Biomarkers of immune capacity, infection and inflammation are associated with poor outcome and mortality after stroke - the PREDICT study

A Mengel, L Ulm, B Hotter, H Harms, S K Piper, U Grittner, J Montaner, C Meisel, A Meisel, S Hoffmann, A Mengel, L Ulm, B Hotter, H Harms, S K Piper, U Grittner, J Montaner, C Meisel, A Meisel, S Hoffmann

Abstract

Background: Almost 40% of stroke patients have a poor outcome at 3 months after the index event. Predictors for stroke outcome in the early acute phase may help to tailor stroke treatment. Infection and inflammation are considered to influence stroke outcome.

Methods: In a prospective multicenter study in Germany and Spain, including 486 patients with acute ischemic stroke, we used multivariable regression analysis to investigate the association of poor outcome with monocytic HLA-DR (mHLA-DR) expression, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha) and lipopolysaccharide-binding protein (LBP) as markers for immunodepression, inflammation and infection. Outcome was assessed at 3 months after stroke via a structured telephone interview using the modified Rankin Scale (mRS). Poor outcome was defined as a mRS score of 3 or higher which included death. Furthermore, a time-to-event analysis for death within 3 months was performed.

Results: Three-month outcome data was available for 391 patients. Female sex, older age, diabetes mellitus, atrial fibrillation, stroke-associated pneumonia (SAP) and higher National Institute of Health Stroke Scale (NIHSS) score as well as lower mHLA-DR levels, higher IL-6 and LBP-levels at day 1 were associated with poor outcome at 3 months in bivariate analysis. Furthermore, multivariable analysis revealed that lower mHLA-DR expression was associated with poor outcome. Female sex, older age, atrial fibrillation, SAP, higher NIHSS score, lower mHLA-DR expression and higher IL-6 levels were associated with shorter survival time in bivariate analysis. In multivariable analysis, SAP and higher IL-6 levels on day 1 were associated with shorter survival time.

Conclusions: SAP, lower mHLA-DR-expression and higher IL-6 levels on day one are associated with poor outcome and shorter survival time at 3 months after stroke onset.

Trial registration: www.clinicaltrials.gov, NCT01079728 , March 3, 2010.

Keywords: Biomarkers; Ischemic stroke; Mortality; Outcome.

Conflict of interest statement

Christian and Andreas Meisel have issue of a patent on anti-infective and immunomodulatory agents used for preventive antibacterial therapy after stroke (EP1480646). As one of the co-authors, Andreas Meisel, is a section editor of this journal. The other authors report no conflict of interest.

This study was supported by Siemens Healthcare Diagnostics (collection of data).

