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(Stroke. 2007;38:1097.)
© 2007 American Heart Association, Inc.
Comments, Opinions, and Reviews |
From the Stroke Unit (A.C., X.U.), Hospital Clínic and Institut d Investigacions Biomédiques August Pi i Sunyer (IDIBAPS). University of Barcelona, Spain; and the Pharmacology and Toxicology Department (A.M.P.), Consejo Superior de Investigaciones Científicas (IIBB-CSIC) and IDIBAPS, Barcelona, Spain.
Correspondence to Prof Ángel Chamorro, Hospital Clínic, 08036, Barcelona, Spain. E-mail achamorro{at}ub.edu
| Abstract |
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Summary of Review Many patients develop infections shortly after acute stroke regardless of optimal management. Mortality is higher in these patients and the severity of stroke is the strongest determinant of the infectious risk. However, it is controversial whether infections promote neurological worsening or alternatively represent a marker of severe disease. The brain and the immune system are functionally linked through neural and humoral pathways, and decreased immune competence with higher incidence of infections has been demonstrated in several acute neurological conditions. In experimental brain ischemia, infections are associated with the activation of the autonomous nervous system and neuroendocrine pathways, which increase the strength of anti-inflammatory signals. A strong cytokine-mediated anti-inflammatory response was recently observed in stroke patients at higher risk of infection, although infection could not demonstrate an independent association with the progression of the symptoms.
Conclusions The appearance of infection in patients with acute stroke obeys in part to immunological mechanisms triggered by acute brain injury. An excessive anti-inflammatory response is a key facilitating factor for the development of infection, and it is likely that this immunological response represents an adaptive mechanism to brain ischemia. Contrarily, it is unclear whether infection contributes independently to poor outcome in human stroke. Overall, a better understanding of the cross-talk between the brain and the immune system might lead to more effective therapies in patients with acute stroke.
Key Words: acute stroke complications immunology infectious disease pathogenesis
| Introduction |
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| Infection After Acute Stroke: Magnitude of the Problem |
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| Is Infection a Cause of Worsening Stroke? Uncertain |
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release,37 activation of the tissue factormediated extrinsic pathway of blood coagulation,38 reduction of thrombomodulin (anticoagulant), and inhibition of the fibrinolytic system.39 With few exceptions,40 subfebrile temperatures (37.5°C to 39°C) and fever (>39°C) during the first days of stroke are associated with larger infarct volumes, higher mortality, and poorer functional outcome.41,42 However, the support to infection as an independent cause of stroke worsening is controversial.29,43,44 Only few studies29,43 accounted for the critical effect of the initial severity of stroke, and in some studies,22 the recognition of stroke worsening relied on the neurological scale used for assessment. Recent prospective studies did not find an independent association between infection and stroke worsening in multivariate analysis.29,44 It has been argued that the inclusion of soft end points, such as acute bronchitis, could have minimized the clinical relevance of poststroke infection45 although acute bronchitis in the elderlyan age group representative of the stroke populationconveys a similar risk of death than pneumonia: 10% and 8%, respectively.46 Further, acute respiratory infection with "normal" chest x-rays may indicate pneumonia in about 30% of the cases, if a high resolution lung tomography is performed.47 | Could Infection Be a Manifestation of Stroke-Induced Immunodepression in Human Stroke? Most Likely |
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| Humoral Pathways for Brain to Immune System Communication |
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, and IL-6, secreted by cells in different tissues and organs including the brain50 can stimulate specialized neurons in the PVN to synthesize corticotropin-releasing factor.51 Blood-borne cytokines derived from white blood cells may also reach the PVN through activation of specific carriers, binding to endothelial receptors that mediate the production of diffusible mediators, such as prostaglandins or NO, or through anatomical structures lacking blood-brain barrier, like the organum vascularis of the lamina terminals, or the area postrema.50,52 Once released into the pituitary portal blood system, corticotropin-releasing factor interacts within the anterior pituitary with a specific G proteincoupled receptor (corticotrophin-releasing factor-F1) facilitating the secretion of adrenocorticotropin hormone precursor peptide proopiomelanocortin, and adrenocorticotropin hormone (ACTH).53 Secondarily, ACTH induces the secretion of glucocorticoids from the zona fasciculata of the adrenal cortex which suppress the production of pro-inflammatory mediators, including IL-1ß, IL-11, IL-12, interferon-
