In a well-designed, epidemiological study, UK researchers have found that Asian ethnicity is strongly linked to COVID-related stroke. Among patients with ischaemic stroke, which is caused by a blocked artery, nearly 1 in 5 (20%) of those with COVID-19 infection when they had their stroke were Asian-more than twice the proportion seen in ischaemic stroke patients without COVID-19. Based on the study, and their extensive experience, the researchers gave recommendations on how to manage stroke patients during the ongoing COVID-19 pandemic.

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With no efficacious drug as silver bullet to treat, COVID-19 continues to affect adversely large sections of the population globally. Physicians recognise COVID-19 mainly as a viral pneumonia. Its characteristic features are a dry cough, high fever, shortness of breath and loss of taste and smell. However, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for this illness, may influence the presentation of ischaemic stroke, a conclusion that remains controversial because of a lack of high-quality evidence.

One of the major issues is that the largest studies have compared patients with COVID-19-associated stroke with historical controls, whose strokes tend to be milder than those seen in contemporaneous controls, resulting in a bias towards overestimating the influence of COVID-19 on stroke severity and any other parameters correlated with severity.

The present study led by Dr Richard J Perry, Comprehensive Stroke Service, National Hospital for Neurology & Neurosurgery, UCL Hospitals NHS Foundation Trust, London, and others and published on line on 5th November 2020 in the Journal of Neurology Neurosurgery and Psychiatry showed that Asian ethnicity is strongly linked to COVID-related strokes. Their data suggest that COVID-19 may be an important modifier of the onset, characteristics and outcome of acute ischaemic stroke. The researchers have given recommendations on how to manage stroke patients during the pandemic.

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Research objectives

The researchers wanted to determine whether COVID-19 is associated with: a different demographic group; a higher proportion of ischaemic strokes; higher *D-dimer values in ischaemic strokes, as may be expected of a SARS-CoV-2-related hypercoagulable state; a different distribution of stroke mechanisms, possibly with a predominance of large vessel occlusions; more severe strokes with worse outcomes, including a higher inpatient mortality; a higher rate of early recurrence of stroke; and a delay between the onset of symptoms of infection and of stroke.

*D-dimer levels

Levels of D-dimers, a protein marker for the stickiness of blood, were also higher in COVID-19-related strokes than in other strokes. [D-dimers test: This is a blood test to look for a substance called D-dimer. This test is used to rule out a blood clot. D-dimer is a protein fragment from the breakdown of a blood clot. Blood clots generally start to slowly break down after they are formed, and this process releases D-dimer into the blood.]

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The study

SETICOS (Service Evaluation of The Impact of COVID-19 on Stroke) is an ongoing project in 13 stroke centres across England and Scotland. The researchers carried out a case-control study from within the project to address the research objectives. It included patients admitted with stroke to 13 hospitals in England and Scotland between 9th March and 5th July 2020. They collected data on 86 strokes (81 ischaemic strokes and 5 intracerebral haemorrhages) in patients with evidence of COVID-19 at the time of stroke onset (cases). The controls were 1384 strokes (1193 ischaemic strokes and 191 intracerebral haemorrhages) in patients admitted during the same time period who never had evidence of COVID-19

In addition, the whole group of stroke admissions including another 37 in patients who appear to have developed COVID-19 after their stroke were included in two statistical analyses examining which features were independently associated with COVID-19 status and with inpatient mortality.

They defined cases (strokes inpatients withSARS-CoV-2 at the time of stroke onset) and controls. For the SARS-CoV-2-positive “case” group, they included all strokes inpatients who tested positive within 4 days of admission (or within 4 days of their stroke for inpatient strokes), even if they were negative on their first test, because RT-PCR on respiratory samples has a low sensitivity for SARS-CoV-2. The researchers assumed that these patients would be very unlikely to have acquired the infection in hospital and turned PCR-positive within such a short time. They also included strokes inpatients who already had clinical features suspicious of COVID-19 at the time of admission and were found to be SARS-CoV-2-positive at any point during the first 10 days of admission.

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Results

Previous research has suggested that COVID-19 infection might make the blood stickier and so more liable to clot, so potentially boosting the risk of a stroke, but this finding has been undermined by the poor quality of the evidence to date and the reliance on comparisons with historical stroke data.

