Background and Purpose: Experimental and clinical data suggest that overactivation of the sympathetic nerve system (SNS) is an essential mediator of stroke-induced immunodepression, which in turn increases susceptibility to post-stroke infections. In a post hoc analysis of the PANTHERIS (Preventive Antibacterial Treatment in Acute Stroke) trial, we investigated the impact of distinct lesion patterns on SNS activation, immunodepression, and frequency of post-stroke infections. Methods: Stroke volume, stress hormone levels, and immune function were determined on day 1 after stroke onset. Stroke localization was graded using the Alberta Stroke Programme Early CT score (ASPECTS). In univariate analysis, we investigated the impact of clinical (National Institutes of Health Stroke Scale, NIHSS) and imaging stroke characteristics (lesion volume, lateralization, localization grading) on autonomous nervous system activity (norepinephrine, cortisol), immune competence (monocytic HLA-DR expression), and the frequency of post-stroke infections. In a logistic regression model, we tested for independent factors that might increase susceptibility to post-stroke infections. Results: In a single-factor analysis, large stroke volume, lesions affecting distinct regions of the MCA cortex, and SNS activation (elevated norepinephrine levels) were associated with an impaired immune function (reduced mHLA-DR expression) and a higher susceptibility to post-stroke infections. Multivariate analysis identified increased levels of norepinephrine and infarction of the anterior MCA cortex as independent risk factors of post-stroke infections. Neither stroke severity nor stroke volume was independently associated with post-stroke infections. Conclusions: Apart from sympathetic activation, our data suggest that ischemic lesion in the anterior MCA cortex may be a major determinant of stroke-associated infection. This finding has to be confirmed in larger prospective studies.

1.
Elenkov IJ, Chrousos GP: Stress system – organization, physiology and immunoregulation. Neuroimmunomodulation 2006;13:257–267.
2.
Tracey KJ: Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 2007;117:289–296.
3.
Chamorro A, Urra X, Planas AM: Infection after acute ischemic stroke: a manifestation of brain-induced immunodepression. Stroke 2007;38:1097–1103.
4.
Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U: Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci 2005;6:775–786.
5.
Woiciechowsky C, Schöning B, Lanksch WR, Volk HD, Döcke WD: Mechanisms of brain-mediated systemic anti-inflammatory syndrome causing immunodepression. J Mol Med 1999;77:769–780.
6.
Prass K, Meisel C, Höflich C, Braun J, Halle E, Wolf T, Ruscher K, Victorov IV, Priller J, Dirnagl U, Volk HD, Meisel A: 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;198:725–736.
7.
Offner H, Subramanian S, Parker SM, Afentoulis ME, Vandenbark AA, Hurn PD: Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab 2006;26:654–665.
8.
Klehmet J, Harms H, Richter M, Prass K, Volk HD, Dirnagl U, Meisel A, Meisel C: Stroke-induced immunodepression and post-stroke infections: lessons from the preventive antibacterial therapy in stroke trial. Neuroscience 2009;158:1184–1193.
9.
Haeusler KG, Schmidt WU, Föhring F, Meisel C, Helms T, Jungehulsing GJ, Nolte CH, Schmolke K, Wegner B, Meisel A, Dirnagl U, Villringer A, Volk HD: Cellular immunodepression preceding infectious complications after acute ischemic stroke in humans. Cerebrovasc Dis 2008;25:50–58.
10.
Harms H, Prass K, Meisel C, Klehmet J, Rogge W, Drenckhahn C, Göhler J, Bereswill S, Göbel U, Wernecke KD, Wolf T, Arnold G, Halle E, Volk HD, Dirnagl U, Meisel A: Preventive antibacterial therapy in acute ischemic stroke: a randomized controlled trial. PLoS One 2008;3:e2158.
11.
Vogelgesang A, Grunwald U, Langner S, Jack R, Bröker BM, Kessler C, Dressel A: Analysis of lymphocyte subsets in patients with stroke and their influence on infection after stroke. Stroke 2008;39:237–241.
