Review

Acute ischaemic stroke and infection: recent and emerging concepts

Hedley CA Emsley, Stephen J Hopkins

The relation between acute ischaemic stroke and infection is complex. Infection appears to be an important trigger that precedes up to a third of ischaemic strokes and can bring about stroke through a range of potential mechanisms. Infections that present subsequent to stroke also complicate up to a third of cases of stroke and might worsen outcome. Inammatory responses, which are a defence mechanism against infection but can also be a pathogenic mechanism that precipitates stroke and neurological sequelae, are important features. Although factors such as stroke severity and dysphagia are important predictors of poststroke infection, there is evidence from experimental and clinical settings of impaired immunity or brain-induced immunodepression after stroke. Greater understanding of the relation between inammation and both infection and ischaemic mechanisms is needed. This might be particularly important because new treatment strategies for acute ischaemic stroke are being investigated, including those that modulate cytokines and the immune system.

Lancet Neurol 2008; 7: 34153 Division of Neuroscience, The University of Liverpool, The Walton Centre for Neurology and Neurosurgery, Liverpool, UK (HCA Emsley PhD); and Injury Research and Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford, UK (SJ Hopkins PhD) Correspondence to: Hedley CA Emsley, Division of Neuroscience, The University of Liverpool, The Walton Centre for Neurology and Neurosurgery, Liverpool L9 7LJ, UK h.emsley@liverpool.ac.uk

Introduction
There is considerable interest in the role of inammatory mechanisms in ischaemic stroke. Much of this interest has focused on CNS and peripheral inammatory responses to cerebral ischaemic injury and the identication of suitable targets in the inammatory cascade for intervention. However, inammation also includes important aspects of the host immune response to infection. The occurrence of infection, whether preceding or following ischaemic stroke, is becoming well recognised and is accompanied by an expansion in the literature in recent years. This has led to experimental and clinical developments in our understanding of how acute infection can trigger stroke and how preceding infection can inuence outcome. Simultaneously, there has been progress in understanding the risk of poststroke infection, including the emerging concept of braininduced immunodepression and how this might aect clinical outcome. Improvements in our understanding of preceding and poststroke infection are also important in terms of current and emerging treatment strategies for ischaemic stroke. The aim of this Review is to present a coherent account of the association between infection before or after acute ischaemic stroke and the implications for treatment by bringing together evidence from clinical and experimental studies.

concentrations of plasma brinogen, C-reactive protein (CRP), and interleukin-6 (IL-6),1 and might, therefore, contribute similarly to an increase in stroke risk, although perhaps at a lower level. The complex interactions between conventional stroke risk factors, systemic inammation, and chronic infections, such as Chlamydia pneumoniae, Helicobacter pylori and periodontal disease, have been reviewed elsewhere1,2 and will not be discussed in detail here.

Acute infection preceding stroke

Unexpected seasonal variations in stroke incidence in a retrospective series of 64 young adults (1640 years) who had ischaemic stroke led to the identication of 18 patients (28%) with a history of possible acute infection at the time of stroke.5 Syrjnen and colleagues did one of the earliest systematic studies to screen for preceding infection in patients who had stroke and found increased serum bacterial antibody levels in 44% of patients with stroke who were under 45 years of age, compared with 9% of controls.6 Acute infection, usually respiratory and of bacterial origin and particularly in the week preceding stroke, is a signicant risk factor for cerebral infarction, possibly in all age groups, even when the eects of other risk factors are taken into account.715 Direct comparison between studies is dicult owing to their various designs and analyses, but estimates of the relative risk [RR] of stroke after infection in the preceding month range from 18 (95% CI 0636)14 to 90 (22800).7 Overall, the reported prevalence of infection in the month preceding ischaemic stroke ranges from 18% to 40%, and in the week preceding stroke from 10% to 35% (table 1).717 The eects of preceding infections or inammatory events on stroke subtype have also been studied. Respiratory tract infection has been linked to large-vessel and cardioembolic ischaemic stroke, particularly in patients without vascular risk factors.14 Infective and non-infective acute inammatory events that occur during the 30 days before stroke onset were signicantly associated with ischaemic
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Infection preceding acute ischaemic stroke

Chronic infection and conventional stroke risk factors
The capacity of chronic infections to induce inammation in tissues might provide a link to the progression of atherosclerotic plaques.13 Prospective seroepidemiological studies could help to establish potential causal links between particular chronic infections and stroke, although the contribution to overall stroke risk might be small.4 However, a range of infections can increase risk when associated with conventional stroke risk factors and genetic predisposition.2 As with acute infection, chronic infections are associated with systemic manifestations of inammation, such as raised
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Study design

Type of infection(s)

Number of patients with infection (%) 19 (35%) 17 (34%) 31 (16%) 38 (19%) 13 (35%) 41 (23%) 44 (24%) 37 (22%) 8 (5%) 45 (27%) 6 (10%) 20 (33%) 26 (43%) 43 (18%)

Prestroke interval Number of (for prevalence patients estimate) (controls) 1m 1m 1w 4 w 1w 1w 2m 1w 24 w 4w 1w 2 w >2 w 1m 54 (54) 50 197 (197) 37 (47, 34) 182 (194)

Prestroke Outcome statistic Description of outcome statistic interval (95% CI) (for risk analysis) 1m 1w 2m RR 90 (22800) OR 46 (19113)* OR 29 (1653) RR of stroke after infection Estimated OR for stroke after infection Risk of preceding infection in patients with acute ischaemic stroke Risk of cerebrovascular ischaemia after infection

Syrjnen and co-workers7 Ameriso and co-workers8 Grau and co-workers9 Macko and co-workers10 Bova and co-workers11 Grau and co-workers12 Nagaraja and co-workers13 Paganini-Hill and co-workers14 Nencini and co-workers15 Smeeth and co-workers16

