Pathophysiologie der Sepsis

Jonas Gregorius; Thorsten Brenner

doi:10.1055/a-1813-2057

AINS - Anästhesiologie · Intensivmedizin · Notfallmedizin · Schmerztherapie, Table of Contents

Anästhesiol Intensivmed Notfallmed Schmerzther 2023; 58(01): 13-27
DOI: 10.1055/a-1813-2057

CME-Fortbildung

Topthema

Pathophysiologie der Sepsis

Pathophysiology of sepsis

Jonas Gregorius

,

Thorsten Brenner

Abstract

Die Sepsis ist noch immer eines der bedrohlichsten Krankheitsbilder der modernen Medizin mit einer hohen Mortalitätsrate. Das zunehmende Wissen um die Komplexität und Heterogenität der septischen Immunpathologie kann Wege eröffnen, zukünftig Sepsispatienten individueller – und somit erfolgreicher – behandeln zu können. Dieser Beitrag stellt den aktuellen Kenntnisstand der Pathophysiologie der Sepsis und des septischen Schocks dar.

Abstract

Up to now, sepsis is one of the most threatening diseases and its therapy remains challenging. Sepsis is currently defined as a severely dysregulated immune response to an infection resulting in organ dysfunction. The pathophysiology is mainly driven by exogenous PAMPs (“pathogen-associated molecular patterns”) and endogenous DAMPs (“damage-associated molecular patterns“), which can activate PRRs (“pattern recognition receptors”) on different cell types (mainly immune cells), leading to the initiation of manifold downstream pathways and a perpetuation of patients’ immune response. Sepsis is neither an exclusive pro- nor an anti-inflammatory disease: both processes take place in parallel, resulting in an individual immunologic disease state depending on the severity of each component at different time points. Septic shock is a complex disorder of the macro- and microcirculation, provoking a severe lack of oxygenation further aggravating sepsis defining organ dysfunctions. An in-depth knowledge of the heterogeneity and the time-dependency of the septic immunopathology will be essential for the design of future sepsis trials and therapy planning in patients with sepsis. The big aim is to achieve a more individualized treatment strategy in patients suffering from sepsis or septic shock.

