key: cord-282956-f7if9e5q authors: Yaghi, Shadi; Ishida, Koto; Torres, Jose; Mac Grory, Brian; Raz, Eytan; Humbert, Kelley; Henninger, Nils; Trivedi, Tushar; Lillemoe, Kaitlyn; Alam, Shazia; Sanger, Matthew; Kim, Sun; Scher, Erica; Dehkharghani, Seena; Wachs, Michael; Tanweer, Omar; Volpicelli, Frank; Bosworth, Brian; Lord, Aaron; Frontera, Jennifer title: SARS2-CoV-2 and Stroke in a New York Healthcare System date: 2020-05-26 journal: Stroke DOI: 10.1161/strokeaha.120.030335 sha: doc_id: 282956 cord_uid: f7if9e5q BACKGROUND AND PURPOSE: With the spread of coronavirus disease 2019 (COVID-19) during the current worldwide pandemic, there is mounting evidence that patients affected by the illness may develop clinically significant coagulopathy with thromboembolic complications including ischemic stroke. However, there is limited data on the clinical characteristics, stroke mechanism, and outcomes of patients who have a stroke and COVID-19. METHODS: We conducted a retrospective cohort study of consecutive patients with ischemic stroke who were hospitalized between March 15, 2020, and April 19, 2020, within a major health system in New York, the current global epicenter of the pandemic. We compared the clinical characteristics of stroke patients with a concurrent diagnosis of COVID-19 to stroke patients without COVID-19 (contemporary controls). In addition, we compared patients to a historical cohort of patients with ischemic stroke discharged from our hospital system between March 15, 2019, and April 15, 2019 (historical controls). RESULTS: During the study period in 2020, out of 3556 hospitalized patients with diagnosis of COVID-19 infection, 32 patients (0.9%) had imaging proven ischemic stroke. Cryptogenic stroke was more common in patients with COVID-19 (65.6%) as compared to contemporary controls (30.4%, P=0.003) and historical controls (25.0%, P<0.001). When compared with contemporary controls, COVID-19 positive patients had higher admission National Institutes of Health Stroke Scale score and higher peak D-dimer levels. When compared with historical controls, COVID-19 positive patients were more likely to be younger men with elevated troponin, higher admission National Institutes of Health Stroke Scale score, and higher erythrocyte sedimentation rate. Patients with COVID-19 and stroke had significantly higher mortality than historical and contemporary controls. CONCLUSIONS: We observed a low rate of imaging-confirmed ischemic stroke in hospitalized patients with COVID-19. Most strokes were cryptogenic, possibly related to an acquired hypercoagulability, and mortality was increased. Studies are needed to determine the utility of therapeutic anticoagulation for stroke and other thrombotic event prevention in patients with COVID-19. C oronavirus disease 2019 (COVID-19), the illness caused by the severe acute respiratory syndrome CoV-2 coronavirus, has an unclear impact on the cerebrovascular system. With over 200 000 confirmed cases as of April 15, 2020, New York State currently accounts for ≈10% of all confirmed cases worldwide. Given early reports of an association between COVID-19 and cerebrovascular disease, there is a critical, unmet need to define associations and outcomes of patients with cerebrovascular disease and COVID-19. Understanding factors associated with stroke in patients with COVID-19 will aid in the diagnosis, treatment, and prevention of COVID-19 associated cerebrovascular disease as well as potentially identify underlying Stroke. 2020;51:00-00. DOI: 10.1161/STROKEAHA.120.030335 mechanisms. In this study, we aim to characterize ischemic stroke in patients with COVID-19 from a large healthcare system with a diverse patient population in the New York metropolitan area and compare these characteristics to those of contemporary and historical ischemic stroke controls without COVID-19. We obtained institutional review board approval from NYU Langone Health to perform the study, and informed consent was waived by the institutional review board. Data from the study are available for sharing upon reasonable request to the corresponding author. This is a retrospective observational study including patients admitted to one of 3 comprehensive stroke centers in the New York metropolitan area (NYU Langone Manhattan, NYU Langone Brooklyn in Sunset Park, Brooklyn, and NYU Langone Winthrop in Mineola, Long Island) with acute ischemic stroke hospitalized between March 15, 2020, and April 19, 2020. All consecutive patients with radiological confirmation of acute ischemic stroke during this time frame were included. In addition, we included consecutive patients from 2 of our facilities (NYU Langone Brooklyn and NYU Langone Manhattan) with a discharge diagnosis of ischemic stroke between March 15, 2019, and April 15, 2019, as a historical comparator group (historical control). In general, patients underwent a standard diagnostic evaluation, including brain imaging, intracranial and extracranial vascular imaging, and cardiac evaluation, including ECG, in-house continuous cardiac telemetry for at least 24 hours, and transthoracic echocardiography per institutional protocol. Stroke subtype was classified based on the Trial of ORG 10172 in Acute Stroke Treatment classification. 