Casecontrol Consecutive series Casecontrol Casecontrol Casecontrol

Infections (80% respiratory) Mostly respiratory tract infections Mostly respiratory tract bacterial infections Infections or inammatory events (mostly upper respiratory tract) Infections (mostly respiratory tract or urinary tract) Infections (bacterial or viral)

Casecontrol

166 (166)

1w

OR 29 (1364)

Casecontrol

Infections (bacterial or viral)

60 (60)

Casecontrol Infectious or inammatory events and crossover Casecontrol Case series Infective or non-infective inammatory events Systemic respiratory tract infections

233 (363)

1m

RR 18 (0636)

RR of large-vessel or cardioembolic stroke after respiratory tract infection Risk of ischaemic stroke after inammatory event IR for rst stroke after systemic respiratory tract infections

17 (18%) 37 (40%)

7d 30 d

93 (200) 244 237 368 561 1650 152 158 245 445 1250

7d 30 d 13 d 47 d 814 d 1528 d 2991 d 13 d 47 d 814 d 1528 d 2991 d

OR 25 (1154) OR 22 (1340) IR 32 (2836) IR 23 (2127) IR 21 (1923) IR 1.7 (1.51.8) IR 13 (1314) IR 27 (2332) IR 21 (1825) IR 19 (1721) IR 17 (1619) IR 12 (1213)

Urinary tract infections

IR for rst stroke after urinary tract infections

OR=odds ratio. RR=relative risk. IR=incidence ratio. *By conditional logistic regression analysis; a later report by the same group used a dierent statistical model resulting in an OR of 43, 95% CI 18105.17 Two control groups (47 community, 34 hospitalised). 22 400 participants exposed. 14 603 participants exposed.

Table 1: Studies that report infections preceding stroke

stroke and increased the risk of atherothrombotic and cardioembolic strokes.15 Viral infections, most notably inuenza, also precede stroke. Lavalle and co-workers18 did structured interviews with 90 consecutive patients with brain infarction and 180 matched controls that included an assessment of vaccination status in the year of study and the preceding 5 years. After adjustment for age, conventional risk factors, and antibiotic use, stroke risk was reduced with odds ratios [OR] of 050 (95% CI 026094) and 042 (021081), respectively, for the two time periods. Grau and co-workers19 also did standardised interviews with 370 consecutive patients with ischaemic or haemorrhagic stroke or transient ischaemic attack, as well as 370 controls. They found that inuenza vaccination, after adjustment for other factors, was associated with reduced risk of stroke or transient ischaemic attack (OR 046, 027077), although no protective eect was seen during summer months, and there was considerable variation between
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the winter seasons investigated. The prevention of inuenza might, therefore, lower stroke risk, although interventional studies are needed to conrm the role of inuenza vaccination in stroke prevention. Probably the most robust evidence for acute infection as a trigger for stroke derives from the UK General Practice Research Database (UKGPRD).16 This study of myocardial infarction and stroke risk after common vaccinations and acute infections enrolled more than 50 000 patients who had a rst or subsequent stroke. Risk of rst stroke was substantially higher after acute infection, and the risk was highest during the rst 3 days, with an incidence ratio (IR) of 32 (2836) after systemic respiratory tract infection and 27 (2332) after urinary tract infection. By contrast, the IR for myocardial infarction during the rst 3 days after systemic respiratory tract infection was 50 (4455), and 17 (1321) after urinary tract infection. The risk remained signicantly raised for 3 months, although the magnitude of the eect gradually reduced. The rates of
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subsequent stroke after systemic respiratory tract infection followed similar patterns to the rates for rst stroke, albeit with slightly lower eect estimates. A small but apparently protective eect of vaccination was also seen in this study but was attributed to giving the vaccination to people when they were in good health. The association between stroke and acute infection is supported by a recent study that used a separate UK primary care database (IMS Disease Analyzer Mediplus database) to identify 9208 patients after their rst stroke.20 Stroke risk in the 7 days after respiratory infection was increased (OR 192, 1297), but the strength of the association decreased over time. Urinary tract infection in the preceding month also increased stroke risk (OR 267, 1355). The IMS database included extensive data on cardiovascular risk factors, which enabled the investigators to infer that the mechanisms that link infection and stroke risk operate across dierent levels of prior risk of stroke. A common precipitant for acute infection and stroke seems implausible, and there is now extensive evidence that acute infection is indeed a trigger for acute stroke. Owing to the range of infection types (eg, respiratory and urinary tract) and causative organisms (eg, viral and bacterial) that precede stroke, stroke risk associated with preceding infection seems generic, rather than linked to specic types of infection or organism.

