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

Mengel et al. BMC Neurology (2019) 19:148 https://doi.org/10.1186/s12883-019-1375-6 RESEARCH ARTICLE Open Access Biomarkers of immune capacity, infection and inflammation are associated with poor outcome and mortality after stroke - the PREDICT study A. Mengel1,2*, L. Ulm1,3, B. Hotter1,4, H. Harms1, S. K. Piper5,6,7, U. Grittner5,6,7, J. Montaner8, C. Meisel9, A. Meisel1,4,9† and S. Hoffmann1,9† 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: Ischemic stroke, Biomarkers, Mortality, Outcome * Correspondence: † A. Meisel and S. Hoffmann contributed equally to this work. 1 Department of Neurology Berlin, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10115 Berlin, Germany 2 Department of Neurology and Stroke, Universitätsklinik Tuebingen, Hoppe-Seyler-Str.3, 72076 Tuebingen, Germany Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mengel et al. BMC Neurology (2019) 19:148 Background Many stroke patients experience severe consequences, with more than 40% of patients in the population suffering from disability, institutionalisation or even death at 3 months after the index event [1]. An early risk assessment of stroke outcome could help to optimize stroke care allocation in order to improve outcome [2], and to predict the patient’s individual prognosis. However, reliably predicting stroke outcome remains challenging. Several attempts to identify characteristics associated with poor outcomes have been made. A consistent association with poor outcome was found for the clinical factors age and stroke severity [3–5], as well as for poststroke complications such as stroke-associated pneumonia (SAP) [6]. Further interesting targets for investigation have been blood-based biomarkers. It has been shown that several biomarkers are associated with poor outcome [7]. However, the added value of biomarkers over clinical variables with regard to prognosis remains controversial [8, 9]. In relation to the patient’s living will, biomarkers could help us to predict individual poor outcomes as early as possible in order to prevent pain and inefficient treatment. The PREDICT study was initially designed to better understand the underlying pathophysiology leading to SAP. We were able to demonstrate that a key biomarker of stroke-induced immunodepression syndrome (SIDS), mHLA-DR, was associated with SAP independently of dysphagia as the main risk for aspiration pneumonia [10]. By analysing the secondary end points of the PREDICT study, we wanted to evaluate and quantify the association of biomarkers of SIDS with poor outcome at 3 months after stroke which might serve to build more reliable prediction models for stroke outcome in the future. Methods The methods used in this study (especially assessment of clinical and immunological data) have been described previously in the primary analysis of the PREDICT study (www.clinicaltrials.gov, NCT01079728, March 3, 2010) [10]. In short, the PREDICT study was a prospective, international, multicenter study with 11 participating study sites in Germany and Spain designed to better understand the underlying pathophysiology leading to SAP [10]. The study was approved by the ethics committees of the Charité- Universitätsmedizin Berlin (EA1/216/09), and of Hospital Vall d’Hebron Barcelona (No. 199 25/05/2012). All patients or their legal representatives gave written informed consent in accordance with the Declaration of Helsinki. The four inclusion criteria were: clinical diagnosis of acute ischemic stroke (NIHSS≥1) with any localization (anterior and posterior circulation) and with any recurrence rate (first-ever and recurrent stroke); symptom onset ≤36 h, and age ≥ 18 years [10]. During the Page 2 of 10 study, the diagnosis was radiologically confirmed. Exclusion criteria were preexisting dysphagia, mechanical ventilation, antibiotic treatment or immunosuppressive therapy within the last 4 weeks and clinical or para-clinical signs of infection at study inclusion. Overall, 486 patients were recruited between January 2010 and December 2012. Blood samples were obtained within 36 h after symptom onset (day 1) and repeated on day 2 to 4. With the focus on early outcome we restricted the analysis to blood samples taken on day 1 after stroke. Clinical data Clinically we documented socio-demographics, neurological deficits, comorbidities and stroke severity (NIHSS) on admission, as well as complications, and (...truncated)