Prognostic value of blood interleukin-6 in the prediction of functional outcome after stroke: A systematic review and meta-analysis
Graphical abstract
Introduction
Accurately predicting stroke outcome is challenging. Despite the wide number of factors that may influence stroke prognosis, it has been suggested that they could be simplified as the interaction between baseline characteristics of the patient, such as age, gender or stroke severity (Appelros et al., 2003, Saposnik G., Hill M.D., O'Donnell M., Fang J., Hachinski V., Kapral M.K., Registry of the Canadian Stroke Network for the Stroke Outcome Research Canada (SORCan) Working Group, 2008, Wahlgren et al., 2008), and several circumstances that occur after stroke leading to a poor outcome, such as those related to acute therapies (resistance to recanalization, reocclusions, hemorrhagic transformation), edema or increased intracranial pressure, or post-stroke infections (Koennecke et al., 2011, Grube et al., 2013). These latter factors represent a unique opportunity for clinicians and researchers to intervene and modify stroke outcome. Even though some blood biomarkers have shown a significant association with neurological deterioration, three-months disability or mortality (Whiteley et al., 2009a), at present there is no biomarker that has proved to be useful for these purposes in the clinical setting, and it is still uncertain whether blood biomarkers add information to simple predictive models based on clinical variables, such as age and severity of stroke (Montaner et al., 2012, Whiteley et al., 2012). Furthermore, a good biomarker should be associated not just with an end point but also with a decision-making process to make easier its translation to clinical practice.
Cerebral ischemia triggers an inflammatory response characterized by the up-regulation of inflammatory cytokines within the brain, as well as in peripheral blood (del Zoppo et al., 2000). Although the over expression of interleukin-6 (IL-6) by astrocytes and microglia may have a dual role in acute ischemia, with both neurotoxic and neuroprotective roles attributed to this cytokine (Van Wagoner and Benveniste, 1999, Muller, 2002), blood levels of IL-6 have been repeatedly associated with poor outcome (Smith et al., 2004, Waje-Andreassen et al., 2005) after stroke. The reason for this association, however, is not fully understood. IL-6 concentration in blood has been correlated with baseline stroke severity, suggesting a plausible role as a biomarker of acute cerebral injury (Orion et al., 2008, Whiteley et al., 2012), but circulating IL-6 may also be related to other factors such as post-stroke infections (Wartenberg et al., 2011). Whether determination of IL-6 adds predictive value to prognostic models of stroke outcome in terms of additional predictive value is also unclear (Orion et al., 2008, Whiteley et al., 2012). Systematic review and meta-analysis of candidate biomarkers has been proposed as an evidence-generating approach (Garcia-Berrocoso et al., 2013a), which may confer a Class II level of evidence for a diagnostic tool (Leone et al., 2013). In this study, our main objective was to evaluate and quantify the association of IL-6 with functional outcome after stroke. Secondary objectives were to explore its added predictive value over clinical information and to assess whether specific causes of poor outcome could underlie this association.
Section snippets
Search
We searched PubMed up to October 2013. A combination of MeSH terms and text words for the terms “stroke”, “IL-6” and “outcome”, using 75 different entry terms, was applied (Supplementary data, S1). Duplicated studies were considered only once. Reference lists of the included articles and reviews that were identified in the search (Laskowitz et al., 1998, Whiteley et al., 2009a, Whiteley et al., 2009b) were hand-searched.
Three authors screened articles considering studies for potential inclusion
Search
Our search revealed 669 articles, of which 634 were initially excluded in the first screening (Fig. 1). From 35 potentially includible articles only 3 had all the necessary information to be included in the meta-analysis, with the level of IL-6 expressed as mean ± SD being the most frequently missed variable. The corresponding authors of the other 32 studies were contacted by e-mail to request additional data. All authors but 7 provided us with the information and 4 more studies were excluded at
Discussion
Our study confirmed the association of IL-6 levels with poor functional outcome after stroke, independent of age, gender and stroke severity. However, the additional predictive value in terms of discrimination between poor and good outcomes and reclassification to highest or lowest risk categories over these clinical variables was modest, although statistically significant. We were able to perform a comprehensive analysis, including more than 4700 patients, with enough statistical power to test
Acknowledgments
Alejandro Bustamante is supported by a Rio Hortega contract CM/00265 from the Instituto de Salud Carlos III. V.L. is supported by a pre-doctoral fellowship from Vall Hebrón Institute of Research. Neurovascular Research Laboratory takes part in the Spanish stroke research network INVICTUS (RD12/0014/0005) and is supported on stroke biomarkers research by FIS 11/0176.
The authors are grateful to Ana Maria Simundic (Zagreb, Croatia) and Guo-Yuan Yang (Shangai, China) for contributing data for the
References (54)
- et al.
Pro-inflammatory and anti-inflammatory cytokines in acute ischemic stroke and their relation to early neurological deficit and stroke outcome
Clin. Biochem.
(2008) - et al.
Toll-like receptors 7 and 8 expression is associated with poor outcome and greater inflammatory response in acute ischemic stroke
Clin. Immunol.
(2011) - et al.
Interleukin-6 gene − 174 G/C promoter polymorphism predicts severity and outcome in acute ischemic stroke patients from north India
J. Stroke Cerebrovasc. Dis.
(2013) - et al.
Meta-analysis in clinical trials
Control. Clin. Trials
(1986) - et al.
From brain to blood: new biomarkers for ischemic stroke prognosis
J Proteomics
(2013) - et al.
IL-6 is a predictive biomarker for stroke associated infection and future mortality in the elderly after an ischemic stroke
Exp. Gerontol.
(2013) - et al.
Serum markers of cerebral ischemia
J. Stroke Cerebrovasc. Dis.
(1998) Cytokine imbalance in non-immunological disease
Cytokine
(2002)- et al.
proMetalloproteinase-10 is associated with brain damage and clinical outcome in acute ischemic stroke
J. Thromb. Haemost.
(2013) - et al.
Meta-analysis of the literature or of individual patient data: is there a difference?
Lancet
(1993)
Interleukin-6 expression and regulation in astrocytes
J. Neuroimmunol.
Poor outcome after first-ever stroke: predictors for death, dependency, and recurrent stroke within the first year
Stroke
High blood pressure and inflammation are associated with poor prognosis in lacunar infarctions
Cerebrovasc. Dis.
Inflammation-mediated damage in progressing lacunar infarctions: a potential therapeutic target
Stroke
The release of tumor necrosis factor-alpha is associated with ischemic tolerance in human stroke
Ann. Neurol.
Copeptin adds prognostic information after ischemic stroke: results from the CoRisk study
Neurology
Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia
Brain Pathol.
Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach
Biometrics
Tumor necrosis factor alpha serum levels and inflammatory response in acute ischemic stroke
Neurosciences (Riyadh)
Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis
Biometrics
Copeptin, procalcitonin and routine inflammatory markers-predictors of infection after stroke
PLoS One
B-type natriuretic peptides and mortality after stroke: a systematic review and meta-analysis
Neurology
Role of beta-defensin-2 and interleukin-4 receptor as stroke outcome biomarkers
J. Neurochem.
Influence of acute complications on outcome 3 months after ischemic stroke
PLoS One
Usefulness of serum procalcitonin levels for the early diagnosis of stroke-associated respiratory tract infections
Neurocrit. Care.
Factors influencing in-hospital mortality and morbidity in patients treated on a stroke unit
Neurology
Medical complications after stroke: a multicenter study
Stroke
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