Acute infection as a trigger of stroke

The highest stroke risk seems to be within 1 week of an acute infection; however, the concept of a short-term period of greatly elevated risk of ischaemic stroke after transient ischaemic attack, particularly in the rst week, is relatively new,21 and there might be a corollary with the apparently high short-term risk of stroke after acute infection. Perhaps the stroke-prone statea condition of acute susceptibility to stroke22is a common factor. The notion that acute infection can trigger stroke by inducing a period of heightened susceptibility is consistent with a range of observations. Progress in the study of plaque biology has advanced our knowledge of the vulnerability of atherosclerotic plaques to rupture and subsequent embolic events, including transient ischaemic attack and ischaemic stroke. The composition of the plaque, including the degree of inammatory activity, crucially determines the stability of the plaque.23 The results of functional imaging studies show actively inamed carotid plaque in clinically relevant vascular locations.24 Whether immune cells in atherosclerotic plaques are activated by acute infection, which leads to plaque rupture, is the subject of ongoing research.25 Disturbances in immunohaematological mechanisms occur in the context of infection-associated stroke. Alterations to these mechanisms include slightly elevated concentrations of anticardiolipin antibodies in young and middle-aged patients, although these were probably indirect indicators of infection, rather than directly
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pathogenic;26 reduced concentrations of circulating antithrombotic activated protein C;27 elevated plasma concentrations of C4b-binding protein (a main inhibitor of the anticoagulant protein S); a lower ratio of active tissue plasminogen activator to plasminogen activator inhibitor;27 and signicantly increased brin D-dimer concentration, cardiolipin immunoreactivity, and brinogen concentrations.8 However, no dierences in the concentrations of various markers of coagulation and brinolysis or thrombomodulin were seen in two further studies.12,28 Seasonal variations in concentrations have been noted for brinogen and factor VIIc, with higher concentrations in the winter attributed to respiratory infections by way of the acute-phase response activation, which perhaps contributes to the observed seasonal variation in stroke incidence.29,30 Increased peripheral concentrations of C-reactive protein and proinammatory cytokines are associated with systemic infection and can contribute to a procoagulant state. C-reactive protein might promote localised coagulation, and therefore thrombosis, by stimulating monocytes to produce tissue factor, a membrane-bound glycoprotein that initiates the extrinsic pathway of coagulation.31 Raised IL-6 concentrations in patients with acute ischaemic stroke have been associated with decreased levels of free protein S, leading to the suggestion that IL-6 can partly modulate this anticoagulant pathway.32 Platelet activation in patients with acute ischaemic stroke was increased among patients with a history of infection in the week preceding stroke.33 Increased platelet reactivity has also been seen in volunteers with presumed upper respiratory tract infection of viral cause.34 Increased leucocyte counts are associated with a reduction in endothelial reactivity,35 and infections seem to impair endothelium-dependent relaxation transiently.36 Large-vessel atherothromboembolic or cardioembolic stroke subtypes were seen more commonly in patients with recent respiratory tract infection.14 Bacterial and viral infection increased the risk for cardioembolic stroke, often in association with atrial brillation.12,28 In this context, infection might be an additional trigger that increases the prothrombotic state seen in patients with atrial brillation, which leads to thrombosis and embolism. There is also a signicant association between recent infection and cervical artery dissection, which is another important cause of ischaemic stroke, particularly in young and middle-aged patients.37,38 Pre-existing abnormalities of extracellular matrix proteins might increase susceptibility to infection-associated injury of the arterial wall.38

Eects of preceding infection on stroke outcome

The severity and clinical outcome of ischaemic stroke might be worse when preceded by infection. Greater severity of stroke in terms of neurological decit at presentation has been reported in patients with recent
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infection,9,10,14 although not all the results of studies are in accord with this observation.8,11 In one study,39 inammatory markers, including C-reactive protein concentration and peripheral white blood cell count, were signicantly increased, and neurological impairment at day one and day four was signicantly worse in patients with ischaemic stroke who had preceding infection compared with those who did not.39 However, if infection and inammation are risk factors for stroke, there might be uncertainty about whether measurements made after admission show the inuence of the stroke or the preexisting inammation. Indeed, there is evidence of an early inammatory response to acute ischaemic stroke that aects the concentrations of markers such as C-reactive protein;40 for example, the concentration of C-reactive protein was signicantly higher in patients sampled 412 hours after the onset of stroke symptoms compared with patients sampled 04 hours after stroke onset.40 Previous studies have also reported systemic elevation of peripheral inammatory markers early after acute ischemic stroke in patients who did not have signs of pre-existing bacterial infection.41 The concept of acute inammation as a trigger for ischaemic events is strengthened by the observation that within the week before ischaemic stroke increased leucocyte counts predict increased risk.42 Preceding infection might be one driving factor for such a pre-existing inammatory condition. The eect of systemic inammation concurrent with stroke has been investigated in experimental models of stroke. This approach might oer insights into the poorer outcome seen in patients with stroke preceded by infection or, potentially, infection developing shortly after stroke onset. In addition to its role as an acute-phase protein, C-reacitve protein is a component of innate immunity that binds ligands exposed in damaged tissue and activates complement. Rats given human C-reactive protein 5 mins, 24 hours, and 48 hours after middle cerebral artery occlusion had signicantly larger cerebral infarct volumes at 72 hours.43 Systemic lipopolysaccharide given as an acute systemic inammatory stimulus had a detrimental eect on outcome that included brain damage and neurological decit, and IL-1 was shown to be a crucial mediator of the pathology.44 The principal signalling receptor for lipopolysaccharide is toll-like receptor 4, and toll-like receptor 4-decient mice had smaller cerebral infarctions and lower inammatory responses compared with wild-type mice.45 Whether the apparent role of toll-like receptor 4 signalling in the exacerbation of the inammatory response and cerebral injury is due to its activation by endogenous ligands in necrotic cells, extracellular matrix components or damaged blood vessel, or by exogenous ligands, such as bacterial lipopolysaccharide, is unclear. However, the study of bacterial lipopolysaccharide might provide a possible mechanism to account for worse neurological outcome from stroke that is preceded by infection.
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Whether preceding infection (or endotoxin exposure) always has a deleterious eect on outcome is uncertain, particularly in light of experimental and clinical data to suggest that prior subthreshold insults might confer endogenous neuroprotection.46 Ischaemic preconditioning/ischaemic tolerance refers to a subthreshold ischaemic insult that activates endogenous protective mechanisms and helps to reduce the damage of subsequent ischaemic episodes. Theoretically, transient ischaemic attack/ischaemic stroke is a clinical model of ischaemic preconditioning/ischaemic tolerance. Apart from ischaemia itself, a range of injurious stimuli can, when applied below the threshold of damage, protect the brain against subsequent ischaemia. An example is endotoxin exposure, leading to the concept of endotoxin preconditioning. Lipopolysaccharide priming shows protective eects in experimental models of stroke, with reductions in infarct volume and inammatory cell activation and inltration.47,48 Endogenous neuroprotection by endotoxin preconditioning is speculated to be conferred by negative regulatory changes at the genomic level, which limit subsequent ischaemic injury.48 Future studies should investigate whether recovery from stroke in certain circumstances (eg, timing or level of exposure) might be better after preceding infection rather than worse.

