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

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 SARSCoV-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 ethnicitymatched 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. JAMA Network Open. 2021;4(4):e217498. doi:10.1001/jamanetworkopen.2021.7498 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. Author affiliations and article information are listed at the end of this article. Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2021;4(4):e217498. doi:10.1001/jamanetworkopen.2021.7498 (Reprinted) April 22, 2021 1/12 Downloaded From: https://jamanetwork.com/ by a Non-Human Traffic (NHT) User on 08/23/2021


Introduction
As the COVID-19 pandemic progresses, many asymptomatic or mildly symptomatic cases of COVID-19 infection have been identified, either by contact tracing [1][2][3] or through surveillance programs, in various risk-stratified population groups. [4][5][6] At the same time, there have been reports of symptoms emerging or persisting long after the resolution of the original acute infection, which have been described as long-haul symptoms of COVID- 19. 7 Acute ischemic stroke (AIS) is a known neurological complication in patients with acute COVID-19 infection. 8,9 The mechanism of AIS that is associated with COVID-19 has been postulated to be secondary to an associated coagulopathy 10 either by antiphospholipid antibodies 11 or endotheliopathy. 12 This theory has been observed in critically ill patients and in younger patients presenting with a large vessel occlusion. 13 However, it is unknown whether patients who had an asymptomatic or a minimally symptomatic COVID-19 infection are similarly at risk for AIS as those patients who had overt acute respiratory COVID-19 illness.
In the city-state of Singapore, COVID-19 has been confirmed in 57 889 individuals as of October 14, 2020. 14 Most of the infections have been localized to clusters of workers from South Asian countries (India and Bangladesh) who were living in dormitories, 14,15 accounting for 94% (54 485 cases) of all COVID-19 cases in Singapore. This clustering was primarily associated with the proximity of the inhabitants in residential complexes. Active surveillance of close contacts has identified many cases of COVID-19 through serological tests. In this case series, we assessed AIS that occurred in a series of men aged 50 years or younger in the convalescent phase of asymptomatic  infection.

Methods
In this case series, all patients who experienced AIS and were under the care of public health care institutions in Singapore from May 21 to October 14, 2020 (a total of 21 weeks), were identified prospectively. These patients were admitted or referred to neurology units for the care of their AIS. 16 This study was approved by the Singhealth Centralised Institutional Review Board, which granted a waiver of informed consent because of the observational nature of the study. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. 17 We retrieved clinical course, imaging, and laboratory data from the electronic medical records of each participating hospital. Acute ischemic stroke was confirmed by neuroimaging using either computed tomography angiography and computed tomography of the brain or magnetic resonance imaging and magnetic resonance angiography of the brain. Included patients had asymptomatic or no respiratory symptoms of COVID-19, which was confirmed by a positive SARS-CoV-2 serological (antibodies) test result. Serological testing was performed using either the Architect SARS-CoV-2 IgG assay (Abbott Diagnostics) or the Elecsys Anti-SARS-CoV-2 assay (Roche Diagnostics), which are immunoassays designed to detect the nucleocapsid antibody of SARS-CoV-2. All patients were managed by their respective neurologists, and the tests performed were according to the physician's discretion. Patients were excluded if they had ongoing respiratory symptoms or positive SARS-CoV-2 test results confirmed through reverse transcriptase-polymerase chain reaction (RT-PCR) nasopharyngeal swabs.
We calculated the annual incidence rate of AIS for this study population and compared it with the annual incidence rate of a historical, national ischemic stroke cohort (obtained from the Singapore Ministry of Health) that was matched by age, sex, and ethnicity (Indian and Bangladeshi). 18 The population at risk in the study cohort was the total number of confirmed COVID-19 cases (n = 54 485) within the dormitory population in Singapore.

Statistical Analysis
Rate ratio (95% CI) and significance were calculated with the statistical test described by Rothman,19 in which a 2-sided, unpaired P < .05 was used to indicate statistical significance. Stata release 16 (StataCorp LLC) was used for the statistical analysis.

