Preceding infection and risk of stroke: An old concept revived by the COVID-19 pandemic

Wrong, wrong, wrong! We don't need lazy predictions, WE NEED PREVENTIONS! GET THERE!

Preceding infection and risk of stroke: An old concept revived by the COVID-19 pandemic

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Kieron South, Laura McCulloch, Barry W McColl, ...

First Published July 24, 2020 Review Article Find in PubMed

https://doi.org/10.1177/1747493020943815

Article information

Abstract

Anecdotal reports and clinical observations have recently emerged suggesting a relationship between COVID-19 disease and stroke, highlighting the possibility that infected individuals may be more susceptible to cerebrovascular events. In this review we draw on emerging studies of the current pandemic and data from earlier, viral epidemics, to describe possible mechanisms by which SARS-CoV-2 may influence the prevalence of stroke, with a focus on the thromboinflammatory pathways, which may be perturbed. Some of these potential mechanisms are not novel but are, in fact, long-standing hypotheses linking stroke with preceding infection that are yet to be confirmed. The current pandemic may present a renewed opportunity to better understand the relationship between infection and stroke and possible underlying mechanisms.

Keywords COVID-19, infection, ischemic stroke, risk factors, SARS-CoV-2, stroke prevalence, vascular events

Introduction

The SARS-CoV-2 global pandemic

At the time of writing, the global number of confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases is approaching 9 million, with over 470,000 reported fatalities. The current novel coronavirus outbreak began to receive worldwide media attention in early January 2020 with the earliest cluster of cases traced back to December 2019 in the city of Wuhan in China. By 30 January the World Health Organization (WHO) declared the outbreak a “public health emergency of international concern” and, after cases were reported in 210 countries, the outbreak was recognized by WHO as a pandemic on 11 March 2020.
SARS-CoV-2 is a member of the betacoronavirus genus of the coronaviridae family of enveloped, single-stranded RNA viruses, several of which are known to cause mild respiratory disease in humans. It was named because of its similarity to SARS-CoV, the virus responsible for an epidemic in 2002–2003 that infected approximately 8000 people with almost 800 fatalities. Both SARS-CoV and SARS-CoV-2 cause acute respiratory symptoms but due to enhanced rates of transmission derived from transmission from asymptomatic individuals¹ and a high level of early viral shedding in the upper respiratory tract,² this recent pandemic has attained a large global impact.
Angiotensin-converting enzyme 2 (ACE2), the “receptor” for host cell entry of SARS-CoV-2,³ is most prominently expressed on the surface of lung alveolar epithelial cells, venous and arterial endothelial cells, arterial smooth muscle cells and enterocytes of the small intestine.⁴ Notably, considering the possible neurotropism of SARS-CoV-2 discussed later, ACE2 is also found on cardio-respiratory neurons of the brainstem, in the hypothalamus and the motor cortex.⁵ There is evidence that SARS-CoV (and possibly SARS-CoV-2) is able to infect lymphocytes, monocytes and lymphoid tissues.⁶ This tissue distribution is a critical determinant of the COVID-19 disease course and may drive some of the thromboinflammatory alterations that might influence stroke pathophysiology, as discussed in this review.

Clinical presentation of COVID-19

Unlike its predecessor SARS, COVID-19 manifests as a broad spectrum of disease severity from a completely asymptomatic state of infection, through mild flu-like symptoms, to the life-threatening acute respiratory distress syndrome (ARDS). It has been estimated that as many as 86% of cases in China were asymptomatic or mildly symptomatic and were, therefore, undocumented.¹ The multitude of factors contributing to this disparity in disease severity are not yet fully understood and are likely to include genetic, environmental and host response factors and would, therefore, be outside the scope of this review. However, it is already clear that disease progression is, to some extent, linked to viral load,⁷ age, sex, ethnicity and comorbidity.^8,9
At onset of illness the most common symptoms are fever, cough, myalgia, anosmia and fatigue. Common chest radiological findings are bilateral ground–glass opacity, interlobular septal thickening, and thickening of the pleura.¹⁰ In patients who went on to develop ARDS, pleural effusion, lymphadenopathy and round cystic changes were also observed, similar to those seen previously in SARS,¹¹ Middle East respiratory Syndrome (MERS)¹² and H₅N₁ influenza.¹³ Patients who develop ARDS experience severe hypoxemia, and the leading causes of mortality are respiratory failure, heart failure, fulminant myocarditis and multiple organ failure.

Cerebrovascular complications in COVID-19 patients

The possible relationship between respiratory tract infection and the incidence of stroke, particularly ischemic stroke, is not a new concept. Early case–control studies identified respiratory tract infections as a significant risk factor across all age groups despite adjusting for other known vascular risk factors.¹⁴ A large case-series analysis of UK medical records identified a significant risk of either first stroke or recurrent stroke associated with a diagnosis of acute respiratory tract infection.¹⁵ This risk was highest in the first few days after infection, steadily declining thereafter but remaining elevated over baseline for some time. The incidence ratio of first stroke was found to be 3.19 (95% CI 2.81 to 3.62) within three days of infection and 2.09 (95% CI 1.89 to 2.32) within 14 days. A later retrospective case-crossover study of administrative data in the US, focusing on respiratory tract infections defined using Centers for Disease Control and Prevention criteria as “influenza-like illness”, identified a similar risk of ischemic stroke within 15 days of infection (odds ratio 2.88, 95% CI 1.86 to 4.47).¹⁶
Large, systematically collated datasets are not yet available for the current SARS-CoV-2 pandemic and, as such reliable estimates of the associated risk of stroke have not yet been published. This is also true of the previous SARS pandemic that only affected 8000 individuals. Although, an approximate stroke incidence rate of 1 per 42 SARS patients was determined from a small, retrospective single-center analysis.¹⁷ For now, assumptions on the prevalence of stroke among COVID-19 patients are based on small, single center observational studies,¹⁸ which estimate an incidence rate of approximately 5% among the most severe cases. In a larger single center study of 3556 COVID-19 patients the estimated stroke incidence rate was much lower at 0.9%.¹⁹
It is likely that any estimation of stroke incidence will be confounded by under-reporting; both in severe infection with competing risk of mortality and milder infections (and strokes) not presenting to hospital or primary care.