In the present study, the researchers used contemporary data. The researchers collected data for 1470 strokes among patients admitted to 13 hospitals between March and July this year, during the first wave of the coronavirus pandemic to obtain a clearer real-time picture of the potential impact of COVID-19 on stroke risk. During this period, there were 86 strokes in patients with evidence of COVID-19 at the time: 81 of these strokes were ischaemic (caused by blocked blood vessels); the remainder were intracerebral haemorrhages (caused by burst blood vessels).

Researchers determined evidence of infection by a positive coronavirus test within 4 days of admission or suspected COVID-19 at the time of admission and confirmed on testing at any point during the subsequent 10 days.

They compared the features of these 'COVID' strokes with 1384 (1193 ischaemic and 191 intracerebral) among patients admitted during the same time period, but with no evidence of COVID-19.

Researchers recorded the ethnicity in 86% of COVID cases and 78% of non-COVID cases. Among patients with ischaemic stroke nearly 1 in 5 (19%) of those with COVID-19 infection when they had their stroke were Asian--more than twice the proportion seen in ischaemic stroke patients without COVID-19 (7%). This rate was higher than that seen in people of Afro-Caribbean ethnicity.

In a press release, the lead study author, Dr Richard Perry, commented:

"Our study suggests that COVID-19 has had more impact on strokes in the Asian community than in other ethnic groups. We cannot say from our data whether this is because Asians are more likely to catch COVID-19, but it seems unlikely that this is the sole explanation."

He clarified:

"Evidence from Public Health England suggests that, in the UK, people of Afro-Caribbean origin are at the highest risk of catching COVID-19, whereas those of Asian descent have only a marginally higher risk than White people. We suspect, therefore, that Asian people who contract COVID-19 may have a higher risk of COVID-19-associated stroke than is seen in other ethnic groups."

Ischaemic strokes in COVID patients were around twice as likely to be caused by the blockage of more than one large blood vessel in the brain (18% vs 8%), and to be more severe, with an average stroke severity *(NIHSS) score of 8 vs 5.

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A note on *(NIHSS) score

NIH Stroke Score (NIHSS) The National Institutes of Health Stroke Scale, or NIH Stroke Scale (NIHSS) is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. [Score 0: No stroke symptoms; 1-4: Minor stroke; 5-15: Moderate stroke 16-20 Moderate to severe stroke 21-42 Severe stroke]

Ischaemic strokes in COVID-19 patients were associated with more severe disability on discharge--average disability score of 5 (out of a possible 6)--and death while in hospital (20% vs 10%), even after accounting for other influential risk factors.

1. In the 45 COVID patients who had had an ischaemic stroke, and for whom both dates were recorded, cardinal COVID-19 symptoms occurred an average of 6 days before the stroke.
2. Among the 3 patients who had a brain bleed, and for whom both dates were recorded, COVID-19 symptoms occurred an average of 4 days after the stroke. Although the numbers are small, this difference is significant, say the researchers.

They did not find any evidence to back up previous suggestions that SARS-CoV-2, the virus responsible for COVID-19 infection, is associated with younger age or male sex in stroke patients.

The researchers acknowledge that a major limitation of their study was that they were only able to report investigations done as part of routine clinical care. But they included patients from 13 centres across the UK, so it may be more representative than existing studies from a single hospital system or city, they suggest.

According to the researchers, these findings confirm that COVID-19 has an important influence over the onset, characteristics and outcome of acute ischaemic stroke. How the virus exerts its influence is still unclear, but one single factor is unlikely to be responsible, they explain.

They suggest that COVID-19 may provoke the onset of an ischaemic stroke through a variety of thrombotic [clot forming] and inflammatory mechanisms, promoting generation of thrombus [blood clot] in the heart or large vessels or via small vessel occlusion [blockage]. They stated, "Which of these mechanisms manifests in a given patient may be determined by that individual's conventional vascular risk factors, such as atrial fibrillation [abnormal heart beat], large vessel atheroma [artery narrowing], hypertension [high blood pressure] or type 2 diabetes mellitus."