1 Large artery atherosclerosis was defined as 50% or more narrowing in an artery supplying the ischemic infarct territory, small vessel disease was defined as a small (≤1.5 cm on head computed tomography or ≤2 cm on diffusion-weighted imaging sequence) subcortical infarct in patients with risk factors for small vessel disease, cardioembolic was defined as the presence of a major cardioembolic source, such as atrial fibrillation, endocarditis, or ejection fraction ≤30%, and other was defined as an alternative mechanism such as dissection or known hypercoagulability, excluding de novo hypercoagulability in the setting of a COVID-19. Cryptogenic was defined as cases not meeting criteria for any of the above stroke subtypes, including those with incomplete workup or with multiple competing high-risk mechanisms. 1 In addition, we defined embolic stroke of undetermined source according to the criteria proposed by the Cryptogenic Stroke/ Embolic Stroke of Undetermined Source International Working Group. 2 Finally, we also classified strokes based on the ASCOD criteria (atheroclerosis, small-vessel disease, cardiac pathology, other cause, and dissection). 3 The following variables were abstracted from the medical records of patients: 1. Screening for COVID-19 was performed at first provider contact and included evaluation for recent COVID-19 exposure, history of fever or respiratory symptoms, or chest radiographic findings. In general, patients with a negative screen do not undergo COVID-19 testing. A positive screen would trigger testing, and this is generally the case when screening could not be completed. Assays for COVID-19 were performed in accordance with standards established by the World Health Organization. A reverse-transcriptase polymerase chain reaction study was performed in each center's laboratory using a sample obtained via a nasopharyngeal swab. The primary variable of interest was COVID-19 status (positive versus negative). No sample-size calculations were performed. All patients (cases and control groups) were divided into 3 groups: group 1 included patients with ischemic stroke and COVID-19 (cases), group 2 included contemporary patients with ischemic stroke without COVID-19 (contemporary controls), and We then performed binary logistic regression analyses to determine baseline characteristics and laboratory values associated with stroke in the setting of COVID-19 compared with historical and contemporary controls. In these models, we included variables with a 2-sided P<0.05 on univariate models. In addition, we performed binary logistic regression analyses to determine the association between COVID-19 related stroke and in-hospital mortality adjusting for age and admission NIHSS score. Analysis was performed using SPSS version 25.0 (Chicago, IL), and a 2-sided P<0.05 was considered significant. Out of 3556 patients hospitalized with COVID-19 infection during the study period, we identified a total of 32 patients (0.9%) who had radiologically proven ischemic stroke. Among contemporary controls, 70% (32/46) underwent the COVID-19 test and the rest screened negative and were not tested. Of the 32 patients (Table 1) Figure 2 shows brain and chest imaging of 2 patients with COVID-19 and cryptogenic stroke subtype. Treatments before stroke symptoms/diagnosis included hydroxychloroquine (40.6%, n=13), lopinavir-ritonavir (3.1%, n=1), and tocilizumab (6.3%, n=2). When compared with contemporary stroke controls, patients with COVID-19 and stroke were younger The left shows chest imaging (CT or x-ray) and the right shows brain imaging of 2 patients with cryptogenic stroke and COVID-19 infection in our patient cohort. In binary logistic regression models (Table 3) , when compared with contemporary controls, patients with COVID-19 had non-significantly higher admission NIHSS score (odds ratio [OR] per point increase 1.14 [95% CI, 0.99-1.31], P=0.079) and higher peak d-dimer In binary logistic regression models (Table 3) , when compared with historical controls, COVID-19 positive patients were non-significantly more likely to be younger ( In this multi-ethnic study, we report key demographic and clinical characteristics of patients who develop ischemic stroke associated with acute severe acute respiratory syndrome CoV-2 coronavirus infection. The observed rate of imaging-confirmed acute ischemic stroke in hospitalized patients with COVID-19 of 0.9% was lower compared with prior reports from Chinese COVID-19 studies. Reasons for difference are unknown but could possibly be related to