References

    1. Heuschmann PU, Wiedmann S, Wellwood I, Rudd A, Di Carlo A, Bejot Y, et al. Three-month stroke outcome: the european registers of stroke (Eros) investigators. Neurology. 2011;76:159–165. doi: 10.1212/WNL.0b013e318206ca1e.
    1. Garcia-Berrocoso T, Giralt D, Bustamante A, Etgen T, Jensen JK, Sharma JC, et al. B-type natriuretic peptides and mortality after stroke: a systematic review and meta-analysis. Neurology. 2013;81:1976–1985. doi: 10.1212/01.wnl.0000436937.32410.32.
    1. Appelros P, Nydevik I, Viitanen M. Poor outcome after first-ever stroke: predictors for death, dependency, and recurrent stroke within the first year. Stroke. 2003;34:122–126. doi: 10.1161/01.STR.0000047852.05842.3C.
    1. Saposnik G, Hill MD, O’Donnell M, Fang J, Hachinski V, Kapral MK, et al. Variables associated with 7-day, 30-day, and 1-year fatality after ischemic stroke. Stroke. 2008;39:2318–2324. doi: 10.1161/STROKEAHA.107.510362.
    1. Wahlgren N, Ahmed N, Eriksson N, Aichner F, Bluhmki E, Davalos A, et al. Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: safe implementation of thrombolysis in stroke-monitoring study (sits-most) Stroke. 2008;39:3316–3322. doi: 10.1161/STROKEAHA.107.510768.
    1. Popovic N, Stefanovic-Budimkic M, Mitrovic N, Urosevic A, Milosevic B, Pelemis M, et al. The frequency of poststroke infections and their impact on early stroke outcome. J Stroke Cerebrovasc Dis. 2013;22:424–429. doi: 10.1016/j.jstrokecerebrovasdis.2013.03.003.
    1. Whiteley W, Chong WL, Sengupta A, Sandercock P. Blood markers for the prognosis of ischemic stroke: a systematic review. Stroke. 2009;40:e380–e389. doi: 10.1161/STROKEAHA.108.528752.
    1. Bustamante A, Sobrino T, Giralt D, Garcia-Berrocoso T, Llombart V, Ugarriza I, et al. Prognostic value of blood interleukin-6 in the prediction of functional outcome after stroke: a systematic review and meta-analysis. J Neuroimmunol. 2014;274:215–224. doi: 10.1016/j.jneuroim.2014.07.015.
    1. Tu WJ, Dong X, Zhao SJ, Yang DG, Chen H. Prognostic value of plasma neuroendocrine biomarkers in patients with acute ischaemic stroke. J Neuroendocrinol. 2013;25:771–778. doi: 10.1111/jne.12052.
    1. Hoffmann S, Harms H, Ulm L, Nabavi DG, Mackert BM, Schmehl I, et al. Stroke-induced immunodepression and dysphagia independently predict stroke-associated pneumonia - the predict study. J Cereb Blood Flow Metab. 2016;37(12):3671–3682. doi: 10.1177/0271678X16671964.
    1. Baird AE, Dambrosia J, Janket S, Eichbaum Q, Chaves C, Silver B, et al. A three-item scale for the early prediction of stroke recovery. Lancet. 2001;357:2095–2099. doi: 10.1016/S0140-6736(00)05183-7.
    1. Harms H, Prass K, Meisel C, Klehmet J, Rogge W, Drenckhahn C, et al. Preventive antibacterial therapy in acute ischemic stroke: a randomized controlled trial. PLoS One. 2008;3:e2158. doi: 10.1371/journal.pone.0002158.
    1. Weimar C, Kurth T, Kraywinkel K, Wagner M, Busse O, Haberl RL, et al. Assessment of functioning and disability after ischemic stroke. Stroke. 2002;33:2053–2059. doi: 10.1161/.
    1. 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. doi: 10.1161/STROKEAHA.108.532085.
    1. Ulm L, Harms H, Ohlraun S, Reimnitz P, Meisel A. Impact of infections on long-term outcome after severe middle cerebral artery infarction. J Neurol Sci. 2012;319:15–17. doi: 10.1016/j.jns.2012.05.042.
    1. Wolk K, Docke WD, von Baehr V, Volk HD, Sabat R. Impaired antigen presentation by human monocytes during endotoxin tolerance. Blood. 2000;96:218–223.
