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Neurology

Acute Ischemic Stroke During the Convalescent Phase of Asymptomatic COVID-2019 Infection in Men

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To identify the key insights or developments described in this article

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JAMA Network Open

Published Online: April 22, 2021

Original Investigation

Article Information and Disclosures

Tian Ming Tu, MRCP¹;

Christopher Ying Hao Seet, MRCP¹;

Jasmine Shimin Koh, MRCP¹;

Carol Huilian Tham, MRCP¹;

Hui Jin Chiew, MRCP¹;

Jasmyn Angon De Leon, MD²;

Christopher Yuan Kit Chua, MRCP³;

Andrew Che-Fai Hui, MRCP⁴;

Shaun Shi Yan Tan, MBChB⁵;

Shawn Sushilan Vasoo, MRCP⁶;

Benjamin Yong-Qiang Tan, MRCP³;

N. Thirugnanam Umapathi, MRCP¹;

Paul Anantharajah Tambyah, MD⁷;

Leonard Leong Litt Yeo, MRCP, PhD³

Author Affiliations

¹Department of Neurology, National Neuroscience Institute, Singapore
²Department of General Medicine, Khoo Teck Puat Hospital, Singapore
³Division of Neurology, Department of Medicine, National University Health System, Singapore
⁴Division of Neurology, Department of Medicine, Ng Teng Fong General Hospital, Singapore
⁵Department of Laboratory Medicine, National University Health System, Singapore
⁶Department of Infectious Diseases, Tan Tock Seng Hospital and National Centre for Infectious Diseases, Singapore
⁷Division of Infectious Diseases, Department of Medicine, National University Health System, Singapore

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Key Points

Question Is the risk of acute ischemic stroke (AIS) elevated in patients in the convalescent phase of an asymptomatic COVID-19 infection?

Findings In this case series of 18 male adults aged 50 years or younger who presented with AIS during the convalescent phase of an asymptomatic COVID-19 infection confirmed by a positive SARS-CoV-2 serological (antibodies) test result, the median onset of stroke was 2 months after the diagnosis of COVID-19.

Meaning Results of this study suggest a persistent increased risk of AIS in individuals with asymptomatic COVID-19 months after serological diagnosis, warranting stroke units to be on alert and use SARS-CoV-2 serological testing.

Abstract

Importance Acute ischemic stroke (AIS) is a known neurological complication in patients with respiratory symptoms of COVID-19 infection. However, AIS has not been described as a late sequelae in patients without respiratory symptoms of COVID-19.

Objective To assess AIS experienced by adults 50 years or younger in the convalescent phase of asymptomatic COVID-19 infection.

Design, Setting, and Participants This case series prospectively identified consecutive male patients who received care for AIS from public health hospitals in Singapore between May 21, 2020, and October 14, 2020. All of these patients had laboratory-confirmed asymptomatic COVID-19 infection based on a positive SARS-CoV-2 serological (antibodies) test result. These patients were individuals from South Asian countries (India and Bangladesh) who were working in Singapore and living in dormitories. The total number of COVID-19 cases (54 485) in the worker dormitory population was the population at risk. Patients with ongoing respiratory symptoms or positive SARS-CoV-2 serological test results confirmed through reverse transcriptase–polymerase chain reaction nasopharyngeal swabs were excluded.

Main Outcomes and Measures Clinical course, imaging, and laboratory findings were retrieved from the electronic medical records of each participating hospital. The incidence rate of AIS in the case series was compared with that of a historical age-, sex-, and ethnicity-matched national cohort.

Results A total of 18 male patients, with a median (range) age of 41 (35-50) years and South Asian ethnicity, were included. The median (range) time from a positive serological test result to AIS was 54.5 (0-130) days. The median (range) National Institutes of Health Stroke Scale score was 5 (1-25). Ten patients (56%) presented with a large vessel occlusion, of whom 6 patients underwent intravenous thrombolysis and/or endovascular therapy. Only 3 patients (17%) had a possible cardiac source of embolus. The estimated annual incidence rate of AIS was 82.6 cases per 100 000 people in this study compared with 38.2 cases per 100 000 people in the historical age-, sex-, and ethnicity-matched cohort (rate ratio, 2.16; 95% CI, 1.36-3.48; P < .001).

Conclusions and Relevance This case series suggests that the risk for AIS is higher in adults 50 years or younger during the convalescent period of a COVID-19 infection without respiratory symptoms. Acute ischemic stroke could be part of the next wave of complications of COVID-19, and stroke units should be on alert and use serological testing, especially in younger patients or in the absence of traditional risk factors.

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Article Information

Accepted for Publication: March 4, 2021.

Published: April 22, 2021. doi:10.1001/jamanetworkopen.2021.7498

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Tu TM et al. JAMA Network Open.

Corresponding Author: Tian Ming Tu, MRCP, Department of Neurology, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433 (tu.tian.ming@singhealth.com.sg).

Author Contributions: Dr Tu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Tu, Seet, Umapathi.

