Diagnostic and prognostic utility of soluble CD 14 subtype (presepsin) for severe sepsis and septic shock during the first week of intensive care treatment

Michael Behnes 0 1 Thomas Bertsch 1 Dominic Lepiorz 0 1 Siegfried Lang 0 1 Frederik Trinkmann 0 1 Martina Brueckmann 1 Martin Borggrefe 0 1 Ursula Hoffmann 0 1 0 First Department of Medicine, University Medical Centre Mannheim (UMM), Faculty of Medicine Mannheim, University of Heidelberg , Theodor-Kutzer-Ufer 1-3, 68167 Mannheim , Germany 1 Authors' information Martina Brueckmann: Lecturer associated to the Faculty of Medicine Mannheim, University of Heidelberg , Heidelberg , Germany Introduction: The aim of this study was to evaluate the diagnostic and prognostic value of presepsin in patients with severe sepsis and septic shock during the first week of ICU treatment. Methods: In total, 116 patients with suspected severe sepsis or septic shock were included during the first 24 hours of ICU treatment. Blood samples for biomarker measurements of presepsin, procalcitonin (PCT), interleukin 6 (IL-6), C reactive protein (CRP) and white blood cells (WBC) were drawn at days 1, 3 and 8. All patients were followed up for six months. Biomarkers were tested for diagnosis of sepsis, severe sepsis, septic shock and for prognosis of 30-days and 6-months all-cause mortality at days 1, 3 and 8. Diagnostic and prognostic utilities were tested by determining diagnostic cutoff levels, goodness criteria, C-statistics and multivariable Cox regression models. Results: Presepsin increased significantly from the lowest to most severe sepsis groups at days 1, 3 and 8 (test for linear trend P <0.03). Presepsin levels revealed valuable diagnostic capacity to diagnose severe sepsis and septic shock at days 1, 3 and 8 (range of diagnostic area under the curves (AUC) 0.72 to 0.84, P = 0.0001) compared to IL-6, PCT, CRP and WBC. Goodness criteria for diagnosis of sepsis severity were analyzed (sepsis, cutoff = 530 pg/ml; severe sepsis, cutoff = 600 pg/ml; septic shock, cutoff = 700 pg/ml; P <0.03). Presepsin levels revealed significant prognostic value for 30 days and 6 months all-cause mortality (presepsin: range of AUC 0.64 to 0.71, P <0.02). Patients with presepsin levels of the 4th quartile were 5 to 7 times more likely to die after six months than patients with lower levels. The prognostic value for all-cause mortality of presepsin was comparable to that of IL-6 and better than that of PCT, CRP or WBC. Conclusions: In patients with suspected severe sepsis and septic shock, presepsin reveals valuable diagnostic capacity to differentiate sepsis severity compared to PCT, IL-6, CRP, WBC. Additionally, presepsin and IL-6 reveal prognostic value with respect to 30 days and 6 months all-cause mortality throughout the first week of ICU treatment. - Introduction Severe sepsis and septic shock represent major challenges of modern intensive care medicine, and still recently published international guidelines demand ongoing research about the pathophysiology, diagnostics and treatment [1]. Worldwide at least 19 million people are estimated to suffer from severe sepsis [2] and - if ever - only half of these patients are treated according to best standard of care even in the Western world [3]. Today, alert and earliest timing of diagnosis and treatment is still recommended as the best method of choice to prevent severe sepsis and septic shock. No single new effective medical therapy or decisive diagnostic tool has been found over the last decades [3]. Additionally, the increasing number of patients surviving severe sepsis or septic shock is endangered by an adverse long-term prognosis and therefore these patients need to be increasingly focused upon [1,3]. A broad range of clinical and laboratory parameters are specifically combined and define the diagnostic standard of severe sepsis and septic shock [1]. However, there is a great lack of evidence for biomarkers to reliably diagnose and predict the future course of patients suffering from severe sepsis or septic shock [4-6]. Soluble cluster of differentiation 14 subtype (sCD14-ST) so-called presepsin - is cleaved from the monocyte/macrophage-specific CD14 receptor complex after binding with lipopolysaccharides (LPS) and LPS binding protein (LPB) during systemic infections [7-10]. Presepsin appears to reveal significant diagnostic capacity to diagnose sepsis, severe sepsis and septic shock compared to procalcitonin (PCT) in patients presenting to the emergency department [11-14]. However, a comparative evaluation of the diagnostic and prognostic implications between presepsin and PCT, interleukin 6 (IL-6), white blood cells (WBC) as well as C-reactive protein (CRP) in patients with severe sepsis and septic shock being treated on an internal ICU has rarely been investigated within one single study. Therefore, this study aims to comparatively evaluate the diagnostic, as well as shortand long-term prognostic utility of presepsin in patients with severe sepsis and septic shock during the first week of intensive care treatment. Materials and methods Study patients, design and data collection The Mannheim Sepsis Study (MaSep, clinicaltrials.gov identifier: NCT01535534) was conducted as a mono-centric prospective controlled study at the University Medical Centre Mannheim (UMM), Germany. Patient enrolment started in October 2011. The study was carried out according to the principles of the declaration of Helsinki and was approved by the medical ethics commission II of the Faculty of Medicine Mannheim, University of Heidelberg, Germany. Informed consent was obtained from all participating patients or their legal representatives. The study was designed to reflect a representative cohort of patients with a minimum age of 18 years, who had proven criteria of severe sepsis or septic shock, found at a typical internal ICU. Main exclusion criteria were any traumatic or postoperative cause of sepsis development (that is, poly-trauma, cerebral trauma, critical postoperative status, or burns). Diagnosis of systemic inflammatory response syndrome (SIRS) and of sepsis severity was based on established criteria [15,16]: when patients revealed a microbiologically or clinically proven infection, they were assigned to the sepsis group. Patients were categorized to the severe sepsis group if they developed at least one of the following newly developed, sepsis-induced organ failures: acute encephalopathy, pulmonary organ failure defined as the ratio of the partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2) PaO2/FiO2 < 250, renal organ failure with urine output <0.5 ml/kg/h, hematological organ failure with platelet count <100,000/mm3 or unexplained metabolic acidosis with pH <7.3 and lactate levels >1.5 times the upper limit of normal. Sepsis-induced organ failures in these patients were strongly connected to infection and were present for less than 24 h. Patients developing cardiovascular organ failure with need for vasopressors longer than 1 h were categorized as suffering from septic shock. Disease severity on the ICU was documented by the acute ph (...truncated)