C-reactive Protein, Infection, and Outcome After Acute Ischemic Stroke: A Registry and Systematic Review

Author(s): Lu Wang, Yuxiao Li, Changyi Wang, Wen Guo, Ming Liu*

Journal Name: Current Neurovascular Research

Volume 16 , Issue 5 , 2019

Become EABM
Become Reviewer
Call for Editor


Background: A number of studies have explored the prognostic role of CRP in patients with acute ischemic stroke, however, the results have been inconclusive. The aim of our study was to investigate the impact of infection on the association between CRP and 3-month functional outcome by performing a registry study and systematic review.

Methods: Patients admitted within 24 hours of acute ischemic stroke onset and had CRP measured within 24 hours after admission were included. Patients admitted between June 2016 and December 2018 in Chengdu Stoke Registry were enrolled. The PubMed database was searched up to July 2019 to identify eligible studies. Poor outcome was defined as modified Rankin Scale scores at 3-month more than 3.

Results: Totally, 368 patients in the registry and 18 studies involving 15238 patients in the systematic review were included. A statistically significant association between CRP values on admission and 3-month poor outcome in patients without infection was found, both in our registry (CRP per 1-mg/L increment, OR 1.04, 95% CI 1.01 to 1.07, p=0.008) and meta-analysis (CRP per 1-mg/dL increment, OR 1.66 [95% CI 1.37 to 2.01, p<0.001]). In patients with infection, CRP was not associated with a 3-month poor outcome according to registry data (OR 1.00, 95% CI 0.99 to 1.01, p=0.663) and meta-analysis (OR 1.01, 95% CI 0.99 to 1.01, p=0.128).

Conclusion: High CRP value was independently associated with a 3-month poor outcome after stroke in patients without infection. Further studies are required to examine the value of infection on CRP measures and long-term functional outcomes.

Keywords: C-reactive protein, acute ischemic stroke, prognosis, infection, systemic inflammation, tissue necrosis.