Results
A total of 18 consecutive male patients, with a median (range) age of 41 (35-50) years (Table 1), presented with AIS as the initial but delayed manifestation of COVID-19. Seventeen patients were asymptomatic for acute respiratory illness but were diagnosed with COVID-19 (by a positive SARS-CoV-2 serological test result) before their AIS. One patient (6%) was tested during an acute hospital stay for AIS. One patient (6%) reported mild diarrhea during the time of isolation but had no respiratory symptoms or anosmia. All patients were tested (and had negative results) at least once for COVID-19 using RT-PCR swabs because they were either in direct contact with individuals with COVID-19 infection or had stayed in the same dormitory facilities as others with COVID-19 infection.
All patients survived with no evidence of respiratory symptoms during their AIS hospitalization.
All patients had negative nasopharyngeal and pharyngeal RT-PCR swab results for COVID-19 during their acute hospitalization for AIS.
The median (range) time from positive serological result to AIS was 54.5 (0-130) days. Chest radiographs were unremarkable in all patients, and 12 patients (67%) had no known preexisting risk factors of AIS (ie, hypertension and hyperlipidemia). The spectrum and severity of stroke varied among the 18 cases, with a median (range) National Institutes of Health Stroke Scale score of 5 (1-25) ( Table 2). Six patients (33%) had intravenous thrombolysis and/or endovascular therapy. Ten  (Table 2). Eight patients (44%) were diagnosed with a large vessel occlusion but had no obvious atherosclerosis, and the cause of stroke was classified as undetermined.
A screen for underlying coagulopathy was performed for all patients, and increased levels of dimerized plasmin fragment D (D-dimer) were detected in 3 patients (17%; Table 4). Two patients (11%) had positive results for lupus anticoagulant antibodies but negative results for other antiphospholipid antibodies ( Table 5). Although not universally tested, von Willebrand factor antigen levels were elevated in 2 of 3 patients tested ( Table 5).
The annual incidence rate of AIS in this all-male cohort with asymptomatic COVID-19 infection was 82.6 cases per 100 000 people. This rate was calculated on the basis of 18 patients who experienced AIS and a population at risk of 54 485 people over a study period of 21 weeks. The historical annual age-, sex-, and ethnicity-matched incidence rate of AIS was 38.2 cases per 100 000 people. This rate was calculated on the basis of 34 age-, sex-, and ethnicity-matched patients who experienced AIS from the 2018 national data and a similarly matched population at risk of 89 069 people over the same period. 21 Therefore, the annual incidence rate in this all-male cohort was significantly higher compared with the annual incidence rate of the historical age-, sex-, and ethnicity-matched cohort (rate ratio, 2.16; 95% CI, 1.36-3.48; P < .001).   23 In addition, with an estimated production and persistence of  COVID-19 antibodies about 2 weeks (although ranging from 1 to 6 weeks) after the initial COVID-19

JAMA Network Open | Neurology
infection, 24 coagulopathy may likely be observed for months after the initial exposure in patients with a subclinical COVID-19 infection. 25 In most of the cohort (56%), large vessel occlusions were detected on initial computed tomography or magnetic resonance angiography imaging, and 7 patients (39%) had an anterior   circulation large vessel occlusion. This percentage was higher than an estimated 13% of patients in Hong Kong who had an ischemic stroke and an anterior circulation large vessel occlusion. 26 Even in patients without a large vessel occlusion, the infarct pattern suggested an embolic phenomenon from a proximal source. Further evaluation did not reveal the origin of any proximal thrombus or any atherosclerotic-related lesions. These observations suggest an embolic or a prothrombotic phenomenon as the cause of AIS. Despite assessing a thorough stroke workup, we were unable to find an underlying mechanism except the unifying positive SARS-CoV-2 serological test results in all 13 patients (72%) whose stroke had an undetermined classification. The percentage (72%) of strokes classified as having an undetermined cause is higher than the estimated 20% to 25% cryptogenic stroke observed in Asian patients. 27 In particular, a thorough cardiac workup showed that 1 patient  studies need to examine the association of COVID-19 with the increased risk of strokes in the older population, which may be potentially higher.

JAMA Network Open | Neurology
A previous study has shown that serological assays exhibit diagnostic accuracy for COVID-19 only after 14 days of symptom onset, allowing appropriate antibody seroconversion in the host. 32 The present report suggests another suitable case-use criterion for COVID-19 serological tests, taking into consideration its natural history and clinical course of infection. Given that these tests are designed to be qualitative in nature, future research may identify the association between quantitative antibody titers and the severity of stroke.
The need for universal COVID-19 serological screening in younger adults without respiratory symptoms who experienced a stroke is debatable, and further studies are required to define the subgroups in whom and the duration in which a prothrombotic or persistent inflammatory state is

Limitations
This study has limitations. First, it was purely observational in nature, and coagulopathy testing was dependent on physician discretion and the availability of clinical resources at each health care institution during the pandemic. This limitation was exemplified by the minimal testing for von Willebrand factor 36 and other blood clotting factors, which are known coagulopathy risk factors in patients with COVID-19 infection. Second, all of the patients in this cohort were men from the South Asia region; most patients with COVID-19 infection in Singapore were living in the foreign worker dormitories with overwhelmingly male inhabitants. Hence, the findings related to AIS after COVID-19 infection may be generalizable only to a male South Asian population. In addition, the annual incidence rate was based on the single case series and should be interpreted with caution. A larger, population-based incidence rate is needed to verify the findings.