key: cord-0964182-5ow3uc8s
authors: Bhatia, Rohit; Padma Srivastava, M. V.; Sylaja, P. N.; Komakula, Snigdha; Upadhyay, Ashish; Pardasani, Vibhor; Iype, Thomas; Parthasarathy, Rajsrinivas; Reddy, Rajshekhar; Kushwaha, Suman; Roy, Jayanta; Satish, P; Trikha, Anjan; Wig, Naveet; Dhar, Lalit; Vibha, Deepti; Vishnu, Venugopalan Y.; Pandit, Awadh Kishore; Gupta, Anu; Elavarasi, A; Agarwal, Ayush; Gupta, Vipul; Singh, Rakesh K.; Oza, Harsh; Halani, Hiral; Ramachandran, Dileep; George, Githin B.; Panicker, Praveen; Suresh, MK; Kumaravelu, S; Khurana, Dheeraj; Rajendran, Srijithesh P.; Pamidimukkala, Vijaya; Gupta, Salil; Pandian, Jeyaraj D.; Chowdhury, Debashish; Rai, Nirendra K.; Sharma, Arvind; Nambiar, Vivek K.
title: Clinical Features and Outcome of Stroke with COVID-19. COVID-19 Stroke Study Group (CSSG), India
date: 2021-08-30
journal: Ann Indian Acad Neurol
DOI: 10.4103/aian.aian_122_21
sha: 59c4b1d6c5333726f18332998a7ca9dde4fd58d0
doc_id: 964182
cord_uid: 5ow3uc8s

BACKGROUND AND PURPOSE: Occurrence of stroke has been reported among patients with COVID-19. The present study compares clinical features and outcomes of stroke patients with and without COVID-19. METHODS: The COVID-19 Stroke Study Group (CSSG) is a multicentric study in 18 sites across India to observe and compare the clinical characteristics of patients with stroke admitted during the current pandemic period and a similar epoch in 2019. The present study reports patients of stroke with and without COVID-19 (CoVS and non-CoVS, respectively) seen between February 2020 and July 2020. Demographic, clinical, treatment, and outcome details of patients were collected. RESULTS: The mean age and gender were comparable between the two groups. CoVS patients had higher stroke severity and extent of cerebral involvement on imaging. In-hospital complications and death were higher among CoVS patients (53.06% vs. 17.51%; P < 0.001) and (42.31% vs. 7.6%; P < 0.001), respectively. At 3 months, higher mortality was observed among CoVS patients (67.65% vs. 13.43%; P < 0.001) and good outcome (modified Rankin score [mRS]: 0–2) was seen more often in non-CoVS patients (68.86% vs. 33.33%; P < 0.001). The presence of COVID-19 and baseline stroke severity were independent predictors of mortality. CONCLUSIONS: CoVS is associated with higher severity, poor outcome, and increased mortality. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and baseline stroke severity are independent predictors of mortality.

The COVID-19 Stroke Study Group (CSSG) is a multicentric study conducted in 18 sites across India, to observe and compare the clinical characteristics of patients with stroke admitted during the current pandemic period and a similar epoch in 2019. Collaborative sites prospectively recruited patients with stroke seen during this period. The study was approved by the institutional ethics committee. The current paper compares patients with stroke and COVID-19 (CoVS) with patients with stroke and without COVID-19 (non-CoVS), seen between February 2020 and July 2020. Data were collected from sites where both CoVS and non-CoVS patients were seen in this period. Details of patient demographics, stroke risk factors (hypertension, diabetes mellitus, history of previous stroke, coronary artery disease, dyslipidemia, smoking, alcohol use, and renal dysfunction), type of stroke (ischemic, intracerebral hemorrhage [ICH] , and cerebral venous thrombosis), time of onset, hospital arrival, and evaluation time taken [CT (computerised tomography time), thrombolysis treatment time, and endovascular treatment (EVT) details], imaging findings (Alberta Stroke Program Early CT Score [ASPECTS] and ICH volume), laboratory parameters wherever available (total leukocyte count [TLC], absolute lymphocyte count, erythrocyte sedimentation rate [ESR] , C-reactive protein [CRP] , lactate dehydrogenase [LDH] , Ferritin, D-dimer, blood sugar), evaluation details including Holter and echocardiography, ischemic stroke subtyping using trial of ORG 10172 in acute stroke treatment (TOAST) classification, medical treatment details, and surgical interventions performed (decompressive hemicraniectomy, hematoma evacuation, combination of hematoma evacuation and decompressive craniectomy, endarterectomy, and stenting), complications (pneumonia, deep venous thrombosis, urinary tract infection, bedsore, and cardiac) and outcomes (mortality at 1 and 3 months and modified Rankin score [mRS]) were collected. mRS ≤2 was taken as a good outcome.