Acquisition, analysis, or interpretation of data: Tu, Seet, Tham, Koh, Chiew, De Leon, Chua, Hui, S. S. Y. Tan, Vasoo, B. Y.-Q. Tan, Tambyah, Yeo.

Drafting of the manuscript: Tu, Seet, Koh, De Leon, Chua, B. Y.-Q. Tan, Tambyah.

Critical revision of the manuscript for important intellectual content: Tu, Tham, Chiew, Hui, S. S. Y. Tan, Vasoo, B. Y.-Q. Tan, Umapathi, Tambyah, Yeo.

Statistical analysis: Tu, De Leon, B. Y.-Q. Tan.

Administrative, technical, or material support: Tham, Koh, Chiew, Hui, S. S. Y. Tan, B. Y.-Q. Tan, Umapathi, Tambyah, Yeo.

Supervision: Umapathi, Yeo.

Conflict of Interest Disclosures: Dr Tambyah reported receiving grants paid to the institution from Roche, Shionogi, Arcturus, and Johnson and Johnson as well as honorarium paid to the institution from AJ Biologics. Dr Yeo reported receiving personal fees from Stryker and grants from the National Medical Research Council of Singapore outside the submitted work. No other disclosures were reported.

References

Ji T , Chen HL , Xu J , et al. Lockdown contained the spread of 2019 novel coronavirus disease in Huangshi City, China: early epidemiological findings. Clin Infect Dis. 2020;71(6):1454-1460. doi:10.1093/cid/ciaa390 PubMed Google Scholar Crossref

Bi Q , Wu Y , Mei S , et al. Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study. Lancet Infect Dis. 2020;20(8):911-919. doi:10.1016/S1473-3099(20)30287-5 PubMed Google Scholar Crossref

Furuse Y , Sando E , Tsuchiya N , et al. Clusters of coronavirus disease in communities, Japan, January-April 2020. Emerg Infect Dis. 2020;26(9):2176-2179. doi:10.3201/eid2609.202272 PubMed Google Scholar

Dong Y , Mo X , Hu Y , et al. Epidemiology of COVID-19 among children in China. Pediatrics. 2020;145(6):e20200702. doi:10.1542/peds.2020-0702 PubMed Google Scholar

Shi SM , Bakaev I , Chen H , Travison TG , Berry SD . Risk factors, presentation, and course of coronavirus disease 2019 in a large, academic long-term care facility. J Am Med Dir Assoc. 2020;21(10):1378-1383.e1. doi:10.1016/j.jamda.2020.08.027 PubMed Google Scholar Crossref

Rivett L , Sridhar S , Sparkes D , et al; CITIID-NIHR COVID-19 BioResource Collaboration. Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission. Elife. 2020;9:e58728. doi:10.7554/eLife.58728 PubMed Google Scholar

Rubin R . As their numbers grow, COVID-19 “long haulers” stump experts. JAMA. 2020;324(14):1381-1383. doi:10.1001/jama.2020.17709 PubMed Google Scholar Crossref

Merkler AE , Parikh NS , Mir S , et al. Risk of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) vs patients with influenza. JAMA Neurol. 2020;77(11):1366-1372. doi:10.1001/jamaneurol.2020.2730 PubMed Google Scholar Crossref

Tan YK , Goh C , Leow AST , et al. COVID-19 and ischemic stroke: a systematic review and meta-summary of the literature. J Thromb Thrombolysis. 2020;50(3):587-595. doi:10.1007/s11239-020-02228-y PubMed Google Scholar Crossref

Bikdeli B , Madhavan MV , Jimenez D , et al; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(23):2950-2973. doi:10.1016/j.jacc.2020.04.031 PubMed Google Scholar Crossref

Zhang Y , Xiao M , Zhang S , et al. Coagulopathy and antiphospholipid antibodies in patients with COVID-19. N Engl J Med. 2020;382(17):e38. doi:10.1056/NEJMc2007575 PubMed Google Scholar

Goshua G , Pine AB , Meizlish ML , et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol. 2020;7(8):e575-e582. doi:10.1016/S2352-3026(20)30216-7 PubMed Google Scholar Crossref

Oxley TJ , Mocco J , Majidi S , et al. Large-vessel stroke as a presenting feature of COVID-19 in the young. N Engl J Med. 2020;382(20):e60. doi:10.1056/NEJMc2009787 PubMed Google Scholar

Ministry of Health, Singapore. COVID-19 interactive situation report. Updated October 14, 2020. Accessed October 14, 2020. https://www.moh.gov.sg/docs/librariesprovider5/local-situation-report/situation-report---14-oct-2020.pdf

De Deyn MLZQ , Ng QX , Loke W , Yeo WS . A tale of two cities: a comparison of Hong Kong and Singapore’s early strategies for the coronavirus disease 2019 (COVID-19). J Infect. 2020;81(3):e51-e52. doi:10.1016/j.jinf.2020.06.058 PubMed Google Scholar Crossref

Koh JS , De Silva DA , Quek AML , et al. Neurology of COVID-19 in Singapore. J Neurol Sci. 2020;418:117118. doi:10.1016/j.jns.2020.117118 PubMed Google Scholar

von Elm E , Altman DG , Egger M , Pocock SJ , Gøtzsche PC , Vandenbroucke JP ; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370(9596):1453-1457. doi:10.1016/S0140-6736(07)61602-X PubMed Google Scholar Crossref

Ministry of Health, Singapore. Singapore Stroke Registry annual report 2018. Health Promotion Board; National Registry of Diseases Office. June 9, 2020. Accessed October 14, 2020. https://www.nrdo.gov.sg/docs/librariesprovider3/default-document-library/ssr-web-report-2018.pdf?sfvrsn=58eb7c4c_0

Rothman KJ . Modern Epidemiology. Little Brown & Co; 1986.

