Infection as a Stroke Risk Factor and Determinant of Outcome After Stroke

Abstract

Understanding the relationship between infection and stroke has taken on new urgency in the era of the coronavirus disease 2019 (COVID-19) pandemic. This association is not a new concept, as several infections have long been recognized to contribute to stroke risk. The association of infection and stroke is also bidirectional. Although infection can lead to stroke, stroke also induces immune suppression which increases risk of infection. Apart from their short-term effects, emerging evidence suggests that poststroke immune changes may also adversely affect long-term cognitive outcomes in patients with stroke, increasing the risk of poststroke neurodegeneration and dementia. Infections at the time of stroke may also increase immune dysregulation after the stroke, further exacerbating the risk of cognitive decline. This review will cover the role of acute infections, including respiratory infections such as COVID-19, as a trigger for stroke; the role of infectious burden, or the cumulative number of infections throughout life, as a contributor to long-term risk of atherosclerotic disease and stroke; immune dysregulation after stroke and its effect on the risk of stroke-associated infection; and the impact of infection at the time of a stroke on the immune reaction to brain injury and subsequent long-term cognitive and functional outcomes. Finally, we will present a model to conceptualize the many relationships among chronic and acute infections and their short- and long-term neurological consequences. This model will suggest several directions for future research.

Keywords: coronavirus; dementia; infection; pneumonia; risk factor; stroke.

Figure 1.. Stroke with COVID-19

A 37 year old woman with a history of morbid obesity, type 2 diabetes mellitus, hypertension, and preeclampsia presented with acute left hemiplegia. She had a 3-day history of cough and dyspnea, with mild fever, but outpatient polymerase chain reaction (PCR) test of the nasopharynx was negative for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). On examination, there was right gaze preference, mild left spatial neglect, left facial weakness, dysarthria, left arm plegia, left leg paresis, and intact sensation. Head CT showed a subtle dense right MCA sign. She received intravenous tissue plasminogen activator. CT angiography showed a retropharyngeal course of the right internal carotid artery with retropharyngeal edema and filling defect in the medial aspect of the artery (arrow) (A); the distal right carotid artery and middle cerebral artery stem were occluded, with distal collateralization (B). CT perfusion study (C) demonstrated no definite evidence of infarction, with a large perfusion defect in the right hemisphere. Angiography demonstrated occlusion of the right petrous carotid artery (D). Thrombectomy was performed with good recanalization. Repeat PCR testing for SARS-CoV-2 was positive. D-dimer and interleukin-6 levels were elevated. The patient had a good recovery and was discharged two days later.

Figure 2.. Proposed model for short- and long-term associations of infection, stroke, cognitive decline and dementia

Over the course of adult life (X-axis), individual cognition and function gradually decline, as represented by the blue line, which reflects cognitive or functional status (Y-axis). At the time of stroke, there is an acute decline in function, followed by gradual recovery. In many individuals, and in animal models, late cognitive decline, leading to dementia, occurs. The role of infectious events throughout the life course, neurological outcomes, and related mechanisms are depicted. Chronic infections include chronic or latent infections (such as syphilis and varicella zoster virus), as well as cumulative exposures to more acute infections (“infectious burden”); these may contribute to vasculopathies, including atherosclerosis, arteritis, or non-arteritic vasculopathies, and may contribute to long-term risks of stroke and cognitive decline/dementia. Certain severe acute infections (e.g., influenza, sepsis, possibly COVID-19), transiently increase stroke risk. After stroke, stroke-associated infections (e.g., stroke-associated pneumonia) and consequent immune changes may then lead to chronic autoreactivity against the brain, which in turn contributes to chronic neuroinflammation and neurodegeneration and associated clinical cognitive impairment and dementia. Stroke-induced immunodepression may both increase risk of post-stroke infections and reduce chronic autoreactivity against the brain. Conceptual short- and longer-term vulnerable windows to stroke, infection, and cognitive decline are depicted above the depiction of cognitive/functional trajectory. COVID-19, coronavirus disease 2019; SAP, stroke associated pneumonia; UTI, urinary tract infection.