Poststroke infection
Frequency of poststroke infection
The frequency of poststroke infection has been the focus of several studies (table 2),4969 which have been done in various settings, including developing and developed countries. Direct comparisons between these studies is dicult when factors such as dierences in study design, selection bias, setting, location, denition of infections, and poststroke reporting interval are taken into account. The studies also span more than a decade, during which time stroke management has changed considerably. Such factors might potentially have increased or decreased the frequencies of infection reported in the studies; hence, the wide ranges of reported frequencies for respiratory tract infection (133%) and urinary tract infection (227%) are, perhaps, not surprising. The possibility cannot be excluded that some of the infections reported early poststroke actually developed prior to stroke onset but worsened thereafter. Higher frequencies of poststroke infection were found among patients in neurological intensive care units and rehabilitation settings. An audit of complications among 245 patients with stroke who were included in a randomised controlled trial of stroke unit rehabilitation found signicant dierences in the frequency of chest infections (16% vs 8%, p<005) and urinary tract infections (33% vs 17%, p<0005) between patients in general wards and in rehabilitation settings.70 The evident variation in hospital-acquired infection between institutions will also aect the data, but the overall
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Study design Rosenzweig and co-workers49 Fassbender and co-workers50 Prospective cohort Prospective series

Poststroke interval Hospital admission (mean 37 d) 1w

Number of patients 607 (91% ischaemic stroke) 52

Type of infection Chest infection Urinary tract infection Pneumonia Urinary tract infection Other Pneumonia Urinary tract infection Other Respiratory tract infection Urinary tract infection Other Respiratory tract infection Urinary tract infection Other Pneumonia Urinary tract infection Chest infection Urinary tract infection Other Pneumonia

Frequency of infection 12% 16% 10% 19% 2% 10% 11% 3% 10% 12% 1% 11% 2% 6% 7% 9% 22% 23% 19% 20% 19% 7% 12% 4% 21% 7% 33% 14% 17% 10% 13% 27% 10% 7% 2% 17% 1% 6% 4% 22% 1% 2% 2%

Johnston and co-workers51

Prospective multicentre trial

Trial duration (3 m)

279

Georgilis and co-workers52

Retrospective series

Hospital admission (duration not specied)

330 (85% ischaemic stroke)

Grau and co-workers53

Prospective series

48 h

119

Tirschwell and co-workers54 Langhorne and co-workers55

Population-based hospital discharge database Prospective cohort

Hospital admission (mean 78 d) Hospital admission (mean ~51 d)

4757 311 (90% ischaemic stroke)

Roth and co-workers56 Kammersgaard and co-workers57 Weimar and co-workers58 Hamidon and co-workers59 Hilker and co-workers60 Katzan and co-workers61 Pittock and co-workers62 Aslanyan and co-workers63 Ovbiagele and co-workers64 Ersoz and co-workers65 Kwan and Hand66

Consecutive series Prospective communitybased cohort Prospective hospital-based registry Consecutive series Prospective series Population-based cohort Consecutive series Prospective international trial Prospective stroke registry Prospective series Prospective cohort

Mean interval 174149 d 3d 7d 3d Intensive care unit admission (mean latency 1819 d) Hospital admission (duration not specied) 2w Trial duration (3 m) Hospital admission (duration not specied) Mean interval 188285 d 5d

1029 (71% ischaemic stroke)

1156 (92% ischaemic stroke)* Any infection 3866 163 124 14 293 (subtypes not specied) 106 (2-week survivors) 1455 663 82 439 (91% ischaemic stroke, 9% TIA) 229 (82% ischaemic stroke) Pneumonia Pneumonia Urinary tract infection Stroke-associated pneumonia Pneumonia Respiratory tract infection Pneumonia Urinary tract infection Pneumonia Urinary tract infection Symptomatic urinary tract infection Pneumonia Urinary tract infection Other Acute bronchial Pneumonia Urinary tract infection Other Stroke-associated pneumonia Pneumonia Urinary tract infection Other

Vargas and co-workers67

Prospective cohort

Hospital admission (median 9 days)

Walter and co-workers68 Wong and co-workers69

Prospective series Prospective series

Intensive care unit admission (mean latency 2029 d) 48 h

236 156

TIA=transient ischaemic attack. *Those with stroke subtype reported. First month.

Table 2: Studies that report poststroke infections

picture is one of increased susceptibility to infection, and multiple factors are likely to be involved. In part, the situation might be analogous to the immune suppression seen after brain trauma.71

Poststroke infection and clinical outcome

Several researchers have investigated the associations between poststroke infection and clinical outcome
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(table 3).51,54,57,5961,63,64,66,67 The largest study to investigate the eect of pneumonia on mortality in hospitalised patients with acute stroke reported a 27% 30-day mortality rate in 635 patients with pneumonia compared with a 4% mortality rate among patients without pneumonia (p<0001).61 An estimated 10% of deaths within 30 days of admission among hospitalised patients with stroke are due to pneumonia and, on the basis of number-needed345

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Associations with mortality Johnston and co-workers51 Not reported separately