Schlüsselwörter

Sepsis - septischer Schock - Inflammation - COVID-19

Keywords

sepsis - septic shock - inflammation - COVID-19

Full Text

References

Literatur
1 Schuster HG, Müller-Werdan U. Definition und Diagnose von Sepsis und Multiorganversagen. In: Schuster HG, Werdan K. Intensivtherapie bei Sepsis und Multiorganversagen. 3. Heidelberg: Springer; 2000: 3-26
2 Funk DJ, Parrillo JE, Kumar A. Sepsis and septic shock: a history. Crit Care Clin 2009; 25: 83-101
3 Thomas L. Germs. N Engl J Med 1972; 287: 553-555
4 American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med [Anonym]. 1992; 20: 864-874
5 Levy MM, Fink MP, Marshall JC. et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31: 1250-1256
6 Kaukonen KM, Bailey M, Pilcher D. et al. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med 2015; 372: 1629-1638
7 Singer M, Deutschman CS, Seymour CW. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315: 801-810
8 Ferreira FL, Bota DP, Bross A. et al. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 2001; 286: 1754-1758
9 Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 2013; 13: 260-268
10 Beutler B, Rietschel ET. Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol 2003; 3: 169-176
11 Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140: 805-820
12 Desaki Y, Miya A, Venkatesh B. et al. Bacterial lipopolysaccharides induce defense responses associated with programmed cell death in rice cells. Plant Cell Physiol 2006; 47: 1530-1540
13 Dammermann W, Wollenberg L, Bentzien F. et al. Toll like receptor 2 agonists lipoteichoic acid and peptidoglycan are able to enhance antigen specific IFNγ release in whole blood during recall antigen responses. J Immunol Methods 2013; 396: 107-115
14 Zhang Q, Raoof M, Chen Y. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010; 464: 104-107
15 Sagan L. On the origin of mitosing cells. J Theor Biol 1967; 14: 255-274
16 Mnich ME, van Dalen R, van Sorge NM. C-type lectin receptors in host defense against bacterial pathogens. Front Cell Infect Microbiol 2020; 10: 309
17 Drouin M, Saenz J, Chiffoleau E. C-type lectin-like receptors: head or tail in cell death immunity. Front Immunol 2020; 11: 251
18 Bermejo-Jambrina M, Eder J, Helgers LC. et al. C-Type Lectin Receptors in Antiviral Immunity and Viral Escape. Front Immunol 2018; 9: 590
19 Park BS, Song DH, Kim HM. et al. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 2009; 458: 1191-1195
20 Hayashi F, Smith KD, Ozinsky A. et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 2001; 410: 1099-1103
21 Broere F, van der Zee R, van Eden W. Heat shock proteins are no DAMPs, rather “DAMPERs”. Nat Rev Immunol 2011; 11: 565
22 Yu M, Wang H, Ding A. et al. HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock 2006; 26: 174-179
23 Kato H, Takeuchi O, Mikamo-Satoh E. et al. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med 2008; 205: 1601-1610
24 Saito T, Owen DM, Jiang F. et al. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 2008; 454: 523-527
25 Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol 2009; 21: 317-337
26 Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol 2011; 29: 707-735
27 Vourc’h M, Roquilly A, Asehnoune K. Trauma-induced damage-associated molecular patterns-mediated remote organ injury and immunosuppression in the acutely ill patient. Front Immunol 2018; 9: 1330
28 Liu J, Tan Y, Zhang J. et al. C5aR, TNF-α, and FGL2 contribute to coagulation and complement activation in virus-induced fulminant hepatitis. J Hepatol 2015; 62: 354-362
29 Stouthard JM, Levi M, Hack CE. et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost 1996; 76: 738-742
30 Markiewski MM, Nilsson B, Ekdahl KN. et al. Complement and coagulation: strangers or partners in crime?. Trends Immunol 2007; 28: 184-192
31 van der Poll T, Opal SM. Host-pathogen interactions in sepsis. Lancet Infect Dis 2008; 8: 32-43
32 Prince LR, Allen L, Jones EC. et al. The role of interleukin-1beta in direct and toll-like receptor 4-mediated neutrophil activation and survival. Am J Pathol 2004; 165: 1819-1826
33 Kramer F, Torzewski J, Kamenz J. et al. Interleukin-1beta stimulates acute phase response and C-reactive protein synthesis by inducing an NFkappaB- and C/EBPbeta-dependent autocrine interleukin-6 loop. Mol Immunol 2008; 45: 2678-2689
34 Cahill CM, Rogers JT. Interleukin (IL) 1beta induction of IL-6 is mediated by a novel phosphatidylinositol 3-kinase-dependent AKT/IkappaB kinase alpha pathway targeting activator protein-1. J Biol Chem 2008; 283: 25900-25912
35 Brown GT, Narayanan P, Li W. et al. Lipopolysaccharide stimulates platelets through an IL-1β autocrine loop. J Immunol 2013; 191: 5196-5203
36 Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998; 38: 97-120
37 Fielding CA, McLoughlin RM, McLeod L. et al. IL-6 regulates neutrophil trafficking during acute inflammation via STAT3. J Immunol 2008; 181: 2189-2195