They concluded that their study provides the most compelling evidence yet that COVID-19-associated ischaemic strokes are more severe and more likely to result in severe disability or death, although the outlook is not quite as bleak as previous studies have suggested. The researchers found that recurrence of stroke during the patient’s admission was rare in cases and controls (2.3% vs1.0%).

Results of the study (in brief)

Cases with ischaemic stroke were

• more likely than ischaemic controls to occur in Asians (18.8% vs 6.7%),
• more likely to involve multiple large vessel occlusions (17·9% vs 8.1%),
• more severe (median NIHSS 8 vs 5),
• associated with higher D-dimer levels, and
• associated with more severe disability on discharge (median *mRS 4 vs 3) and in patient death (19.8% vs 9·6%).

*mRS : The Modified Rankin Score (mRS) is a 6 point disability scale with possible scores ranging from 0 to 5. A separate category of 6 is usually added for patients who expire. The Modified Rankin Score (mRS) is the most widely used outcome measure in stroke clinical trials.

The researchers found that recurrence of stroke during the patient’s admission was rare in cases and controls (2.3% vs 1.0%).

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Recommendations

Based on their results, they gave the following recommendations for management of stroke patients during the ongoing COVID-19 pandemic:

If at any point a stroke centre is not routinely testing all stroke admissions for SARS-CoV-2, patients presenting with ischaemic stroke and very elevated D-dimers with no other explanation should be considered for testing, even if the clinical suspicion of COVID-19 is otherwise low. Criteria for requesting CT angiography in stroke patients may now need to take account of their COVID-19 status, because the finding of multiple large vessel occlusions may require a specific management strategy such as mechanical thrombectomy or possibly, in the future, a different antithrombotic agent. On the other hand, in most patients with COVID-19-associated ischaemic stroke, very early anticoagulation is probably not warranted as a strategy to prevent inpatient stroke recurrence, as this outcome is too uncommon to justify the increased risk of secondary haemorrhage.

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Expert comments

Dr. David Strain, Senior Clinical Lecturer, University of Exeter, in his comment provided to the Science Media Centre, London stated that it is well established that people of South Asian heritage develop stroke approximately 10 years earlier than their counterparts of European descent.

He clarified, “This is often described as being a result of premature vascular ageing and a predisposition towards type 2 diabetes. Separately people of South Asian descent have been demonstrated to have a higher risk of hospitalisation, admission and ultimately death due to COVID-19. Further, the two of the biggest risk factors for stroke (namely ischaemic heart disease and type 2 diabetes) are more common in people of South Asian descent and are independent risk factors for COVID-19. Multiple arterial blood clots are a well-recognised complication of COVID-19 and, personally, I have seen multiple ischaemic strokes in people with COVID-19.”

“The only surprise in this, therefore, is the rather large incidence of stroke in those of South Asian descent. One important confounder that is not mentioned however the geographical location the data was collated from is. At the time these data were collected, regions of the country with a greater South Asian population were also those with a higher prevalence of COVID-19 (i.e. COVID-19 was centred around London, Birmingham and Leicester, which coincidentally have higher South Asian population – on average 4 – 7% of the population, and 26.4% in the epicentre of the UK COVID-19 first wave outbreak), therefore stroke from these regions were both more likely to be in people of Asian descent and to have COVID-19, whereas areas of the country with lower COVID-19 cases also had smaller ethnic minority populations (such as Manchester, Stoke on Trent or Glasgow (all <2% and very low prevalence of COVID-19 in the first wave)."

“If the North of the UK provided the majority of the control cases whereas the South East and Midlands provided the majority of cases (in keeping with the distribution of COVID-19 in the first wave) this would easily account for the residual ethnic difference between.:

He cautioned, “This manuscript would be substantially stronger if it reported the geographical location of cases and controls, and adjusted for background prevalence of COVID in the first wave compared to local ethnic diversity. If these observations stand up to that type of analysis they would warrant further investigation to determine if the mechanism by which COVID appears to be more deadly in people of South Asia descent is due to an increased impact on the risk of widespread blood clots.”

Dr. David Strain’s comments highlight the need to find out and account for the presence of confounding factors in epidemiological studies.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr. K S Parthasarathy is a freelance science journalist and a former Secretary of the Atomic Energy Regulatory Board. He is available at ksparth@yahoo.co.uk