Associations with functional outcome Logistic regression analysis, adjusted for admission National Institutes of Health Stroke Scale score, age, and history of diabetes mellitus, found that serious medical events (42% were infections) were associated with poor 3-month outcome (OR 61, 25151) on Barthel Index (<60) Not reported

Tirschwell and co-workers54

Multivariate logistic regression analysis for risk of hospital fatality associated with pneumonia (OR 37, 95% CI 2848) or urinary tract infection (OR 06, 0408); analyses adjusted for age, gender, and comorbid-related and stroke-related discharge diagnoses

Kammersgaard In-hospital death associated with early infection in univariate analysis (p<00001) but not and co-workers57 after multiple logistic regression analysis adjusted for covariates Hamidon and co-workers59 Hilker and co-workers60 Multivariate analysis for mortality risk with early infection OR 148 (43511) Relative risk of death based on mortality rate in patients with and without SAP, during intensive care admission (RR 33; p<005 [ test]) or during poststroke follow-up (mean interval 14637 months from discharge; RR 25, 1059; p<005 [2 test]) Multivariable logistic regression analysis to determine the eect of pneumonia on 30-day mortality: RR 59 (5168) when adjusted for age, race, sex, and teaching hospital status; RR declines to 30 (2437) when also adjusted for admission severity and propensity to develop pneumonia Multiple regression modelling to correct for prognostic factors and to determine HR for association between infectious event at day seven and death by 3 months: for aspiration pneumonia HR 22 (1533) or urinary tract infection HR 10 (0716)

Mean discharge stroke severity (Scandinavian Stroke Scale score) was greater in patients with early infection compared with those without (p<00001); early infection did not predict discharge score with multiple linear regression Not reported At follow-up, patients with SAP had a signicantly higher Rankin Scale score (unpaired t test p<005) and lower Barthel Index (unpaired t test p<005) compared with patients without SAP, which indicates impaired functional outcome in patients with pneumonia Not reported

Katzan and co-workers61

Aslanyan and co-workers63

Multiple regression modelling to correct for prognostic factors to determine OR for association between infectious events at day seven and poor outcome by 3 months; Barthel Index <60: for aspiration pneumonia OR 38 (2267), or urinary tract infection OR 19 (1229); modied Rankin Scale 2: for aspiration pneumonia OR 34 (1483), or urinary tract infection OR 31 (1659)

Ovbiagele and co-workers64 Kwan and Hand66 Vargas and co-workers67

Risk of death in hospital based on mortality rate in patients with and without pneumonia OR Odds of independent ambulation at discharge among patients with and without 64 (38106) (risk was still signicantly elevated after adjustment for age, sex, vascular risk pneumonia: OR 014 (008025) (dierence highly signicant in unadjusted and factors, and dementia), or with and without urinary tract infection OR 11 (0620) adjusted analyses), or with and without urinary tract infection: OR 052 (023117) Risk of death in patients with poststroke infection in the rst 5 days compared with those without infection OR 27 (1164) or in hospital OR 25 (1349) after adjustment for case mix Not reported separately Not reported

Logistic regression model of factors associated with poor outcome (modied Rankin Scale score >2 or death): stroke-associated infection OR 09 (0910) or interaction term stroke-associated infection*antibiotic use OR 08 (0330) did not enter in the model of stroke outcome

OR=odds ratio. HR=hazard ratio. RR=relative risk. SAP=stroke-associated pneumonia.

Table 3: Studies that have found associations between poststroke infection and clinical outcome

to-treat analyses, one stroke-related death at 30 days could be avoided for every 11 cases of pneumonia that are prevented. In most studies, functional outcome appears to be adversely inuenced by poststroke infection. Ovbiagele and co-workers64 reported a signicant dierence in functional outcome: among patients with pneumonia, 9% were able to walk without assistance at discharge compared with 43% of those who had not developed pneumonia (p<00001).64 A follow-up survey at a mean of 154 months after discharge from a neurological intensive care unit found that patients with stroke-associated pneumonia had signicantly higher modied Rankin Scale scores and signicantly lower Barthel Index scores, which indicate greater levels of disability than in patients without stroke-associated pneumonia.60 Johnston and coworkers51 reported more severe disability at 3 months in patients who had serious medical events (42% of which were infections), compared with those who did not.51 Pneumonia and urinary tract infections were also associated with poor functional outcome at 3 months
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poststroke in the study by Aslanyan and colleagues.63 However, in the community-based Copenhagen Stroke Study, early infection was not associated with increased severity of stroke at discharge.57 Similarly, Vargas and colleagues found that stroke-associated infection was not an independent predictor of poor outcome at discharge.67 These studies dier considerably in various respects. Hospital-based studies51,59 or studies based in intensive treatment units60 are inevitably subject to selection bias. The use of hospital discharge data or retrospective study designs might have led to the under-recognition or misclassication of stroke and infections and comparatively low poststroke infection frequencies.54,61 Whether deaths were primarily attributable to infection must also be identied. Variations in the observation periods are likely to have inuenced infection frequency and the reported associations with outcome. Secondary, rather than primary, analyses of the relationship between poststroke infection and outcome also need to be interpreted with caution. The two studies of prospectively recruited clinical trial populations51,63 had xed observation
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periods, which included the acute phase, and probably beneted from more rigorous identication of complications. The choice of functional outcome measures is also problematic. Only three studies51,60,63 reported Barthel Index scores, but even this widely used measure of the activities of daily living has limitations. For example, the choice of cut-o point for poor outcome (eg, less than 60)51,63 is arbitrary, and apparently favourable scores can frequently be associated with signicant disability because domains such as communication and cognition are not included. In another study, death was included in the modied Rankin Scale score, which prevents separate reporting of functional outcome.67 One study recorded stroke severity at discharge but did not strictly report any functional outcome measure.57 The extent to which other confounding factors, such as stroke severity, infarct size, age, body temperature, and use of antibiotics, are taken into account also varies between studies (table 3). Whether infectious complications are associated with worse outcomes because of adverse eects on the condition of the patient, or whether factors inherent in the patient or the eects of the stroke predispose to infectious complications, or both, are unclear. Aslanyan and co-workers investigated this, and found that the association between infectious events and poor outcome did not depend on baseline prognostic factors, such as National Institutes of Health Stroke Scale (NIHSS) score, age, gender, stroke risk factors, and Oxfordshire Community Stroke Project classication.63 Other factors such as increased body temperature can further complicate our understanding of the association between poststroke infection and outcome, given that increased body temperature could be due to cerebral infarction per se, infection, or a combination of the two; furthermore, increased body temperature itself could be associated with adverse outcome. Future studies of the inuence of poststroke infection on clinical outcome need to take into account methodological problems by minimising selection bias, maximising prospective recruitment of patients, prospective identication of infections with standard diagnostic criteria for stroke and infections, and reporting of infections for a xed period poststroke. Although there is no ideal functional outcome measure, the limitations of the chosen outcome measures should be acknowledged. The large number of confounding factors also clearly inuences the ndings of these studies. Standardisation of the factors that are analysed, including at least stroke severity measures, infarct size, age, and use of antibiotics, would be benecial. An intriguing explanation for the poorer outcome from stroke complicated by infection is the development of an autoimmune response to the brain after exposure to a systemic inammatory stimulus at the time of the stroke. When lipopolysaccharide was injected intraperitoneally
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at reperfusion in a rat with temporary middle cerebral artery occlusion, to simulate an infectious insult during stroke, a sensitising response to brain antigens (eg, myelin basic protein) was seen in addition to more severe and persistent neurological decits.72

