV-2 were defined according to the World Health Organization interim guidance.[17] Ischemic or hemorrhagic strokes were defined in the presence of a rapid onset of a neurological deficit with evidence of acute ischemic or hemorrhagic lesions on computed tomography or magnetic resonance imaging. Patients who had transient stroke-like symptoms (transient ischemic attack) without acute lesions on computed tomography or magnetic resonance imaging were not included in this study due to the high diagnostic error. [18–20]

The inclusion of the stroke patients was based on the confirmed prior infection by SARS-CoV-2 (and not symptom presentation). Patients who initially presented to the hospital with stroke-related chief complaints and asymptomatic SARS-CoV-2 infection were detected by admission tests, those who had a stroke while being hospitalized for SARS-CoV-2 infection, or patients with stroke-related admission who had confirmed prior diagnosis of SARS-CoV-2 were included in this study.

Data Element and Processing. Collaborators were asked to provide data according to a core protocol. The age, sex, vascular risk factors and comorbidities (ie, hypertension, diabetes, ischemic heart disease, atrial fibrillation, carotid stenosis, chronic kidney disease, cardiac ejection fraction <40%, active neoplasms, rheumatological diseases, smoking status, and history of transient ischemic attack or stroke), and laboratory findings (ie, the count for white blood cells, neutrophils, lymphocytes, and platelets, C-reactive protein, blood urea nitrogen, creatinine, alanine transaminase, aspartate transaminase, lactic acid dehydrogenase, fibrinogen, and D-dimer) were requested for the patients with stroke. We also obtained additional data including the onset of the stroke and SARS-CoV-2 infection diagnosis, the initiation of mechanical ventilation (if applicable), length of hospital stays, and patient disposition—defined as still in the hospital, in-hospital death, being discharged to home, acute rehabilitation service, or nursing home. The details of neurological symptoms and investigations, imaging-based localization of the lesion(s), use of antiplatelets or anticoagulants before the stroke, the NIHSS, the ICH score, administration of intravenous thrombolysis (IVT), and mechanical thrombectomy were also requested. The severity of the stroke according to NIHSS was defined as no stroke symptoms (NIHSS score, 0), minor (NIHSS score, 1–4), moderate (NIHSS score, 5–15), moderate-to-severe (NIHSS score, 16–20), and severe stroke (NIHSS score, 21–42).[21] The TOAST criteria were defined as large artery atherosclerosis, cardioembolism, small artery occlusion, other determined etiology, and undetermined etiology.[22]In addition, the lesions on diffusion-weighted imaging or computed tomography images were categorized as lacunar,[23] embolic/large vessel atherothromboembolism,[24,25] vasculitis pattern,[26] or other phenotypes (borderzone or equivocal lesions). In this study, the AISs due to LVOs are referred as occlusion of the internal carotid artery, middle cerebral artery at M1 and M2, anterior cerebral artery at A1, posterior cerebral artery at P1, intracranial vertebral artery, or basilar artery.[27] Brain imaging findings were evaluated by local radiologists with expertise in neuroimaging. To determine the interval between the infection and stroke, the onset of SARS-CoV-2 was considered as either the symptom onset or the day of taking the sample with a positive result, whichever was first. The interval was considered as zero if the infection was diagnosed at the same visit as the onset of stroke. Countries were considered as either low or middle and high health expenditure based on the World Health Organization reports.[28] The countries' annual health expenditure of above US $1000 per capita (2015–2017; Table I in the Data Supplement) and total health expenditure of above US $10 000 per capita (2010–2017; Figure I in the Data Supplement) were considered as the cutoff.

Outcome Measures. The primary outcome measures in this study were the presence versus absence of LVO, stroke severity as measured by NIHSS, and stroke subtype as measured by the TOAST criteria among the AIS patients.

We further compared the groups of the patients with AIS or intraparenchymal hemorrhage (IPH) according to their age (younger versus older than 55 years and younger versus older than 65 years),[29] sex, geographic regions (America, Europe, Asia, and the Middle East), countries' health expenditure (low versus middle and high income), imaging findings, and the interval of stroke onset and infection diagnosis (same day versus others). We did not analyze the disposition and length of stay as outcome measures since many patients were still in the acute phase or admitted in long-term acute care hospitals at the closure of our study.

Statistical Analyses and Modeling. We used descriptive statistics to summarize the data. Demographic data, comorbidities, laboratory findings, and neurological investigations were reported as medians and interquartile range, mean and SDs, and under stratified categories when possible. The equality of the variances was assessed by Leven test. Categorical variables were reported as absolute frequencies and valid percentages. The comparisons between categorical variables were conducted with the Pearson χ2 test, while the differences among continuous variables were assessed by independent t test and ANOVA. A post hoc z test on the adjusted residuals and Cramér phi, Tukey, or Dunnett tests were used to demonstrate the degree and direction of the associations in comparison of means, while post hoc comparison of medians was conducted by the Dunn-Bonferroni approach to compare subgroups. All tests were performed using IBM SPSS Statistics, version 26,[30] and P<0.05 was considered statistically significant. Bonferroni correction was used for adjusting all P values in multiple comparisons.

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