38 Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 2014; 6: a016295
39 Desai A, Jung MY, Olivera A. et al. IL-6 promotes an increase in human mast cell numbers and reactivity through suppression of suppressor of cytokine signaling 3. J Allergy Clin Immunol 2016; 137: 1863-1871.e6
40 Bickel M. The role of interleukin-8 in inflammation and mechanisms of regulation. J Periodontol 1993; 64 (Suppl. 05) 456-460
41 Takami M, Terry V, Petruzzelli L. Signaling pathways involved in IL-8-dependent activation of adhesion through Mac-1. J Immunol 2002; 168: 4559-4566
42 Heidemann J, Ogawa H, Dwinell MB. et al. Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2. J Biol Chem 2003; 278: 8508-8515
43 Weber GF, Chousterman BG, He S. et al. Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis. Science 2015; 347: 1260-1265
44 Dinarello CA, Novick D, Puren AJ. et al. Overview of interleukin-18: more than an interferon-gamma inducing factor. J Leukoc Biol 1998; 63: 658-664
45 Michie HR, Spriggs DR, Manogue KR. et al. Tumor necrosis factor and endotoxin induce similar metabolic responses in human beings. Surgery 1988; 104: 280-286
46 Plata-Salamán CR. 1998 Curt P. Richter Award. Brain mechanisms in cytokine-induced anorexia. Psychoneuroendocrinology 1999; 24: 25-41
47 Nieto-Vazquez I, Fernández-Veledo S, Krämer DK. et al. Insulin resistance associated to obesity: the link TNF-alpha. Arch Physiol Biochem 2008; 114: 183-194
48 Ming WJ, Bersani L, Mantovani A. Tumor necrosis factor is chemotactic for monocytes and polymorphonuclear leukocytes. J Immunol 1987; 138: 1469-1474
49 Morgan BP. The membrane attack complex as an inflammatory trigger. Immunobiology 2016; 221: 747-751
50 Gennaro R, Simonic T, Negri A. et al. C5a fragment of bovine complement. Purification, bioassays, amino-acid sequence and other structural studies. Eur J Biochem 1986; 155: 77-86
51 Ward PA. The harmful role of c5a on innate immunity in sepsis. J Innate Immun 2010; 2: 439-445
52 Simmons J, Pittet JF. The coagulopathy of acute sepsis. Curr Opin Anaesthesiol 2015; 28: 227-236
53 Oikonomopoulou K, Ricklin D, Ward PA. et al. Interactions between coagulation and complement – their role in inflammation. Semin Immunopathol 2012; 34: 151-165
54 Miyake K. Roles for accessory molecules in microbial recognition by Toll-like receptors. J Endotoxin Res 2006; 12: 195-204
55 Aksoy E, Taboubi S, Torres D. et al. The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock. Nat Immunol 2012; 13: 1045-1054
56 Hagar JA, Powell DA, Aachoui Y. et al. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 2013; 341: 1250-1253
57 von Moltke J, Ayres JS, Kofoed EM. et al. Recognition of bacteria by inflammasomes. Annu Rev Immunol 2013; 31: 73-106
58 Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 2015; 21: 677-687
59 Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140: 821-832
60 Liu X, Zhang Z, Ruan J. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 2016; 535: 153-158
61 Wei Y, Kim J, Ernits H. et al. The septic neutrophil – friend or foe. Shock 2021; 55: 147-155
62 Kaplan MJ, Radic M. Neutrophil extracellular traps: double-edged swords of innate immunity. J Immunol 2012; 189: 2689-2695
63 Berg RE, Forman J. The role of CD8 T cells in innate immunity and in antigen non-specific protection. Curr Opin Immunol 2006; 18: 338-343
64 den Haan JM, Bevan MJ. A novel helper role for CD4 T cells. Proc Natl Acad Sci U S A 2000; 97: 12950-12952
65 Li Q, Zhang Q, Wang C. et al. Disruption of tight junctions during polymicrobial sepsis in vivo. J Pathol 2009; 218: 210-221
66 Duncan DJ, Hopkins PM, Harrison SM. Negative inotropic effects of tumour necrosis factor-alpha and interleukin-1beta are ameliorated by alfentanil in rat ventricular myocytes. Br J Pharmacol 2007; 150: 720-726
67 Niederbichler AD, Hoesel LM, Westfall MV. et al. An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction. J Exp Med 2006; 203: 53-61
68 Arnold RC, Dellinger RP, Parrillo JE. et al. Discordance between microcirculatory alterations and arterial pressure in patients with hemodynamic instability. J Crit Care 2012; 27: 531.e1-531.e7
69 Filho RR, de Freitas Chaves RC, Assunção MSC. et al. Assessment of the peripheral microcirculation in patients with and without shock: a pilot study on different methods. J Clin Monit Comput 2020; 34: 1167-1176
70 van der Poll T, de Boer JD, Levi M. The effect of inflammation on coagulation and vice versa. Curr Opin Infect Dis 2011; 24: 273-278
71 Schmitt FCF, Manolov V, Morgenstern J. et al. Acute fibrinolysis shutdown occurs early in septic shock and is associated with increased morbidity and mortality: results of an observational pilot study. Ann Intensive Care 2019; 9: 19
72 Steppan J, Hofer S, Funke B. et al. Sepsis and major abdominal surgery lead to flaking of the endothelial glycocalix. J Surg Res 2011; 165: 136-141
73 Uchimido R, Schmidt EP, Shapiro NI. The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit Care 2019; 23: 16