Factors associated with poststroke infection

Studies that describe the frequency of poststroke infection and its eects on outcome have also examined risk factors for infection. These risk factors include greater stroke severity on admission, total anterior circulation infarction, Barthel Index of less than 5 (020 scale), Glasgow Coma Scale score of less than 9, infarction in the territory of the middle cerebral artery, being older, current atrial brillation, being a woman, tube feeding, and a history of congestive heart failure.57,59,62,64,66,67 In the neurological intensive care unit, independent risk factors for stroke-associated pneumonia include mechanical ventilation, non-lacunar basal ganglia infarction, dysphagia, NIHSS score of 10 or more, and an abnormal chest X-ray on admission.60,68 Aslanyan and colleagues63 found pneumonia was predicted by total anterior circulation infarction, being a man, a history of diabetes mellitus, higher baseline NIHSS score, and being older, whereas being a woman, having a higher baseline NIHSS score, and being older predicted urinary tract infection.63 Sellars and co-workers,73 who specically investigated risk factors for chest infection in patients with acute stroke, reported the independent predictors of pneumonia as being older than 65 years, dysarthria or no speech due to aphasia, a modied Rankin Scale score of 4 or more, abbreviated mental test score of less than 8, and a failed water swallow test.73 When patients with all stroke subtypes were included, haemorrhagic stroke increased the risk of poststroke pneumonia.61 The most consistently reported predictors of poststroke infection include being older, greater baseline stroke severity, total anterior circulation infarction, and dysphagia. Amelioration of neurological impairment and prevention of complications are already major goals of stroke treatment. The prominence of dysphagia as a risk factor for pneumonia after stroke has encouraged the early diagnosis and management of dysphagia. However, conservative measures, such as tube feeding, provide limited protection against poststroke pneumonia; for example, Dziewas and colleagues74 reported pneumonia in 44 of 100 patients with acute stroke who were fed by nasogastric tube because of dysphagia.74 This raises the possibility that factors other than dysphagia, such as stroke-induced alteration of the systemic immune response, might be important.