Data were presented as mean (SD), median (IQR), and frequency (%). Continuous variables were compared using Student's t-test (following normal distributions) or Wilcoxon's sum-rank test (non-normal distribution). Qualitative variables were compared using Chi-square/Fisher's exact test. Univariate and multivariable analysis using a generalized linear model with family (binomial) and logit link (to account for the effect of different centers) was performed to observe the indepe T:\A-H\AIAN\AIAN_AOP\ Output\PDF\1st Revises\AP Corrections\20210726 ndent effect of COVID-19 on mortality. A two-tailed P value of ≤0.05 was considered significant. Stata version 14 (StataCorp, Lakeway Drive College Station, Texas, USA) was used for analysis.

A total of 665 stroke patients were seen between February 2020 and July 2020 at seven CSSG sites. These sites were chosen as both COVID-19 and non-COVID-19 stroke patients were managed at these sites. The mean age of patients was 60.17 ± 14.42 years; 69.47% (462) were males. In addition, 537 (80.87%) had an ischemic stroke, 118 (17.77%) had ICH, and 9 (1.36%) had cerebral venous thrombosis (CVT). Among these, 169 patients were suspected of having COVID-19. Suspicion was based on the history of fever (n = 22), respiratory symptoms (n = 20) , and other reasons to suspect in the absence of symptoms of infection (place of stay, hot spot, history of contact; n = 127).

A total of 409 patients were tested for SARS-CoV-2 and 52 patients were found positive. The analysis is presented for patients who were tested for SARS-CoV-2. Among the 52 CoVS patients, 35 (67.30%) patients required ICU care, and 17 (32.69%) patients were managed in a non-ICU facility.

The details of CoVS (n = 52) and non-CoVS (n = 357) patients is described in Table 1 . The mean age, gender, and risk factors were comparable between the two groups. Types of stroke were comparable in both groups. CoVS patients had a higher National Institutes of Health Stroke Scale (NIHSS) and lower Alberta Stroke Program Early CT Score (ASPECTS) scores at presentation. Among the available laboratory parameters, baseline TLC, ESR, and D-dimer were higher among CoVS patients. All major risk factors were equally distributed in the two groups. History of renal dysfunction was in higher proportion among CoVS patients. A higher number of non-CoVS patients underwent vascular imaging, echocardiography, Holter monitoring, and surgical interventions. In-hospital complications were higher among CoVS patients compared with non-CoVS. Twenty-two (42.31%) CoVS patients died during the hospital stay compared with 27 (7.6%) non-CoVS patients (P ≤ 0.00001). The hospital stay was longer among CoVS patients (P = 0.001). Three months follow-up was completed for 45 CoVS patients and 335 non-CoVS patients. At three months, higher mortality was observed among CoVS patients (51.11%) versus 13.43%, P < 0.001) and good outcome was seen more often in non-CoVS patients (66.86% vs 33.33%, P < 0.001). We explored factors that could affect in-hospital and 3-months mortality in the two groups [ Contd.. systolic BP, blood sugar level, NIHSS, total leucocyte count, and in-hospital complications were observed among patients with mortality at three months.

Twenty-one patients were symptomatic with either fever or respiratory symptoms and 31 patients had no clinically overt features of COVID-19. The presence of underlying coronary artery disease (CAD), diabetes, and higher total leukocyte count was observed among symptomatic patients [ 

With time, the multifaceted nature of COVID-19 infection is emerging. Now believed to be a multisystem disease in its clinical behavior, cerebrovascular disease has emerged as a predominant comorbidity and a manifestation independent of pulmonary symptomatology or severity. [2] [3] [4] [5] A recent systematic review reported clinical behavior and outcome of patients with stroke and COVID-19. [6] Although it is still unclear if COVID-19 is incidental or causative in the stroke population, a recent study has suggested COVID-19 as an independent risk factor for stroke. [6] In the present study, patients with stroke and COVID-19 had a more severe stroke and a greater extent of ischemic damage on imaging, suggesting a more aggressive disease behavior. Similar observations have also been reported previously. [7] [8] [9] [10] [11] We did not observe any major differences among known risk factors between the two groups of patients as well as the stroke subtypes apart from the history of renal dysfunction being higher among CoVS patients. In previous studies as well, no major differences among risk factors were observed among patients of stroke with or without COVID-19. [8, 12] A recent ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; ASPECTS: Alberta Stroke Program Early CT score; TOAST: Trial of ORG in acute ischemic stroke; LAD-EC: large artery disease extracranial; LAD-IC: large artery disease intracranial; LMWH: low-molecular-weight heparin. *duration in minutes; † when indicated in patients with acute ischemic stroke meta-analysis observed that the outcomes of patients with COVID-19 are influenced by a history of vascular events in the past and a prior history of cerebrovascular events has a 2.5-fold increase in COVID-19 disease severity. [13] The presence of underlying renal disease is also associated with poor outcomes among patients with and without dialysis dependence. [14] We also compared the CoVS patients, who had clinical suspicion of having COVID-19 at the time of initial screening in the hospital (presence of fever and or respiratory symptoms), with the asymptomatic group. Although elevated leucocyte count in the symptomatic group could suggest an inflammatory activity, other potential inflammatory markers were comparable between the groups. However, patients symptomatic at presentation had higher CAD and diabetes suggesting that vascular risk factors could potentially increase the severity and manifestations of COVID-19 and occurrence of stroke.