12.
Zhang DP, Yan FL, Xu HQ, Zhu YX, Yin Y, Lu HQ: A decrease of human leucocyte antigen-DR expression on monocytes in peripheral blood predicts stroke-associated infection in critically-ill patients with acute stroke. Eur J Neurol 2009;16:498–505.
13.
Oppenheimer SM, Saleh TM, Wilson JX, Cechetto DF: Plasma and organ catecholamine levels following stimulation of the rat insular cortex. Brain Res 1992;569:221–228.
14.
Yasui Y, Breder CD, Saper CB, Cechetto DF: Autonomic responses and efferent pathways from the insular cortex in the rat. J Comp Neurol 1991;303:355–374.
15.
Tokgözoglu SL, Batur MK, Topuoglu MA, Saribas O, Kes S, Oto A: Effects of stroke localization on cardiac autonomic balance and sudden death. Stroke 1999;30:1307–1311.
16.
Vingerhoets F, Bogousslavsky J, Regli F, Van Melle G: Atrial fibrillation after acute stroke. Stroke 1993;24:26–30.
17.
Cheung RT, Hachinski V: The insula and cerebrogenic sudden death. Arch Neurol 2000;57:1685–1688.
18.
Toni D, Chamorro A, Kaste M, Lees K, Wahlgren NG, Hacke W; EUSI Executive Committee; EUSI Writing Committee: Acute treatment of ischaemic stroke. European Stroke Initiative. Cerebrovasc Dis 2004;17(suppl 2):30–46.
19.
Döcke WD, Höflich C, Davis KA, Röttgers K, Meisel C, Kiefer P, Weber SU, Hedwig-Geissing M, Kreuzfelder E, Tschentscher P, Nebe T, Engel A, Monneret G, Spittler A, Schmolke K, Reinke P, Volk HD, Kunz D: Monitoring temporary immunodepression by flow cytometric measurement of monocytic HLA-DR expression: a multicenter standardized study. Clin Chem 2005;51:2341–2347.
20.
Barber PA, Demchuk AM, Zhang J, Buchan AM: Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet 2000;355:1670–1674.
21.
Aslanyan S, Weir CS, Diener HC, Kaste M, Lees KR, for the GAIN International Steering Committee and Investigators: Pneumonia and urinary tract infections after actute stroke: a tertiary analyis of the GAIN international trial. Euro J Neurol 2004;11:49–53.
22.
Sallars C, Bowie L, Bagg J, Sweeney P, Miller H, Tilston J, Langhorne P, Stott D: Risk factors for chest infections in acute stroke: a prospective cohort study. Stroke 2007;38:2284–2291.
23.
Walter U, Knoblich R, Steinhagen V, Donat M, Benecke R, Kloth A: Predictors of pneumonia in acute stroke patients admitted to a neurological intensive care unit. J Neurol 2007;254:1323–1329.
24.
Hug A, Dalpke A, Wieczorek N, Giese T, Lorenz A, Auffarth G, Liesz A, Veltkamp R: Infarct volume is a major determiner of post-stroke immune cell function and susceptibility to infection. Stroke 2009;40:3226–3232.
25.
Minnerup J, Wersching H, Brokinkel B, Dzierwas R, Heuschmann PU, Nabavi DG, Ringelstein EB, Schäbitz WR, Ritter MA: The impact of lesion location and lesion size on poststroke infection frequency. JNNP. 2010;81:198–202.
26.
Chamorro A, Amaro S, Vargas M, Obach V, Cervera A, Gómez-Choco M, Torres F, Planas AM: Catecholamines, infection, and death in acute ischemic stroke. J Neurol Sci 2007;252:29–35.
27.
Neveu PJ: Cerebral lateralization and the immune system. Int Rev Neurobiol 2002;52:303–323.
28.