Adams HP Jr , Bendixen BH , Kappelle LJ , et al; TOAST Investigators. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. Stroke. 1993;24(1):35-41. doi:10.1161/01.STR.24.1.35 PubMed Google Scholar Crossref

Department of Statistics Singapore. M810011—Singapore residents by age group, ethnic group and sex, end June, annual. Updated September 24, 2020. Accessed October 14, 2020. https://data.gov.sg/dataset/resident-population-by-ethnicity-gender-and-age-group

Avula A , Nalleballe K , Narula N , et al. COVID-19 presenting as stroke. Brain Behav Immun. 2020;87:115-119. doi:10.1016/j.bbi.2020.04.077 PubMed Google Scholar Crossref

Rothstein A , Oldridge O , Schwennesen H , Do D , Cucchiara BL . Acute cerebrovascular events in hospitalized COVID-19 patients. Stroke. 2020;51(9):e219-e222. doi:10.1161/STROKEAHA.120.030995 PubMed Google Scholar Crossref

Sethuraman N , Jeremiah SS , Ryo A . Interpreting diagnostic tests for SARS-CoV-2. JAMA. 2020;323(22):2249-2251. doi:10.1001/jama.2020.8259 PubMed Google Scholar Crossref

Ferroli P , Villa C , Ciuffi A , Gubertini G , Broggi M . Long lasting hypercoagulability after subclinical COVID-19. J Thromb Thrombolysis. 2020;50(4):822-824. doi:10.1007/s11239-020-02215-3 PubMed Google Scholar Crossref

Tsang ACO , You J , Li LF , et al. Burden of large vessel occlusion stroke and the service gap of thrombectomy: a population-based study using a territory-wide public hospital system registry. Int J Stroke. 2020;15(1):69-74. doi:10.1177/1747493019830585 PubMed Google Scholar Crossref

Kim BJ , Kim JS . Ischemic stroke subtype classification: an Asian viewpoint. J Stroke. 2014;16(1):8-17. doi:10.5853/jos.2014.16.1.8 PubMed Google Scholar Crossref

Klok FA , Kruip MJHA , van der Meer NJM , et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res. 2020;191:148-150. doi:10.1016/j.thromres.2020.04.041 PubMed Google Scholar Crossref

Beyrouti R , Adams ME , Benjamin L , et al. Characteristics of ischaemic stroke associated with COVID-19. J Neurol Neurosurg Psychiatry. 2020;91(8):889-891. doi:10.1136/jnnp-2020-323586 PubMed Google Scholar Crossref

Fournier M , Faille D , Dossier A , et al. Arterial thrombotic events in adult inpatients with COVID-19. Mayo Clin Proc. 2021;96(2):295-303. doi:10.1016/j.mayocp.2020.11.018 PubMed Google Scholar Crossref

von Meijenfeldt FA , Havervall S , Adelmeijer J , et al. Sustained prothrombotic changes in COVID-19 patients 4 months after hospital discharge. Blood Adv. 2021;5(3):756-759. doi:10.1182/bloodadvances.2020003968 PubMed Google Scholar Crossref

Tan SS , Saw S , Chew KL , et al. Comparative clinical evaluation of the Roche Elecsys and Abbott SARS-CoV-2 serology assays for COVID-19. Arch Pathol Lab Med. 2020. doi:10.5858/arpa.2020-0499-SA PubMed Google Scholar

The Lancet Haematology. COVID-19 and thrombosis: a continuing story. Lancet Haematol. 2021;8(2):e95. doi:10.1016/S2352-3026(21)00002-8 PubMed Google Scholar

Rosadas C , Randell P , Khan M , McClure MO , Tedder RS . Testing for responses to the wrong SARS-CoV-2 antigen? Lancet. 2020;396(10252):e23. doi:10.1016/S0140-6736(20)31830-4 PubMed Google Scholar

Yamaoka Y , Jeremiah SS , Miyakawa K , et al. Whole nucleocapsid protein of SARS-CoV-2 may cause false positive results in serological assays. Clin Infect Dis. 2020;ciaa637. doi:10.1093/cid/ciaa637 PubMed Google Scholar

Ladikou EE , Sivaloganathan H , Milne KM , et al. Von Willebrand factor (vWF): marker of endothelial damage and thrombotic risk in COVID-19? Clin Med (Lond). 2020;20(5):e178-e182. doi:10.7861/clinmed.2020-0346 PubMed Google Scholar Crossref

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