Evidence for brain-induced immunodepression

There is increasing evidence that normally well balanced brainimmune interactions become dysregulated after acute ischaemic stroke.75 One eect of this dysregulation is inammation of the brain after acute ischaemic stroke, which is detrimental because it exacerbates acute injury,
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but might also be potentially benecial in terms of clearing and remodelling damaged brain tissue.76 Stroke severity is a key predictor of poststroke infection; indeed, CNS injury, such as stroke, induces immunodepression, which is another result of dysregulated brainimmune interactions. In experimental focal cerebral ischaemia, spontaneous septicaemia and pneumonia occurred within 3 days of ischaemia, with immunodepression detected within a few hours of ischaemia and lasting for several weeks.77 A catecholamine-mediated defect in early lymphocyte activation seemed crucial to the impaired poststroke antibacterial immune response.75 Further work found that harmless intranasal bacterial colonisation developed into pneumonia after experimental stroke, and that such infections were prevented by -adrenoceptor blockade, which suggests that immunodepression as a result of sympathetic nervous system overactivity is necessary for the progression of bacterial aspiration to pneumonia.78 Impairments of cell-mediated immunity after acute stroke were rst reported nearly three decades ago; these include reduced peripheral blood lymphocyte counts, impaired T-cell activity, and reduced production of the pro-inammatory cytokine migration inhibition factor in response to stimulation.79 At the time, the depression of immune function was attributed to severe stress during the course of disease, but such observations have received relatively little attention until recently. Clinical data are currently emerging to support the phenomenon of socalled brain-induced immunodepression after acute ischaemic stroke.80 Elevated concentrations of cortisol or adrenocorticotrophin hormone in patients with acute ischaemic stroke are associated with more severe stroke, larger infarct volume, or worse outcome.81 The early rise in plasma cortisol concentrations within 12 hours of ischaemic stroke, which precedes the rise in IL-6, indicates the magnitude of the rapid stress response to cerebral ischaemia, rather than activation of the hypothalamopituitaryadrenal axis by systemic IL-6.82 Chamorro and colleagues reported a rapid increase in the plasma concentrations of circulating cytokines, with a low ratio of TNF- to anti-inammatory IL-10 preceding the symptoms of infection.83 In another recent study of patients with acute ischaemic stroke, marked signs of suppression of cell-mediated immunity were noted; these included functional deactivation of monocytes and T helper type-1 cells and there was some evidence that these changes occurred before the clinical manifestation of infection.84 A further investigation of immunological changes in patients with ischaemic stroke found a poststroke loss of CD4+ T-cell function, and this loss persisted in patients who developed infection.85 After acute ischaemic stroke, there is evidence of systemic inhibition of the production of cytokines that are associated with the innate immune and inammatory responses.86 Following lipopolysaccharide stimulation of whole blood that was sampled between admission and 57 days poststroke, we found signicantly reduced
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concentrations of IL-1, TNF-, and IL-6 compared with controls. Minimum in vitro cytokine production in the rst week was signicantly associated with poorer clinical outcome and was lower in 12-month non-survivors than survivors (gure 1).86 Although the mechanism was not dened, there was a strong inverse correlation between cortisol concentrations and minimum in vitro cytokine production.82 Our clinical observations are in keeping with experimental data that describe a systemic antiinammatory response; the response is characterised by reduced production of TNF- and increased production of IL-10 in endotoxin-stimulated whole blood after infusion of IL-1 into the brain, through stimulation of the hypothalamopituitaryadrenal axis and the sympathetic nervous system.87 Catecholamines and corticosteroids suppress endotoxin-induced cytokine production by whole blood from healthy volunteers.88,89 Such regulatory responses, and increases in concentrations of inhibitory cytokines, such as the IL-1 receptor antagonist, might contribute to the increased vulnerability to infection of patients with acute ischaemic stroke.

Implications for treatment strategies

Preceding infection
The recognition that vulnerable individuals might have a short-term increased risk of stroke in association with acute systemic infection could have important implications for clinical practice. There is no evidence to support targeting more intensive stroke prevention strategies to patients with a history of stroke or risk factors for stroke during acute infections, but this is an interesting and important area for future study. Emphasising the importance of compliance in patients already on secondary prevention treatment, particularly during acute infection, would be a logical approach. The dramatic reduction in risk of early recurrent stroke with the early initiation of existing treatments for transient ischaemic attack90 underlines the importance of prompt action, particularly if a stroke-prone state exists in vulnerable individuals with acute infection, as is the case in patients with transient ischaemic attack. The pleiotropic eects of statins beyond lipid lowering include stabilisation of atherosclerotic plaques, but statins directly and indirectly modulate many aspects of the immune and inammatory responses that are associated with sepsis and possibly reduce the overall magnitude of the systemic response.91 Reduction of C-reactive protein concentrations and a shift in the coagulation balance away from the prothrombotic state that is typically associated with sepsis are examples of the possible eects of statins that might ameliorate the increased risk of stroke associated with infection.91 Statins might protect against the endothelial dysfunction related to acute infection or inammation,92 and there is evidence that the use of statins in patients with atherosclerosis is associated with a reduced risk of sepsis.93 However, a recent pilot trial of patients in the acute phase of ischaemic stroke found that although
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p=0004 Minimum IL-1 production in rst week (ng/million monocytes) 100 Minimum IL-6 production in rst week (ng/million monocytes) p<0001 p<0001 p<0001 1000

p=0002 Minimum TNF- production in rst week (ng/million monocytes) p<0001 p<0001 100

p=0014 p<0001

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01 Survivor controls Stroke survivors

10 Stroke non-survivors

01

Non-survivor controls

Figure 1: Minimum lipopolysaccharide-stimulated cytokine production in the rst week in patients who survived acute ischaemic stroke and non-survivors at 12 months P values were generated from an analysis of log-transformed data (logistic regression for comparison of survivors and non-survivors, paired t-test for comparisons with controls).86

simvastatin might improve clinical outcomes, use of this statin was associated with increased poststroke infection.94 Such results draw attention to the need to consider carefully the balance between reducing inammation and inhibiting an eective response to infection. The prevention of infection in vulnerable individuals is surely a key strategy to minimise the stroke risk apparently associated with acute infection. Recent evidence implies that inuenza vaccination in patients who have a history of cerebrovascular disease or who are at high risk of stroke might confer protection against not only inuenza but also stroke.19 Indeed, recent guidelines advocate inuenza vaccination as part of a comprehensive secondary prevention strategy in individuals with coronary or other atherosclerotic vascular diseases.95