differences in the patient population studied in our patient population as compared to the other studies and other studies including hemorrhagic stroke and venous sinus thrombosis patients. In addition, the rate of ischemic stroke in our study may be an underestimate as the detection of ischemic stroke symptoms is challenging in those critically ill with COVID-19 infection who are intubated and sedated. When classified according to the Trial of ORG 10172 in Acute Stroke Treatment criteria, 1 a majority (65.6%) of these patients were classified as cryptogenic stroke and 34.4% met embolic stroke of undetermined source criteria. In contrast, 30.4% of the contemporary COVID negative control group and 25.0% of the historical control group were classified as cryptogenic stroke, in keeping with other modern stroke cohorts. 4 Patients with COVID-19 and stroke were very ill as a group; 68.8% of patients required mechanical ventilation and 81.3% had severe illness graded according to the American Thoracic Society/Infectious Diseases Society of America Criteria for pneumonia severity. 5 Our findings are congruent with other studies which reported an increased prevalence of neurological disorders in those with more severe infection. 6 Our study also shows that the number of COVID-19 positive ischemic strokes has increased initially but seems to have peaked and then decreased. This finding may be related to the overall reduction in COVID-19 admissions, likely due to social distancing and stay at home order ( Figure 1 ). In addition, a therapeutic anticoagulation protocol was instated in our institution the week of April sixth, 2020, which suggests the use of therapeutic anticoagulation in patients with high D-dimer levels. This may have led to a lower rate to thrombotic complications including ischemic stroke in hospitalized COVID-19 positive patients. Furthermore, the number of patients with stroke hospitalized in the study period were less than historical controls. This witnessed low volume of acute emergencies during the COVID-19 pandemic has been observed in other institutions as well. 7 The reasons for this are unclear but possibly that patients with stroke and mild symptoms are staying at home and not presenting to the emergency department for stroke treatment. There are multiple, not mutually exclusive, possible mechanisms associating COVID-19 with ischemic stroke. In patients with COVID-19 requiring invasive respiratory support, the median duration of mechanical ventilation has been reported 11 days, 8 which renders them vulnerable to complications associated with critical illness and a prolonged intensive care unit stay including the risk for (1) hypotension and inadequate cerebral perfusion; (2) relative hypertension leading to posterior reversible encephalopathy syndrome; (3) septic embolization in the case of superimposed bacterial infection; (4) stress cardiomyopathy and an attendant reduction in left ventricular ejection fraction; and (5) atrial fibrillation with or without a rapid ventricular response. Additionally, severe COVID-19 has been associated with a hyperinflammatory state (cytokine storm 9 ) and hyperviscosity. Progression to disseminated intravascular coagulation is more common in COVID-19 than in other forms of critical illness; one case series reported an incidence of 8.7% with associated 94% mortality. 10 Mortality is associated with higher fibrin-degradation product levels and prolonged prothrombin and activated partial thromboplastin times. 11 D-dimer was elevated in 36% of patients with COVID-19 in Wuhan, 12 which was associated with a higher risk of mortality, 13 an association suggested to be driven at least partially by increased thrombotic complications. Preliminary reports from China describe patients with COVID-19 who developed multiple, bilateral ischemic cerebral infarcts, antiphospholipid antibodies, and hematologic indices suggestive of an acquired thrombophilia. 14 During the first SARS outbreak in the early 2000s, postmortem studies demonstrated a florid vasculitis in multiple arterial beds, 15 and it is not known whether this disease pattern occurs with severe acute respiratory syndrome CoV-2 coronavirus infection. There are 2 main implications for clinical care that arise from our data. First, many institutions are currently attempting to balance the benefits of rapid, structured neurological evaluations for patients with COVID-19 exhibiting new neurological symptoms with the risks of exposing multiple team members to infection. 