    1. Bustamante Alejandro, López-Cancio Elena, Pich Sara, Penalba Anna, Giralt Dolors, García-Berrocoso Teresa, Ferrer-Costa Carles, Gasull Teresa, Hernández-Pérez María, Millan Mónica, Rubiera Marta, Cardona Pedro, Cano Luis, Quesada Helena, Terceño Mikel, Silva Yolanda, Castellanos Mar, Garces Moisés, Reverté Silvia, Ustrell Xavier, Marés Rafael, Baiges Joan Josep, Serena Joaquín, Rubio Francisco, Salas Eduardo, Dávalos Antoni, Montaner Joan. Blood Biomarkers for the Early Diagnosis of Stroke. Stroke. 2017;48(9):2419–2425. doi: 10.1161/STROKEAHA.117.017076.
    1. Boehme AK, McClure LA, Zhang Y, Luna JM, Del Brutto OH, Benavente OR, et al. Inflammatory markers and outcomes after lacunar stroke: levels of inflammatory markers in treatment of stroke study. Stroke. 2016;47:659–667. doi: 10.1161/STROKEAHA.115.012166.
    1. Aulin J, Siegbahn A, Hijazi Z, Ezekowitz MD, Andersson U, Connolly SJ, et al. Interleukin-6 and c-reactive protein and risk for death and cardiovascular events in patients with atrial fibrillation. Am Heart J. 2015;170:1151–1160. doi: 10.1016/j.ahj.2015.09.018.
    1. Garcia JM, Stillings SA, Leclerc JL, Phillips H, Edwards NJ, Robicsek SA, et al. Role of interleukin-10 in acute brain injuries. Front Neurol. 2017;8:244. doi: 10.3389/fneur.2017.00244.
    1. Klehmet J, Harms H, Richter M, Prass K, Volk HD, Dirnagl U, et al. Stroke-induced immunodepression and post-stroke infections: lessons from the preventive antibacterial therapy in stroke trial. Neuroscience. 2009;158:1184–1193. doi: 10.1016/j.neuroscience.2008.07.044.
    1. Villar J, Maca-Meyer N, Perez-Mendez L, Flores C. Bench-to-bedside review: understanding genetic predisposition to sepsis. Crit Care. 2004;8:180–189. doi: 10.1186/cc2863.
    1. Stanley D, Mason LJ, Mackin KE, Srikhanta YN, Lyras D, Prakash MD, et al. Translocation and dissemination of commensal bacteria in post-stroke infection. Nat Med. 2016;22:1277–1284. doi: 10.1038/nm.4194.
    1. Worthmann H, Tryc AB, Dirks M, Schuppner R, Brand K, Klawonn F, 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 Neuroinflammation. 2015;12:13. doi: 10.1186/s12974-014-0231-2.
    1. Wartenberg KE, Stoll A, Funk A, Meyer A, Schmidt JM, Berrouschot J. Infection after acute ischemic stroke: risk factors, biomarkers, and outcome. Stroke Res Treat. 2011;2011:830614.
    1. Hong KS, Kang DW, Koo JS, Yu KH, Han MK, Cho YJ, et al. Impact of neurological and medical complications on 3-month outcomes in acute ischaemic stroke. Eur J Neurol. 2008;15:1324–1331. doi: 10.1111/j.1468-1331.2008.02310.x.
    1. Katzan IL, Cebul RD, Husak SH, Dawson NV, Baker DW. The effect of pneumonia on mortality among patients hospitalized for acute stroke. Neurology. 2003;60:620–625. doi: 10.1212/01.WNL.0000046586.38284.60.
    1. Koennecke HC, Belz W, Berfelde D, Endres M, Fitzek S, Hamilton F, et al. Factors influencing in-hospital mortality and morbidity in patients treated on a stroke unit. Neurology. 2011;77:965–972. doi: 10.1212/WNL.0b013e31822dc795.
    1. Kumar S, Selim MH, Caplan LR. Medical complications after stroke. Lancet Neurol. 2010;9:105–118. doi: 10.1016/S1474-4422(09)70266-2.
    1. Eriksson M, Glader EL, Norrving B, Terent A, Stegmayr B. Sex differences in stroke care and outcome in the swedish national quality register for stroke care. Stroke. 2009;40:909–914. doi: 10.1161/STROKEAHA.108.517581.
    1. Gargano JW, Reeves MJ, Paul Coverdell National Acute Stroke Registry Michigan Prototype I Sex differences in stroke recovery and stroke-specific quality of life: results from a statewide stroke registry. Stroke. 2007;38:2541–2548. doi: 10.1161/STROKEAHA.107.485482.
    1. Paolucci S, Bragoni M, Coiro P, De Angelis D, Fusco FR, Morelli D, et al. Is sex a prognostic factor in stroke rehabilitation? A matched comparison. Stroke. 2006;37:2989–2994. doi: 10.1161/01.STR.0000248456.41647.3d.
