Stroke Severity, and Not Cerebral Infarct Location, Increases the Risk of Infection
Infection is a leading cause of death in patients with stroke; however, the impact of cerebral infarct size or location on infectious outcome is unclear. To examine the effect of infarct size on post-stroke infection, we utilised the intraluminal middle-cerebral artery occlusion (MCAO) mouse model of ischemic stroke and adjusted the duration of arterial occlusion. At 1 day following stroke onset, the proportion of mice with infection was significantly greater in mice that had larger infarct sizes. Additionally, the presence of lung infection in these mice with severe strokes extended past 2 days, suggestive of long-term immune impairment. At the acute phase, our data demonstrated an inverse relationship between infarct volume and the number of circulating leukocytes, indicating the elevated risk of infection in more severe stroke is associated with reduced cellularity in peripheral blood, owing predominately to markedly decreased lymphocyte numbers. In addition, the stroke-induced reduction of lymphocyte-to-neutrophil ratio was also evident in the lung of all post-stroke animals. To investigate the effect of infarct location on post-stroke infection, we additionally performed a photothrombotic (PT) model of stroke and using an innovative systematic approach of analysis, we found the location of cerebral infarct does not impact on the susceptibility of post-stroke infection, confirming the greater role of infarct volume over infarct location in the susceptibility to infection. Our experimental findings were validated in a clinical setting and reinforced that stroke severity, and not infarct location, influences the risk of infection after stroke.
KeywordsStroke Infection Infarct volume Infarct location
The authors acknowledge the facilities and scientific and technical assistance of the National Imaging Facility, a National Collaborative Research Infrastructure Strategy (NCRIS) capability, at the Monash Biomedical Imaging, Monash University. The authors acknowledge the facilities and technical assistance of Monash Histology Platform, at the Department of Anatomy and Developmental Biology, Monash University.
This work is supported by the National Heart Foundation (NHF, Australia; 100,863), CSL Centenary Fellowship and the National Health and Medical Research Council (NHMRC, Australia: APP1104036). The financial supports have no role in conducting the research and/or preparation of the article.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- 1.Heuschmann PU, Kolominsky-Rabas PL, Misselwitz B, Hermanek P, Leffmann C, Janzen R, et al. Predictors of in-hospital mortality and attributable risks of death after ischemic stroke: the German Stroke Registers Study Group. Arch Intern Med. 2004;164(16):1761–8.PubMedCrossRefPubMedCentralGoogle Scholar
- 3.Vermeij FH, op Reimer WJS, De Man P, Van Oostenbrugge RJ, Franke CL, De Jong G, et al. Stroke-associated infection is an independent risk factor for poor outcome after acute ischemic stroke: data from the Netherlands Stroke Survey. Cerebrovasc Dis. 2009;27(5):465–71.PubMedCrossRefPubMedCentralGoogle Scholar
- 4.Hetze S, Engel O, Römer C, Mueller S, Dirnagl U, Meisel C, et al. Superiority of preventive antibiotic treatment compared with standard treatment of poststroke pneumonia in experimental stroke: a bed to bench approach. J Cereb Blood Flow Metab. 2013;33(6):846–54.PubMedPubMedCentralCrossRefGoogle Scholar
- 5.Kalra L, Irshad S, Hodsoll J, Simpson M, Gulliford M, Smithard D, et al. Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, cluster-randomised, open-label, masked endpoint, controlled clinical trial. Lancet. 2015;386(10006):1835–44.PubMedCrossRefPubMedCentralGoogle Scholar
- 7.Ulm L, Hoffmann S, Nabavi D, Hermans M, Mackert B-M, Hamilton F, et al. The randomized controlled STraWinSKi trial: procalcitonin-guided antibiotic therapy after stroke. Front Neurol. 2017;8.Google Scholar
- 11.Prass K, Meisel C, Höflich C, Braun J, Halle E, Wolf T, et al. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1–like immunostimulation. J Exp Med. 2003;198(5):725–36.PubMedPubMedCentralCrossRefGoogle Scholar
- 12.Wong CH, Jenne CN, Tam PP, Léger C, Venegas A, Ryckborst K, et al. Prolonged activation of invariant natural killer T cells and TH2-skewed immunity in stroke patients. Front Neurol. 2017;8.Google Scholar
- 30.Paxinos G, Franklin KB. Paxinos and Franklin’s the mouse brain in stereotaxic coordinates: Academic Press; 2019.Google Scholar
- 31.Zhang SR, Piepke M, Chu HX, Broughton BR, Shim R, Wong CH, et al. IL-33 modulates inflammatory brain injury but exacerbates systemic immunosuppression following ischemic stroke. JCI Insight. 2018;3(18).Google Scholar
- 32.Phan TG, Kooblal T, Matley C, Singhal S, Clissold B, Ly J, et al. Stroke severity versus dysphagia screen as driver for post-stroke pneumonia. Front Neurol. 2019;10.Google Scholar
- 35.Curbelo J, Bueno SL, Galván-Román JM, Ortega-Gómez M, Rajas O, Fernández-Jiménez G, et al. Inflammation biomarkers in blood as mortality predictors in community-acquired pneumonia admitted patients: importance of comparison with neutrophil count percentage or neutrophil-lymphocyte ratio. PLoS One. 2017;12(3):e0173947.PubMedPubMedCentralCrossRefGoogle Scholar
- 44.Tziomalos K, Ntaios G, Miyakis S, Papanas N, Xanthis A, Agapakis D, et al. Prophylactic antibiotic treatment in severe acute ischemic stroke: the Antimicrobial chemopRrophylaxis for Ischemic STrokEIn MaceDonIa–Thrace Study (ARISTEIDIS). Intern Emerg Med. 2016;11(7):953–8.PubMedCrossRefPubMedCentralGoogle Scholar
- 51.Wen SW, Shim R, Ho L, Wanrooy BJ, Srikhanta YN, Prame Kumar K, et al. Advanced age promotes colonic dysfunction and gut-derived lung infection after stroke. Aging Cell. 2019:e12980.Google Scholar