Smith CJ, Emsley HC, Vail A, et al. Variability of the systemic acute phase response after ischemic stroke. J Neurol Sci 2006; 251(1-2): 77-81.
[http://dx.doi.org/10.1016/j.jns.2006.09.011] [PMID: 17087970]
Verma S, Yeh ET. C-reactive protein and atherothrombosis--beyond a biomarker: An actual partaker of lesion formation. Am J Physiol Regul Integr Comp Physiol 2003; 285(5): R1253-6.
[http://dx.doi.org/10.1152/ajpregu.00170.2003] [PMID: 14557241]
Pedersen ED, Waje-Andreassen U, Vedeler CA, Aamodt G, Mollnes TE. Systemic complement activation following human acute ischaemic stroke. Clin Exp Immunol 2004; 137(1): 117-22.
[http://dx.doi.org/10.1111/j.1365-2249.2004.02489.x] [PMID: 15196251]
VanGilder RL, Davidov DM, Stinehart KR, et al. C-reactive protein and long-term ischemic stroke prognosis. J Clin Neurosci 2014; 21(4): 547-3.
Di Napoli M, Schwaninger M, Cappelli R, et al. Evaluation of C-reactive protein measurement for assessing the risk and prognosis in ischemic stroke: A statement for health care professionals from the CRP Pooling Project members. Stroke 2005; 36(6): 1316-29.
[http://dx.doi.org/10.1161/01.STR.0000165929.78756.ed] [PMID: 15879341]
Matsuo R, Ago T, Hata J, et al. Fukuoka Stroke Registry Investigators. Plasma C-reactive protein and clinical outcomes after acute ischemic stroke: A prospective observational study. PLoS One 2016; 11(6)e0156790
[http://dx.doi.org/10.1371/journal.pone.0156790] [PMID: 27258004]
Karlinski M, Bembenek J, Grabska K, et al. Routine serum C-reactive protein and stroke outcome after intravenous thrombolysis. Acta Neurol Scand 2014; 130(5): 305-11.
[http://dx.doi.org/10.1111/ane.12227] [PMID: 24571644]
Topakian R, Strasak AM, Nussbaumer K, Haring HP, Aichner FT. Prognostic value of admission C-reactive protein in stroke patients undergoing IV thrombolysis. J Neurol 2008; 255(8): 1190-6.
[http://dx.doi.org/10.1007/s00415-008-0866-y] [PMID: 18484234]
Worthmann H, Tryc AB, Dirks M, et al. Lipopolysaccharide binding protein, interleukin-10, interleukin-6 and C-reactive protein blood levels in acute ischemic stroke patients with post-stroke infection. J Neuroinflam 2015; 12: 13.
[http://dx.doi.org/10.1186/s12974-014-0231-2] [PMID: 25613713]
Bustamante A, Vilar-Bergua A, Guettier S, et al. C-reactive protein in the detection of post-stroke infections: Systematic review and individual participant data analysis. J Neurochem 2017; 141(2): 305-14.
[http://dx.doi.org/10.1111/jnc.13973] [PMID: 28171699]
Rocco A, Fam G, Sykora M, Diedler J, Nagel S, Ringleb P. Poststroke infections are an independent risk factor for poor functional outcome after three-months in thrombolysed stroke patients. Int J Stroke 2013; 8(8): 639-44.
den Hertog HM, van Rossum JA, et al. C-reactive protein in the very early phase of acute ischemic stroke: Association with poor outcome and death. J Neurol 2009; 256(12): 2003-8.
[http://dx.doi.org/10.1007/s00415-009-5228-x] [PMID: 19609738]
Tiainen M, Meretoja A, Strbian D, et al. Body temperature, blood infection parameters, and outcome of thrombolysis-treated ischemic stroke patients. Int J Stroke 2013; 8(8): 632-8.
Rocco A, Ringleb PA, Grittner U, Nolte CH, Schneider A, Nagel S. Follow-up C-reactive protein level is more strongly associated with outcome in stroke patients than admission levels. Neurol Sci 2015; 36(12): 2235-41.
Gao Y, Liu J, Wang W, et al. An elevated high-sensitivity C-reactive protein level is associated with unfavorable functional outcomes of small-artery occlusion in patients without diabetes. Eur Neurol 2017; 78(1-2): 48-55.
[http://dx.doi.org/10.1159/000477929] [PMID: 28624820]
Aliasghari F, Izadi A, Khalili M, Farhoudi M, Ahmadiyan S, Deljavan R. Impact of premorbid malnutrition and dysphagia on ischemic stroke outcome in elderly patients: A community-based study. J Am Coll Nutr 2019; 38(4): 318-26.
[PMID: 30252628]
Smith CJ, Emsley HC, Gavin CM, et al. Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol 2004; 4: 2.
[http://dx.doi.org/10.1186/1471-2377-4-2] [PMID: 14725719]
Tsai NW, Lee LH, Huang CR, et al. The association of statin therapy and high-sensitivity C-reactive protein level for predicting clinical outcome in acute non-cardioembolic ischemic stroke. Clin Chim Acta 2012; 413(23-24): 1861-5.
Rajeshwar K, Kaul S, Al-Hazzani A, et al. C-reactive protein and nitric oxide levels in ischemic stroke and its subtypes: Correlation with clinical outcome. Inflammation 2012; 35(3): 978-84.
[http://dx.doi.org/10.1007/s10753-011-9401-x] [PMID: 22038116]
Tu WJ, Zhao SJ, Liu TG, Yang DG, Chen H. Combination of high-sensitivity C-reactive protein and homocysteine predicts the short-term outcomes of Chinese patients with acute ischemic stroke. Neurol Res 2013; 35(9): 912-21.
[http://dx.doi.org/10.1179/1743132813Y.0000000228] [PMID: 23816540]
Deng WJ, Shen RL, Li M, Teng JF. Relationship between procalcitonin serum levels and functional outcome in stroke patients. Cell Mol Neurobiol 2015; 35(3): 355-61.
