Stroke: Preceding Infection May Worsen Outcomes

Professor Stuart Allan Faculty of Life Sciences, AV Hill Building The University of Manchester Manchester, M13 Interview with:
Professor Stuart Allan
Faculty of Life Sciences, AV Hill Building
The University of Manchester
Manchester, M13 9PT What are the main findings of the study?

Dr. Allan: Using an experimental model of stroke it was found that animals with preceding Streptococcus pneumoniae infection had a worse outcome than uninfected animals. This confirms and extends previous data, both clinical and preclinical, that systemic inflammation is a key contributor to stroke outcome. Importantly, effects of infection were also demonstrated in animals with co-morbidities associated with stroke (atherosclerosis and age), with outcomes worse than observed in healthy young subjects. Exacerbating effects of infection on stroke are mediated via the pro-inflammatory cytokine, interleukin-1 (IL-1), shown by reversal of the increased ischaemic brain damage and functional impairments by treatment with the IL-1 receptor antagonist (IL-1Ra). Infection also leads to increased platelet activation and microvascular coagulation after stroke, which contributes to the increased injury. Collectively, these data are the first to show, how systemic inflammatory mechanisms induced by one of the most common non-invasive, human S.pneumoniae isolates, lead to critical illness after stroke in different rodent species and strains, and how common stroke comorbidities interact with infection to worsen outcome after stroke. Were any of the findings unexpected?

Dr. Allan: Although a substantial body of evidence exists to support the role of IL-1 in neuronal injury after stroke we did not expect to find that IL-1 was also a key contributor to effects of preceding systemic inflammation on stroke outcome as seen here. What should clinicians and patients take away from your report?

Dr. Allan: We suggest that targeted anti-inflammatory therapies could be highly beneficial against brain injury and worse neurological outcome if stroke is preceded and/or associated with infection. Specifically, blockade of inflammatory actions by IL-1Ra is safe clinically and already licenced for human therapy in inflammatory diseases. Given the restricted treatment opportunities and the failure of most clinical trials in stroke to date, we suggest IL-1Ra as a leading therapeutic regimen against inflammation-induced injury in the brain. What recommendations do you have for future research as a result of this study?

Dr. Allan: As highlighted in several recent publications it is important that future experimental studies in stroke take into account the co-morbidities associated with stroke, and in particular the key contribution of systemic inflammation. Research to date has rarely done this, which may account for some of the translational failures.


Streptococcus pneumoniae worsens cerebral ischaemia via IL-1 and platelet GPIbα

Dénes A1, Pradillo JM, Drake C, Sharp A, Warn P, Murray KN, Rohit B, Dockrell DH, Chamberlain J, Casbolt H, Francis S, Martinecz B, Nieswandt B, Rothwell NJ, Allan SM.
Ann Neurol. 2014 Mar 19. doi: 10.1002/ana.24146. [Epub ahead of print]