Limited evaluation for stroke etiology in CoVS patients could either reflect a priority for COVID-19 management or feasibility issues of transferring stroke patients to non-COVID-19 designated areas or limited availability of resources and expertise within the COVID-19 care designated centers. A concern about the reduction in stroke admissions, optimum acute stroke care, and reduced acute interventions has been observed during the ongoing pandemic. [15] [16] [17] Guidelines and recommendations for stroke management during the pandemic have been suggested. [18] The initial difficulties with organizing systems of care have likely improved over time.

A higher proportion of CoVS ischemic stroke patients were categorized into cardioembolism and indeterminate stroke etiology. Whether this is suggestive of an underlying cardiac involvement, a prothrombotic milieu or incomplete evaluation due to logistic reasons is unclear. In a recent study from New York, a significantly high number of patients with COVID-19 were placed in the cryptogenic category and embolic source of undetermined source (ESUS), potentially suggesting other mechanisms of stroke in these patients. [12] Relatively few patients with COVID-19 underwent intravenous thrombolysis. Since the decision about thrombolysis depends upon many factors, it is likely that only the most eligible patients, and in areas where a protected code stroke triage [19] is available, were treated with thrombolysis. Higher door to CT time was observed among CoVS patients. Longer times to treatment have been reported during the ongoing pandemic. [20] None of the CoVS patients underwent endovascular therapy and the number of patients in the non CoVS group was also low. This may be related to many factors including no indication, patient's clinical status, availability, and logistics related to the provision of intervention facilities in the COVID-19-designated areas. Challenges related to EVT during COVID-19 have been previously outlined and methods to improve have been discussed. [21] High in-hospital and 3 months mortality and a lower proportion of patients achieving a good outcome at 3 months were observed among CoVS patients. A higher stroke severity, systemic inflammatory effects of COVID-19, ARDS (acute respiratory distress syndrome) and sepsis, cardiac arrhythmias, systemic prothrombotic state, and thromboembolism could be contributing to a poorer outcome. [8, 12, [22] [23] [24] [25] [26] Higher mortality among CoVS patients has been observed in previous studies as well. [6] This is also suggested by the presence of increased inflammatory markers such as leukocyte counts, ferritin, LDH, and D-dimer levels among patients with COVID-19 with or without stroke. [7, [25] [26] [27] [28] [29] [30] [31] However, in the present study, we could only observe higher leucocyte counts and ferritin among COVID-19-positive patients. No major difference was observed in other markers. This could be either due to the data being unavailable from all patients, dynamic nature of these values that could change with the severity of the disease or due to incidental occurrence of stroke in these patients where COVID-19 positivity may be a bystander and not a direct inciting agent. COVID-19 seems to be an independent risk factor for mortality in the present study. We could not, however, establish it as an independent risk factor for stroke occurrence as this was not a case-control study.

The strength of the study includes the multicentric, prospective follow-up data, unlike historical controls used in other studies. The study has limitations. This includes a low number of COVID-19-positive patients with stroke. Data from all stroke patients having COVID-19 could not be ascertained as patients were managed in designated locations and it was difficult to retrieve all data. EVT comparison could not be made as data were not available for COVID-19-positive patients. The study was underrepresented by female patients. Not all patients who presented with stroke were tested for SARS-CoV-2. Therefore, a higher number of patients with associated-asymptomatic COVID-19 may have been missed. Specific laboratory parameters were not available for all patients and 3 months outcome was missing in few patients, limiting the strength of the analysis. Contd.. Contd.. conclusIons Stroke associated with COVID-19 is associated with higher stroke severity, morbidity, and mortality. The presence of COVID-19 and baseline stroke severity are independent risk factors for mortality. Multidisciplinary care and advances in understanding these comorbidities will help in improving outcomes among patients.

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We thank all the faculty, residents, and nursing staff who were involved in the management of stroke patients.

Nil.

There are no conflicts of interest.