UMEÅ UNIVERSITY MEDICAL DISSERTATIONS NEW SERIES NO. 1680 ISSN 0346-6612 ISBN: 978-91-7601-149-2 From the Department of Surgical and Perioperative Sciences Anesthesiology and Intensive Care Medicine Umeå University, Sweden Severe sepsis Epidemiology and sex-related differences in inflammatory markers. Sofie Jacobson Fakultetsopponent: Professor Else Tönnesen Dept. of Clinical Medicine - Anaesthesiology Århus, Danmark Umeå 2014 Cover illustration: "First line of defence" Anders Jacobsson Copyright © 2014 Sofie Jacobson ISBN: 978-91-7601-149-2 NEW SERIES NO. 1680 ISSN 0346-6612 Layout and printed by: Print & Media Umeå, Sweden 2014 To my family A goal is a dream with a deadline. ~ Napolean Hill Contents CONTENTS ABSTRACT......................................................................................................................... iv Svensk sammanfattning .........................................................................................................v Abbreviations..................................................................................................................... viii ORIGINAL PAPERS............................................................................................................x PROLOGUE ........................................................................................................................xi INTRODUCTION..................................................................................................................1 Epidemiology ....................................................................................................................2 The innate immune system, a very brief overview............................................................3 Inflammation .....................................................................................................................5 Cytokines...........................................................................................................................6 Interleukins (IL)............................................................................................................6 Tumor necrosis factor (TNF)........................................................................................7 Interferons (IFN)...........................................................................................................8 Chemokines ..................................................................................................................9 Complement ....................................................................................................................10 Coagulation .....................................................................................................................11 Recombinant Tissue Factor Pathway Inhibitor (rTFPI) ..................................................13 Antithrombin (AT) ..........................................................................................................13 Activated Protein C .........................................................................................................13 Endothelium ....................................................................................................................14 Leptin ..............................................................................................................................15 The protein..................................................................................................................16 Factors affecting leptin production or clearance.........................................................16 The Leptin receptor (LepR, previously denoted Ob-R)..............................................17 Action of leptin...........................................................................................................18 Effects of Adiposity....................................................................................................18 Leptin, inflammation and immunity ...........................................................................19 Leptin and sepsis studies in animals...........................................................................20 Leptin and sepsis in humans.......................................................................................22 Adiponectin .....................................................................................................................22 Adiponectin Receptors................................................................................................23 Actions of adiponectin................................................................................................24 Adiponectin and inflammation ...................................................................................25 Adiponectin and sepsis studies in animals..................................................................26 Adiponectin and sepsis in humans..............................................................................27 Mannose-binding lectin (MBL).......................................................................................27 Mode of action............................................................................................................28 Genetic determinants and inter individual variations in MBL levels..........................28 Factors effecting MBL-levels.....................................................................................30 MBL and disease ........................................................................................................31 MBL and sepsis in animal studies ..............................................................................32 MBL and sepsis in humans.........................................................................................32 ii Contents AIMS OF THE THESIS ......................................................................................................34 METHODS ..........................................................................................................................35 Study design ....................................................................................................................35 Material, study subjects...................................................................................................35 Sepsis definition, main inclusion criteria.........................................................................36 TISS scoring....................................................................................................................37 APACHE II scoring.........................................................................................................37 Sequential Organ Failure Assessment (SOFA) Score .....................................................39 Data collection.................................................................................................................40 Northern Sweden Medical Research Bio-bank,...............................................................40 Nested case-referent studies, Papers III and IV...............................................................41 Clinical examinations and biochemical analysis from the MONICA and VIP cohort. ....................................................................................................................................44 Blood sampling...........................................................................................................44 Enzyme-linked Immunoassay (ELIZA) and Radioimmunoassay (RIA) ....................44 Statistics ..........................................................................................................................45 Ethical aspects .................................................................................................................46 RESULTS ............................................................................................................................47 Main finding Paper I........................................................................................................48 Main findings Paper II:....................................................................................................52 Paper III and IV...............................................................................................................55 Main findings Paper III ...................................................................................................59 Main findings Paper IV ...................................................................................................62 DISCUSSION ......................................................................................................................65 Aspects of epidemiology and study design .....................................................................65 Findings from a small single center study.......................................................................66 Comorbidities and outcome.............................................................................................67 Predictors of in-hospital death.........................................................................................67 Gender differences ..........................................................................................................68 SOFA score and thrombocytes........................................................................................69 Gender versus sex, and adiposity ....................................................................................70