16 As centers develop protocols for the prompt triage and assessment of patients with COVID-19, the co-occurrence of stroke and COVID-19 should be considered when weighing these risks. Second, stroke in the setting of COVID-19 could be a manifestation of systemic hypercoagulability as shown in our patient population with higher D-dimer levels when compared with contemporary controls. Further study is required whether therapeutic anticoagulation in this setting mitigates ischemic stroke risk. In fact, PROTECT COVID (A Randomized Trial of Anticoagulation Strategies in COVID-19) is an ongoing randomized clinical trial testing the safety and efficacy of therapeutic versus prophylactic anticoagulation in patients with COVID-19 infection and mild to moderate elevation in D-dimer level (URL: https://www. clinicaltrials.gov. Unique identifier: NCT04359277). Our study reports the clinical characteristics of a diverse patient population with ischemic stroke in the setting of COVID-19. We report subject level data, including key clinical variables, markers of disease severity, and diagnostic workup for ischemic stroke. Our findings should be interpreted with caution in the context of a number of important limitations. First, our study was a relatively small, retrospective, observational study with potential for selection bias. Second, we did not have outcome data on all patients as some are still admitted receiving active clinical care. Third, we do not have complete laboratory investigations or diagnostic imaging for all study subjects, and therefore, some cryptogenic strokes may be related to another undiagnosed mechanism. This likely contributed to an increased prevalence of cryptogenic stroke subtype in patients with COVID-19 infection. Fourth, our study may not be fully representative of all patients with stroke in our healthcare system; patients who are critically ill may not be diagnosed with stroke due to impaired consciousness, confounding systemic illness, or withdrawal of lifesustaining therapies. Fifth, since this report focused on ischemic stroke, we did not provide information on hemorrhagic stroke and venous sinus thrombosis occurring in patients with COVID-19. These complications in the setting of COVID-19 need further study. Finally, since not all patients were tested for COVID-19, it is possible that some asymptomatic patients with stroke may have been COVID positive but were included in the control group. We observed a relatively low rate of imaging proven ischemic stroke in hospitalized patients with COVID-19 infection. In patients with COVID-19 and ischemic stroke, a majority of strokes were classified as cryptogenic, possibly related to an acquired hypercoagulability, and were associated with increased mortality. Ongoing studies are testing the utility of therapeutic anticoagulation for stroke and other thrombotic event prevention, in select patients with COVID-19 and laboratory evidence suggestive of hypercoagulability. Affiliations From the Department of Neurology Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment Cryptogenic Stroke/ESUS International Working Group. Embolic strokes of undetermined source: the case for a new clinical construct Overlap of diseases underlying ischemic stroke: the ASCOD phenotyping Distribution and temporal trends from 1993 to 2015 of ischemic stroke subtypes: a systematic review and meta-analysis Infectious diseases society of America/American thoracic society consensus guidelines on the management of community-acquired pneumonia in adults Neurologic manifestations of hospitalized patients with coronavirus disease Reduction in STsegment elevation cardiac catheterization laboratory activations in the United States during COVID-19 pandemic Covid-19 in critically ill patients in the seattle region -case series Clinical and immunological features of severe and moderate coronavirus disease 2019 Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): a meta-analysis Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Coagulopathy and antiphospholipid antibodies in patients with COVID-19 The clinical pathology of severe acute respiratory syndrome (SARS): a report from China Acute neurology during the COVID-19 pandemic: supporting the front line Dr Yaghi, B. Mac Grory, Dr Henninger, and Dr Frontera participated in study design and drafting the article. Dr Humbert, Dr Ishida, Dr Alam, Dr Lord, Dr Sanger, Dr Lillemoe, E. Scher, Dr Kim, Dr Raz, and Dr Tanweer participated in data abstraction and article revision. Dr Trivedi performed the statistical analysis. This study is partially funded by the National Institutes of Health (NIH), K08NS091499 from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. Dr Henninger is supported by K08NS091499 from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health and Congressionally Directed Medical Research Program/Department of Defense. Dr Henninger reports personal fees from Astrocyte Pharmaceuticals, Inc and grants from National Institute of Child Health and Human Development outside the submitted work. Dr Yaghi's previous institution received funding from Medtronic for his effort in adjudicating outcomes for the Stroke-AF trial. Dr Dehkharghani received funding from iSchemaView. The other authors report no conflicts.