High C5a levels are associated with increased mortality in sepsis patients — No enhancing effect by actin-free Gc-globulin Olav A. Gressner a, ⁎ ,1 , Alexander Koch b,1 , Edouard Sanson b , Christian Trautwein b , Frank Tacke b a Institute of Clinical Chemistry and Pathobiochemistry, University Hospital Aachen, Aachen University (RWTH), Aachen, Germany b Medical Clinic III, University Hospital Aachen, Aachen University (RWTH), Aachen, Germany Received 11 March 2008; accepted 12 May 2008 Available online 27 May 2008 Abstract Background: Immune paralysis of phagocytic cells due to excess of the complement activation product C5a has been proposed as a critical pathomechanism in sepsis. In vitro studies suggest an interaction of C5a with Group-specific globulin (Gc-globulin). Study objectives: To examine the predictive value of serum concentrations of both, C5a and actin-free Gc-globulin, and their ratio for prognosis (mortality) of critically ill patients. Patients: 154 critically ill (septic and non-septic) adult patients admitted to a Medical ICU and 38 healthy controls. Measurements: Actin-free Gc-globulin and C5a were measured on ICU admission, alongside extensive laboratory, clinical and prospective outcome measures. Results: Actin-free Gc-globulin and C5a serum concentrations were significantly reduced in critically ill patients compared with healthy controls. C5a levels, but not actin-free Gc-globulin, were significantly lower in patients with sepsis (n = 112) than in critically ill patients without sepsis (n = 42). C5a serum level was a prognostic parameter in patients with sepsis: High C5a levels were associated with increased mortality (at ICU and during follow-up). Although C5a and actin-free Gc-globulin were positively correlated, increasing serum concentrations of actin-free Gc- globulin did not enhance the C5a dependent effects in terms of prognosis or mortality in septic patients. Conclusions: Investigation for C5a and/or actin-free Gc-globulin serum levels upon admission to the ICU may be helpful diagnostic tools. In patients with sepsis, C5a levels are an independent predictor of prognosis. However, different to pre-existing in vitro data, a clinically relevant interaction between actin-free Gc-globulin and C5a in terms of prognosis in severe inflammatory conditions is not given. © 2008 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. Keywords: Actin-free Gc-globulin; C5a; Sepsis; Prognosis Introduction The complement system is part of the innate immune system. It promotes the inflammatory response, eliminates pathogens, and enhances the immune response. The complement cascade consists of 3 separate pathways that converge resulting in the cleavage of complement factor 5 (C5) to its activated form, C5a, and in the formation of the membrane attack complex (MAC). The MAC exerts powerful killing ac- tivity by creating perforations in cellular membranes [1]. Under physiological conditions, relatively low C5a levels are present that promote positive effects on the priming of neutrophils and monocytes as well as on the activation of endothelial cells, supporting efficient innate immune responses in the case of infections [2]. In sepsis, excessive systemic C5a levels have been reported that are associated with the exhaustion of the monocytic and granulocytic response or direct detrimental ef- fects on endothelial cells [2]. The possible dysregulation of serum C5a binding to its proposed binding partners during sepsis or critical illness have not been defined at present. Group-specific component globulin (Gc-globulin) [3], also known as vitamin D-binding protein (DBP), is a multifunctional plasma protein with a relative molecular mass of 51–58 kDa and belongs to the albumin superfamily of binding proteins, Available online at www.sciencedirect.com Clinical Biochemistry 41 (2008) 974 – 980 ⁎ Corresponding author. University Hospital of the RWTH, Institute of Clinical Chemistry and Pathobiochemistry, Pauwelsstraße 30, 52074 Aachen, Germany. Fax: +49 241 8082512. E-mail address: ogressner@ukaachen.de (O.A. Gressner). 1 The authors contributed equally to this manuscript. 0009-9120/$ - see front matter © 2008 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2008.05.005