    1. Glader EL, Stegmayr B, Norrving B, Terent A, Hulter-Asberg K, Wester PO, et al. Sex differences in management and outcome after stroke: a swedish national perspective. Stroke. 2003;34:1970–1975. doi: 10.1161/01.STR.0000083534.81284.C5.
    1. Reeves M, Bhatt A, Jajou P, Brown M, Lisabeth L. Sex differences in the use of intravenous rt-pa thrombolysis treatment for acute ischemic stroke: a meta-analysis. Stroke. 2009;40:1743–1749. doi: 10.1161/STROKEAHA.108.543181.
    1. Persky RW, Turtzo LC, McCullough LD. Stroke in women: disparities and outcomes. Curr Cardiol Rep. 2010;12:6–13. doi: 10.1007/s11886-009-0080-2.
    1. Jorgensen H, Nakayama H, Raaschou HO, Olsen TS. Stroke in patients with diabetes. The Copenhagen stroke study. Stroke. 1994;25:1977–1984. doi: 10.1161/01.STR.25.10.1977.
    1. Tuomilehto J, Rastenyte D, Jousilahti P, Sarti C, Vartiainen E. Diabetes mellitus as a risk factor for death from stroke. Prospective study of the middle-aged finnish population. Stroke. 1996;27:210–215. doi: 10.1161/01.STR.27.2.210.
    1. Arnold M, Mattle S, Galimanis A, Kappeler L, Fischer U, Jung S, et al. Impact of admission glucose and diabetes on recanalization and outcome after intra-arterial thrombolysis for ischaemic stroke. Int J Stroke. 2014;9:985–991. doi: 10.1111/j.1747-4949.2012.00879.x.
    1. Meisel A, Meisel C, Harms H, Hartmann O, Ulm L. Predicting post-stroke infections and outcome with blood-based immune and stress markers. Cerebrovasc Dis. 2012;33:580–588. doi: 10.1159/000338080.
    1. Kuhle J, Petzold A. What makes a prognostic biomarker in cns diseases: strategies for targeted biomarker discovery? Part 1: acute and monophasic diseases. Expert Opin Med Diagn. 2011;5:333–346. doi: 10.1517/17530059.2011.578624.
    1. Feuerstein GZ, Chavez J. Translational medicine for stroke drug discovery: the pharmaceutical industry perspective. Stroke. 2009;40:S121–S125. doi: 10.1161/STROKEAHA.108.535104.
    1. Frank R, Hargreaves R. Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov. 2003;2:566–580. doi: 10.1038/nrd1130.
    1. Kissela B, Lindsell CJ, Kleindorfer D, Alwell K, Moomaw CJ, Woo D, et al. Clinical prediction of functional outcome after ischemic stroke: the surprising importance of periventricular white matter disease and race. Stroke. 2009;40:530–536. doi: 10.1161/STROKEAHA.108.521906.
    1. Meyer S, Verheyden G, Brinkmann N, Dejaeger E, De Weerdt W, Feys H, et al. Functional and motor outcome 5 years after stroke is equivalent to outcome at 2 months: follow-up of the collaborative evaluation of rehabilitation in stroke across europe. Stroke. 2015;46:1613–1619. doi: 10.1161/STROKEAHA.115.009421.
    1. Ayis S, Wellwood I, Rudd AG, McKevitt C, Parkin D, Wolfe CD. Variations in health-related quality of life (hrqol) and survival 1 year after stroke: five european population-based registers. BMJ Open. 2015;5:e007101. doi: 10.1136/bmjopen-2014-007101.
    1. Kim GM, Park KY, Avery R, Helenius J, Rost N, Rosand J, et al. Extensive leukoaraiosis is associated with high early risk of recurrence after ischemic stroke. Stroke. 2014;45:479–485. doi: 10.1161/STROKEAHA.113.003004.
    1. Mendyk AM, Labreuche J, Henon H, Girot M, Cordonnier C, Duhamel A, et al. Which factors influence the resort to surrogate consent in stroke trials, and what are the patient outcomes in this context? BMC Med Ethics. 2015;16:26. doi: 10.1186/s12910-015-0018-8.
    1. Flaherty ML, Karlawish J, Khoury JC, Kleindorfer D, Woo D, Broderick JP. How important is surrogate consent for stroke research? Neurology. 2008;71:1566–1571. doi: 10.1212/01.wnl.0000316196.63704.f5.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