, TNF-
, chemokines (IL-8), prostaglandins and NO.54 Glucocorticoids also facilitate the release of anti-inflammatory mediators such as IL-4, IL-10 and transforming growth factor-ß,55 and have strong antiproliferative properties, and apoptotic effects in immune cells.56 In the end, cytokines can activate the release of glucocorticoids, which in turn suppress further cytokine synthesis in a classic negative feedback loop.57 | The Cholinergic Neural Pathway |
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in different organs during experimental endotoxemia and in animals subjected to ischemia-reperfusion.60 | The Adrenergic Pathway to Immunodepression |
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| The Adrenal Medullary Gland |
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| The Lymphoid Organs Are Also Wired |
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, IL-1, IL-12, interferon-
, and nitric oxide production, and the increased production of IL-6 and IL-10 by the immune cells. Elevation of central sympathetic outflow also induces a local release of norepinephrine within the bone marrow,72 and this affects in vivo myelopoiesis and erythropoiesis,73 because the production of granulocytes and macrophages is under a sympathetic inhibitory tone, whereas lymphocyte74 and erythrocyte73 formation require adrenergic stimulation. | Immunological Changes After Acute Brain Ischemia: Experimental and Clinical Studies |
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In brain ischemic mice, stroke induces a long-lasting depression of the cell-mediated immunity, including monocyte deactivation, lymphopenia, and a Th1/Th2 shift associated with spontaneous bacteremia and pneumonia.85 In mice, focal cerebral ischemia also reduces spleen cellularity and response to mitogens,86 and results in a rapid and widespread production of pro-inflammatory factors by splenocytes in relation to adrenergic signaling.87 Propranolol prevents these infections,85 emphasizing the relevance of a catecholamine-mediated immune defect for impaired antibacterial defenses. Lypopolisaccharide preconditioning has also shown to induce significant neuroprotection against middle cerebral artery occlusion, suppressing both neutrophil infiltration into the brain and microglia/macrophage activation in the ischemic hemisphere, and monocyte activation in the peripheral blood.88
In patients, reported defects in immune function after stroke include reduced peripheral blood lymphocyte counts and impaired T- and natural killer cell activity, and reduced mitogen-induced cytokine production and proliferation in vitro.89,90 One small study91 found a higher incidence of severe infections after left hemisphere infarctions although in the larger ESPIAS trial the incidence of infection was not lateralized,48 in agreement with observations in ischemic rats.92 In this clinical trial, levofloxacin was not able to prevent the incidence of infection in patients with nonseptic acute stroke.48 However, antibiotic therapy with moxifloxacin prevented infection in ischemic mice,93 and ongoing studies of antibiotic prophylaxis in stroke patients might indicate that the efficacy of this approach relies on patient selection, differences in antibiotics, or the administration regime.94
The longitudinal changes of plasma cytokines and circulating white blood cells were also assessed in the patients included in the ESPIAS trial.48,95 As described in Figure 2, patients with stroke have a rapid increase of circulating cytokines in plasma, with a low ratio of pro-inflammatory TNF-
to anti-inflammatory IL-10 preceding the appearance of infection,95 in agreement with experimental data,96,97 and clinical studies of patients with fatal community-acquired infection.98 These observations caution about the potential risks of pro-inflammatory cytokine inhibition in patients with sepsis. Monocytes, neutrophils, and total counts of white blood cells are also increased before infections, as shown in Figure 3. Recently, poststroke infection has also been associated with higher admission levels of metanephrine, emphasizing the relevance of sympathoadrenomedullary function for immune competence.99 Indeed, in human adrenals, the medullary tissue (catecholamines) and the cortex (glucocorticoids) are extensively intermingled, and this anatomical disposition allows important intraadrenal paracrine interactions.100
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| Conclusions |
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| Acknowledgments |
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None.
Received September 28, 2006; accepted October 12, 2006.
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