Meador KJ, Koring DW, Ray PG, Helman SW, Vazquez BR, Neveau PJ: Role of cerebral lateralization in control of immune processes in humans. Ann Neurol 2004;55:840–844.
29.
Zamrini EY, Meador Kj, Loring DW, Nichols FT, Lee GP, Figueroa RE, Thompson WO: Unilateral cerebral deactivation produces differential left/right heart rate responses. Neurology 1990;40:1408–1411.
30.
Oppenheimer SM, Gelb A, Grivin JP, Hachinski VC: Cardiovascular effects of human insular cortex stimulation. Neurology 1992;42:1727–1732.
31.
Tokgozoglu SL, Batur MK, Topcuoglu MA, Saribas O, Kes S, Oto A: Effects of stroke localization on cardiac autonomic balance and sudden death. Stroke 1999;30:1307–1311.
32.
Orlandi G, Fanucchi S, Strata G, Pataleo L, Landucci Pellegrini L, Prontera C, Martini A, Murri L: Transient autonomic nervous system dysfunction during hyperacute stroke. Acta Neurol Scand 2000;102:317–321.
33.
Colivicchi F, Bassi A, Santini M, Caltagirone C: Cardiac autonomic derangement and arrhythmias in right-sided stroke with insular involvement. Stroke 2004;35:2094–2098.
34.
Terreberry RR, Neafsey EJ: The rat medial frontal cortex projects directly to autonomic regions of the brainstem. Brain Res Bull 1987;19:639–649.
35.
Verberne AJ, Owens NC: Cortical modulation of the cardiovascular system. Prog Neurobiol 1998;54:149–168.
36.
Cechetto DF, Calaresu FR: Units in the amygdala responding to activation of carotid baro- and chemoreceptors. Am J Physiol 1984;246:R832–R836.
37.
Gelsema AJ, Agarwal SK, Calaresu FR: Cardiovascular responses and changes in neural activity in the rostral ventrolateral medulla elicited by electrical stimulation of the amygdala of the rat. J Auton Nerv Syst 1989;27:91–100.
38.
Bradley DJ, Ghelarducci B, Paton JF, Spyer KM: The cardiovascular responses elicited from the posterior cerebellar cortex in the anaesthetized and decerebrate rabbit. J Physiol 1987;383:537–550.
39.
Nisimaru N, Okahara K, Yanai S: Cerebellar control of the cardiovascular responses during postural changes in conscious rabbits. Neurosci Res 1998;32:267–271.
40.
Kin NW, Sanders VM: It takes nerve to tell T and B cells what to do. J Leukoc Biol 2006;79:1093–1104.
41.
Kohm AP, Sanders VM: Norepinephrine and beta 2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo. Pharmacol Rev 2001;53:487–525.
42.
Guyre PM, Yeager MP, Munck A: Glucocorticoid effects on immune responses. Neuroimmun Biol 2007;7:147–167.
43.
Urra X, Cervera A, Obach V, Climent N, Planas AM, Chamorro A: Monocytes are major players in the prognosis and risk of infection after acute stroke. Stroke 2009;40:1262–1268.
44.
Goldstein DS, Eisenhofer G, Kopin IJ: Sources and significance of plasma levels of catechols and their metabolites in humans. J Pharmacol Exp Ther 2003;305:800–811.
45.
Eisenhofer G, Kopin IJ, Goldstein DS: Catecholamine metabolism: a contemporary view with implication for physiology and medicine. Pharmacol Rev 2004;56:331–349.
46.
Kimmerly DS, O’Leary DD, Menon RS, Gati JS, Shoemaker JK: Cortical regions associated with autonomic cardiovascular regulation during lower body negative pressure in humans. J Physiol 2005;569:331–345.
47.
Hilker R, Poetter C, Findeisen N, Sobesky J, Jacobs A, Neveling M, Heiss WD: Nosocomial pneumonia after stroke: implications for neurological intensive care medicine. Stroke 2003;34:975–981.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.