[http://dx.doi.org/10.1007/s10571-014-0131-0] [PMID: 25370803]
Qu X, Shi J, Cao Y, Zhang M, Xu J. Prognostic value of white blood cell counts and C-reactive protein in acute ischemic stroke patients after intravenous thrombolysis. Curr Neurovasc Res 2018; 15(1): 10-7.
[http://dx.doi.org/10.2174/1567202615666180326101524] [PMID: 29577860]
Wu B, Lin S, Hao Z, et al. Proportion, risk factors and outcome of lacunar infarction: A hospital-based study in a Chinese population. Cerebrovasc Dis 2010; 29(2): 181-7.
[http://dx.doi.org/10.1159/000267277] [PMID: 20029187]
Hacke W, Kaste M, Fieschi C, et al. Second European-Australasian Acute Stroke Study Investigators. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998; 352(9136): 1245-51.
[http://dx.doi.org/10.1016/S0140-6736(98)08020-9] [PMID: 9788453]
S. Cleveland W. J. Devlin S. Weighted regression: An approach to regression analysis by local fitting. J Am Stat Assoc 1988; 83(403): 569-610.
Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in metaanalyses. Available from: http://www.ohri.ca/programs/clinical_ epidemiology/oxford.asp
von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. Lancet 2007; 370(9596): 1453-7.
[http://dx.doi.org/10.1016/S0140-6736(07)61602-X] [PMID: 18064739]
Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: A proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283(15): 2008-12.
[http://dx.doi.org/10.1001/jama.283.15.2008] [PMID: 10789670]
Zheng X, Zeng N, Wang A, et al. Elevated C-reactive protein and depressed high-density lipoprotein cholesterol are associated with poor function outcome after ischemic stroke. Curr Neurovasc Res 2018; 15(3): 226-33.
[http://dx.doi.org/10.2174/1567202615666180712100440] [PMID: 29998802]
Hou D, Liu J, Feng R, Gao Y, Wang Y, Wu J. The role of high-sensitivity C-reactive protein levels in functional outcomes in patients with large-artery atherosclerosis and small-artery occlusion. Neurol Res 2017; 39(11): 981-7.
[http://dx.doi.org/10.1080/01616412.2017.1358937] [PMID: 28749740]
Huţanu A, Iancu M, Bălaşa R, Maier S, Dobreanu M. Predicting functional outcome of ischemic stroke patients in Romania based on plasma CRP, sTNFR-1, D-Dimers, NGAL and NSE measured using a biochip array. Acta Pharmacol Sin 2018; 39(7): 1228-36.
[http://dx.doi.org/10.1038/aps.2018.26] [PMID: 29926842]
Kim SH, Lee JY, Kim DH, et al. Factors related to the initial stroke severity of posterior circulation ischemic stroke. Cerebrovasc Dis 2013; 36(1): 62-8.
[http://dx.doi.org/10.1159/000351512] [PMID: 23921172]
Suda S, Aoki J, Shimoyama T, et al. Stroke-associated infection independently predicts 3-month poor functional outcome and mortality. J Neurol 2018; 265(2): 370-5.
[http://dx.doi.org/10.1007/s00415-017-8714-6] [PMID: 29249057]
Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: An integrated view. Trends Neurosci 1999; 22(9): 391-7.
[http://dx.doi.org/10.1016/S0166-2236(99)01401-0] [PMID: 10441299]
Audebert HJ, Rott MM, Eck T, Haberl RL. Systemic inflammatory response depends on initial stroke severity but is attenuated by successful thrombolysis. Stroke 2004; 35(9): 2128-33.
[http://dx.doi.org/10.1161/01.STR.0000137607.61697.77] [PMID: 15272127]
Gill R, Kemp JA, Sabin C, Pepys MB. Human C-reactive protein increases cerebral infarct size after middle cerebral artery occlusion in adult rats. J Cereb Blood Flow Metab 2004; 24(11): 1214-8.
[http://dx.doi.org/10.1097/01.WCB.0000136517.61642.99] [PMID: 15545914]
Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: An independent prognostic factor. Stroke 2001; 32(4): 917-24.
[http://dx.doi.org/10.1161/01.STR.32.4.917] [PMID: 11283392]
Di Napoli M, Papa F. Inflammation, statins, and outcome after ischemic stroke. Stroke 2001; 32(10): 2446-7.
[http://dx.doi.org/10.1161/str.32.10.2446-a] [PMID: 11588346]
Di Napoli M, Papa F. Angiotensin-converting enzyme inhibitor use is associated with reduced plasma concentration of C-reactive protein in patients with first-ever ischemic stroke. Stroke 2003; 34(12): 2922-9.
[http://dx.doi.org/10.1161/01.STR.0000099124.84425.BB] [PMID: 14605324]
Di Napoli M, Papa F. Villa Pini Stroke Data Bank Investigators. Inflammation, hemostatic markers, and antithrombotic agents in relation to long-term risk of new cardiovascular events in first-ever ischemic stroke patients. Stroke 2002; 33(7): 1763-71.
[http://dx.doi.org/10.1161/01.STR.0000019124.54361.08] [PMID: 12105349]
Winbeck K, Poppert H, Etgen T, Conrad B, Sander D. Prognostic relevance of early serial C-reactive protein measurements after first ischemic stroke. Stroke 2002; 33(10): 2459-64.
[http://dx.doi.org/10.1161/01.STR.0000029828.51413.82] [PMID: 12364738]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 26 October, 2019
Page: [405 - 415]
Pages: 11
DOI: 10.2174/1567202616666191026122011
Price: $65

Article Metrics

PDF: 44