Parneet Grewal, MD
In this article, Dr. Elkind and colleagues aimed to elucidate the putative relationship between infection and stroke, which has gained increased recognition in the era of coronavirus disease 2019 (COVID-19).1 Multiple studies in the past, such as the Cardiovascular Health Study and the Atherosclerosis Risk in Communities study, have provided evidence that systemic infection can trigger or precipitate acute ischemic stroke since bacteremia is a strong stimulus to inflammation and thrombosis. The proposed mechanisms by which infections can trigger stroke include infection-related platelet activation and aggregation, inflammation-related thrombosis, impaired endothelial function, infection-provoked cardiac arrhythmias, and dehydration-induced thrombosis (Figure). On further characterization, it is now known that a variety of infections are associated with an increased risk of ischemic stroke, with the strongest association found for urinary tract infection (UTI) (OR 5.32, 95% CI, 3.69-7.68) within 7 days.2
The authors focus particularly on the role of viral infections as a trigger for stroke. Influenza has been previously studied as a stroke trigger, especially in high-risk elderly population. Data from California provide evidence that the odds of ischemic stroke are higher in the first 15 days after influenza-like illness (OR 2.88, 95%CI 1.86-4.47).3 Many herpes viruses also have a neurotropic tendency, with strong evidence linking Cytomegalovirus (CMV) to atherogenesis and Varicella zoster virus (VZV) to cerebral arteriopathy. Infectious burden (IB) is described as a cumulative effect of exposure to an increasing number of pathogens and lately has gained popularity due to its role in carotid and cerebral atherosclerosis. For example, higher mean IB index in Hispanics, non-Hispanic Blacks, and women in the Northern Manhattan Study provides indirect evidence to explain disparities in stroke risk. Recently, multiple studies have reported an increased risk for stroke in patients who are infected with COVID -19, with incidence ranging from 0.5 to 3%. The incidence is higher in critically ill patients with COVID-19 approaching 6%. Moreover, unexplained large vessel occlusions have been identified as a frequent presentation.
On the other side of the spectrum of the relationship between infection and stroke are infections that present as complications of stroke, mainly UTI and pneumonia which are particularly common in the early period after an intracranial insult (Figure). The interplay between infection reservoir, delivery of infection to the site such as lower respiratory tract, and stroke-induced immune suppression has been proposed to underly these infections. Stroke-induced immune suppression, which occurs within hours of stroke onset and affects both innate and adaptive immunity increases host susceptibility to post-stroke infections. In addition, It has been found that patients with post-stroke infections have increased autoreactive CNS-antigen specific immune responses in blood as compared to stroke patients without infection, which correlates with poorer outcomes. Hence, there has been increased focus on identifying patients at risk of these infections to implement preventative interventions. Patients with post-stroke infections can also have longer-term cognitive decline and dementia, with the highest risk in the first six months after stroke.
In conclusion, this review paper permits a conceptualization of the bidirectional and multiphasic relationship between systemic infection and stroke along with a discussion on molecular mechanisms that impact outcome. It also highlights some of the interesting research that is being done in the field including biological therapies and immunomodulatory treatments.
1. Elkind MSV, Boehme AK, Smith CJ, Meisel A, Buckwalter MS. Infection as a stroke risk factor and determinant of outcome after stroke. Stroke. 2020:STROKEAHA120030429
2. Sebastian S, Stein LK, Dhamoon MS. Infection as a stroke trigger. Stroke. 2019;50:2216-2218
3. Boehme AK, Luna J, Kulick ER, Kamel H, Elkind MSV. Influenza-like illness as a trigger for ischemic stroke. Ann Clin Transl Neurol. 2018;5:456–463. doi: 10.1002/acn3.545