74 Casserly B, Phillips GS, Schorr C. et al. Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med 2015; 43: 567-573
75 Otto GP, Sossdorf M, Claus RA. et al. The late phase of sepsis is characterized by an increased microbiological burden and death rate. Crit Care 2011; 15: R183
76 Wu HP, Wu CL, Chen CK. et al. The interleukin-4 expression in patients with severe sepsis. J Crit Care 2008; 23: 519-524
77 Woodward EA, Prêle CM, Nicholson SE. et al. The anti-inflammatory effects of interleukin-4 are not mediated by suppressor of cytokine signalling-1 (SOCS1). Immunology 2010; 131: 118-127
78 Sun J, Madan R, Karp CL. et al. Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat Med 2009; 15: 277-284
79 O’Garra A, Barrat FJ, Castro AG. et al. Strategies for use of IL-10 or its antagonists in human disease. Immunol Rev 2008; 223: 114-131
80 Sanjabi S, Zenewicz LA, Kamanaka M. et al. Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity. Curr Opin Pharmacol 2009; 9: 447-453
81 Opal SM, Fisher jr. CJ, Dhainaut JF. et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med 1997; 25: 1115-1124
82 Ali A, Na M, Svensson MN. et al. IL-1 receptor antagonist treatment aggravates staphylococcal septic arthritis and sepsis in mice. PLoS One 2015; 10: e0131645
83 Zhan C, Patskovsky Y, Yan Q. et al. Decoy strategies: the structure of TL1A: DcR3 complex. Structure 2011; 19: 162-171
84 Monneret G, Debard AL, Venet F. et al. Marked elevation of human circulating CD4+CD25+ regulatory T cells in sepsis-induced immunoparalysis. Crit Care Med 2003; 31: 2068-2071
85 Cuenca AG, Delano MJ, Kelly-Scumpia KM. et al. A paradoxical role for myeloid-derived suppressor cells in sepsis and trauma. Mol Med 2011; 17: 281-292
86 Hotchkiss RS, Nicholson DW. Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol 2006; 6: 813-822
87 Cui L, Gao Y, Xie Y. et al. An ADAM10 promoter polymorphism is a functional variant in severe sepsis patients and confers susceptibility to the development of sepsis. Crit Care 2015; 19: 73
88 Bopp C, Hofer S, Weitz J. et al. sRAGE is elevated in septic patients and associated with patients outcome. J Surg Res 2008; 147: 79-83
89 Bopp C, Hofer S, Bouchon A. et al. Soluble TREM-1 is not suitable for distinguishing between systemic inflammatory response syndrome and sepsis survivors and nonsurvivors in the early stage of acute inflammation. Eur J Anaesthesiol 2009; 26: 504-507
90 Ertel W, Kremer JP, Kenney J. et al. Downregulation of proinflammatory cytokine release in whole blood from septic patients. Blood 1995; 85: 1341-1347
91 Saturnino SF, Prado RO, Cunha-Melo JR. et al. Endotoxin tolerance and cross-tolerance in mast cells involves TLR4, TLR2 and FcεR1 interactions and SOCS expression: perspectives on immunomodulation in infectious and allergic diseases. BMC Infect Dis 2010; 10: 240
92 Vergadi E, Vaporidi K, Tsatsanis C. Regulation of endotoxin tolerance and compensatory anti-inflammatory response syndrome by non-coding RNAs. Front Immunol 2018; 9: 2705
93 Lin GL, McGinley JP, Drysdale SB. et al. Epidemiology and immune pathogenesis of viral sepsis. Front Immunol 2018; 9: 2147
94 Gu X, Zhou F, Wang Y. et al. Respiratory viral sepsis: epidemiology, pathophysiology, diagnosis and treatment. Eur Respir Rev 2020; 29: 200038
95 Ravindranath TM. Viral sepsis: underrated and underdiagnosed entity in clinical arena. Future Virology 2022; 17: 197-199
96 Karakike E, Giamarellos-Bourboulis EJ, Kyprianou M. et al. Coronavirus disease 2019 as cause of viral sepsis: a systematic review and meta-analysis. Crit Care Med 2021; 49: 2042-2057
97 Parthasarathy U, Martinelli R, Vollmann EH. et al. The impact of DAMP-mediated inflammation in severe COVID-19 and related disorders. Biochem Pharmacol 2022; 195: 114847
98 Gupta A, Madhavan MV, Sehgal K. et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020; 26: 1017-1032
99 Carvelli J, Demaria O, Vély F. et al. Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis. Nature 2020; 588: 146-150
100 Li J, Liu B. The roles and potential therapeutic implications of C5a in the pathogenesis of COVID-19-associated coagulopathy. Cytokine Growth Factor Rev 2021; 58: 75-81
101 Montazersaheb S, Hosseiniyan Khatibi SM, Hejazi MS. et al. COVID-19 infection: an overview on cytokine storm and related interventions. Virol J 2022; 19: 92
102 Hu B, Huang S, Yin L. The cytokine storm and COVID-19. J Med Virol 2021; 93: 250-256
103 Bauer M, Gerlach H, Vogelmann T. et al. Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019 – results from a systematic review and meta-analysis. Crit Care 2020; 24: 239
104 Seymour CW, Kennedy JN, Wang S. et al. Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis. JAMA 2019; 321: 2003-2017
105 Sweeney TE, Azad TD, Donato M. et al. Unsupervised analysis of transcriptomics in bacterial sepsis across multiple datasets reveals three robust clusters. Crit Care Med 2018; 46: 915-925