Poststroke infection
The high incidence of poststroke infection, its adverse eects on outcome, and recent observations on braininduced immunodepression have prompted researchers to investigate preventive antibiotic use in experimental and clinical settings. Moxioxacin given immediately or 12 hours after middle cerebral artery occlusion in mice prevented infections and fever, signicantly reduced mortality, and improved neurological outcome.96 Other antibiotics being investigated for their neuroprotective properties include minocyclinea semi-synthetic tetracycline antibiotic, the use of which was associated with a signicant reduction in infarct size in an experimental model of stroke, even when given intravenously at low doses up to 5 hours poststroke.97 Ceftriaxone was also neuroprotective, albeit only in the in vitro setting.98 Prophylactic levooxacin (500 mg given intravenously daily for 3 days) in patients after acute stroke was no better than optimal care for the prevention of infections, and might have impaired clinical recovery.99 Preliminary clinical data from a double-blind randomised controlled trial in patients with severe stroke in the territory of the middle cerebral artery suggest that moxioxacin (400 mg
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given intravenously daily for 5 days) might prevent complications due to infection, although the infection rates seen between active and placebo groups did not dier signicantly in the intention-to-treat analysis.100 Improved functional outcome in patients with acute ischaemic stroke treated with minocycline (200 mg given orally daily for 5 days) was recently reported in an openlabel trial, although a randomised controlled trial will be required to substantiate these preliminary data.101 Other trials of antibiotics include the recently completed Mannheim Infection in Stroke Study, in which treatment with mezlocillin and sulbactam (32 g/L given intravenously for 4 days) in patients with acute severe ischaemic stroke might have been associated with improved clinical outcome.102 European recommendations for stroke management currently advise against empirical antibiotic treatment in immunocompetent patients,103 although a better understanding of brain-induced immunodepression after stroke might shed further light on this. Poststroke infection is a potential concern associated with treatments that target inammatory responses to stroke. The rationale behind enlimomab, a murine antibody to human intercellular adhesion molecule 1, was the reduction of reperfusion-associated inammation, but stroke outcome was signicantly worse in the treated group.104 Increased rates of fever and infections were reported in enlimomab-treated patients, and pneumonia was a particular concern because it occurred almost ve times more frequently during the rst 5 days of therapy than in placebo-treated patients. Possible mechanisms for negative clinical outcome were investigated in rats; giving a murine antibody to intercellular adhesion molecule 1 induced an inammatory state, which included activation of complement, neutrophils, and endothelium.105 IL-1 has an important role during the initiation of inammatory and innate immune responses, and in the rst clinical trial of IL-1RA in patients with acute stroke the most frequently occurring adverse events were infections:106 a higher rate of infections was seen in
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TIA Conventional risk factors Chronic infection Atherosclerosis Acute ischaemic stroke Neurological impairment Dysphagia Hypathopituitaryadrenal axis or sympathetic nervous system activation

Ischaemic/endotoxin preconditioning?

Poststroke infection

Acute infection

Acute-phase proteins Procoagulant state Endothelial activation Atherosclerotic instability

Brain-induced immunodepression

Inammation (pro-/anti-inammatory mechanisms)

Time

Figure 2: Summary of inter-relations between infection, inammation, and acute ischaemic stroke over time Established processes and relations are depicted in red boxes linked with red arrows; other possible processes or relations are in blue boxes with blue outlines or linked with blue arrows. Solid lines denote upregulating pathways, broken lines denote downregulating pathways.

patients with primary intracerebral haemorrhage, but overall infectious episodes were typical of those generally seen in patients after acute stroke, none was serious, and none was considered attributable to treatment with IL-1RA.

Conclusions
The associations between infection and acute ischaemic stroke are complex (gure 2). Acute infection is an important trigger for stroke; the reported prevalence of infection in the week preceding stroke ranges from 1035%, during which time infection confers at least a 23-times increased risk of stroke. Possible mechanisms include changes in atherosclerotic plaque stability, alterations in immunohaematological mechanisms, proinammatory cytokine activation, platelet activation, and endothelial dysfunction. Outcome from stroke appears to be worsened by preceding infection; possible mechanisms for this include enhanced IL-1 and toll-like receptor-4 signalling. Although endotoxin preconditioning might improve outcome in experiments, no equivalent eect of preceeding infection has been seen clinically. Poststroke infection is common and complicates up to a third of ischaemic strokes. Mortality and functional outcome appear to be worsened by poststroke infection, Search strategy and selection criteria
References for this Review were identied by searches of PubMed from 1966 until January, 2008, with the terms ischaemic or ischemic and stroke and infection. Articles were also identied through searches of the authors own les. Only articles published in English were reviewed. Articles about the association between HIV infection and stroke were excluded; a comprehensive discussion of HIV-associated stroke was deemed to be beyond the scope of the present Review.

but further, well designed studies are required to resolve this controversy denitvely. Risk factors for poststroke infection include age, stroke severity, and dysphagia, but poststroke immunodepression has been recognised as a contributory factor, possibly driven by activation of the sympathetic nervous system and hypothalamopituitary adrenal axis. Intensive stroke prevention strategies might need to be targeted to vulnerable individuals with acute infection. The pleiotropic eects of statins might also be important, and the prevention of infection in vulnerable individuals, such as through inuenza vaccination, might be key. Trials of antibiotics for the prevention of poststroke infection are underway, and the results of these trials show some promise in the improvement of outcomes. Future interventions with drugs that target inammatory responses to stroke need to take into account the complex inter-relations between stroke and infection.
Contributors HCAE conceptualised and wrote this Review. SJH reviewed and contributed to the editing of the Review. Conicts of interest We have no conicts of interest. References 1 Emsley HC, Tyrrell PJ. Inammation and infection in clinical stroke. J Cereb Blood Flow Metab 2002; 22: 13991419. 2 Lindsberg PJ, Grau AJ. Inammation and infections as risk factors for ischemic stroke. Stroke 2003; 34: 251832. 3 Chi H, Messas E, Levine RA, Graves DT, Amar S. Interleukin-1 receptor signaling mediates atherosclerosis associated with bacterial exposure and/or a high-fat diet in a murine apolipoprotein E heterozygote model: pharmacotherapeutic implications. Circulation 2004; 110: 167885. 4 Hankey GJ. Potential new risk factors for ischaemic stroke: what is their potential? Stroke 2006; 37: 218188 5 Hindfelt B, Nilsson O. Brain infarction in young adults (with particular reference to pathogenesis). Acta Neurol Scand 1977; 55: 14557. 6 Syrjnen J, Valtonen VV, Iivanainen M, Hovi T, Malkamki M, Mkel PH. Association between cerebral infarction and increased serum bacterial antibody levels in young adults. Acta Neurol Scand 1986; 73: 27378.

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