Pathophysiologie der Sepsis

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.

Kernaussagen

• Sepsis ist definiert als eine schwerwiegende dysregulierte Immunantwort auf dem Boden einer Infektion, aus der eine Endorganstörung resultiert.

• Im Zentrum der septischen Pathophysiologie steht zu Beginn ein sog. Zytokinsturm, der maßgeblich durch die Antwort des angeborenen Immunsystems getragen wird. Im Verlauf kann sich eine eher immunparalytische Situation einstellen.

• Exogene PAMPs und endogene DAMPs aktivieren sog. PRRs, welche mannigfaltige Downstream-Pathways aktivieren und die weitere Immunantwort bahnen.

• Die Sepsis ist weder ein reines pro- noch antiinflammatorisches Krankheitsbild. Vielmehr laufen pro- und antiinflammatorische Prozesse stets parallel zueinander ab, sodass die immunologische Gesamtsituation je nach Ausprägungsgrad der einzelnen Komponenten patientenindividuell und zeitabhängig deutlich differiert.

• Der septische Schock zeichnet sich durch eine kombinierte Störung sowohl der Makro- als auch der Mikrozirkulation aus. Die hieraus resultierenden Oxygenierungsstörungen bedingen die sepsisdefinierenden Endorganstörungen.

• Das Wissen um die Heterogenität der septischen Immunpathologie muss bei der Konzeption zukünftiger Sepsisstudien sowie der Therapieplanung des individuellen Sepsispatienten Berücksichtigung finden. Das Ziel ist es, eine zunehmende Individualisierung der Sepsistherapie zu erreichen!

Schlüsselwörter

Sepsis - septischer Schock - Inflammation - COVID-19

Keywords

sepsis - septic shock - inflammation - COVID-19

Publikationsverlauf

Artikel online veröffentlicht:
05. Dezember 2023

• 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 DOI: 10.1016/j.ccc.2008.12.003. (PMID: 19268796)
• 3 Thomas L. Germs. N Engl J Med 1972; 287: 553-555 DOI: 10.1056/NEJM197209142871109. (PMID: 5050429)
• 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 (PMID: 1597042)
• 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 DOI: 10.1097/01.Ccm.0000050454.01978.3b. (PMID: 12664219)
• 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 DOI: 10.1056/NEJMoa1415236. (PMID: 25776936)
• 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 DOI: 10.1001/jama.2016.0287. (PMID: 26903338)
• 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 DOI: 10.1001/jama.286.14.1754. (PMID: 11594901)
• 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 DOI: 10.1016/s1473-3099(13)70001-x. (PMID: 23427891)
• 10 Beutler B, Rietschel ET. Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol 2003; 3: 169-176 DOI: 10.1038/nri1004. (PMID: 12563300)
• 11 Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140: 805-820 DOI: 10.1016/j.cell.2010.01.022. (PMID: 20303872)
• 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 DOI: 10.1093/pcp/pcl019. (PMID: 17018557)
• 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 DOI: 10.1016/j.jim.2013.08.004. (PMID: 23954282)
• 14 Zhang Q, Raoof M, Chen Y. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010; 464: 104-107 DOI: 10.1038/nature08780. (PMID: 20203610)
• 15 Sagan L. On the origin of mitosing cells. J Theor Biol 1967; 14: 255-274 DOI: 10.1016/0022-5193(67)90079-3. (PMID: 1154139) (PMID: 2)
• 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 DOI: 10.3389/fcimb.2020.00309. (PMID: 32733813)
• 17 Drouin M, Saenz J, Chiffoleau E. C-type lectin-like receptors: head or tail in cell death immunity. Front Immunol 2020; 11: 251 DOI: 10.3389/fimmu.2020.00251. (PMID: 32133013)
• 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 DOI: 10.3389/fimmu.2018.00590. (PMID: 29632536)
• 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 DOI: 10.1038/nature07830. (PMID: 19252480)
• 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 DOI: 10.1038/35074106. (PMID: 11323673)
• 21 Broere F, van der Zee R, van Eden W. Heat shock proteins are no DAMPs, rather “DAMPERs”. Nat Rev Immunol 2011; 11: 565 DOI: 10.1038/nri2873-c1. (PMID: 21785457)
• 22 Yu M, Wang H, Ding A. et al. HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock 2006; 26: 174-179 DOI: 10.1097/01.shk.0000225404.51320.82.
• 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 DOI: 10.1084/jem.20080091. (PMID: 18591409)
• 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 DOI: 10.1038/nature07106. (PMID: 18548002)
• 25 Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol 2009; 21: 317-337 DOI: 10.1093/intimm/dxp017. (PMID: 19246554)
• 26 Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol 2011; 29: 707-735 DOI: 10.1146/annurev-immunol-031210-101405. (PMID: 21219188)
• 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 DOI: 10.3389/fimmu.2018.01330. (PMID: 29963048)
• 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 DOI: 10.1016/j.jhep.2014.08.050. (PMID: 25200905)
• 29 Stouthard JM, Levi M, Hack CE. et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost 1996; 76: 738-742 (PMID: 8950783)
• 30 Markiewski MM, Nilsson B, Ekdahl KN. et al. Complement and coagulation: strangers or partners in crime?. Trends Immunol 2007; 28: 184-192 DOI: 10.1016/j.it.2007.02.006. (PMID: 17336159)
• 31 van der Poll T, Opal SM. Host-pathogen interactions in sepsis. Lancet Infect Dis 2008; 8: 32-43 DOI: 10.1016/s1473-3099(07)70265-7. (PMID: 18063412)
• 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 DOI: 10.1016/s0002-9440(10)63437-2. (PMID: 15509550)
• 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 DOI: 10.1016/j.molimm.2007.12.017. (PMID: 18262272)
• 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 DOI: 10.1074/jbc.M707692200. (PMID: 18515365)
• 35 Brown GT, Narayanan P, Li W. et al. Lipopolysaccharide stimulates platelets through an IL-1β autocrine loop. J Immunol 2013; 191: 5196-5203 DOI: 10.4049/jimmunol.1300354.
• 36 Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998; 38: 97-120 DOI: 10.1146/annurev.pharmtox.38.1.97. (PMID: 9597150)
• 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 DOI: 10.4049/jimmunol.181.3.2189. (PMID: 18641358)
• 38 Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 2014; 6: a016295 DOI: 10.1101/cshperspect.a016295. (PMID: 25190079)
• 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 DOI: 10.1016/j.jaci.2015.09.059. (PMID: 26774658)
• 40 Bickel M. The role of interleukin-8 in inflammation and mechanisms of regulation. J Periodontol 1993; 64 (Suppl. 05) 456-460 (PMID: 8315568)
• 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 DOI: 10.4049/jimmunol.168.9.4559. (PMID: 11971003)
• 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 DOI: 10.1074/jbc.M208231200. (PMID: 12496258)
• 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 DOI: 10.1126/science.aaa4268. (PMID: 25766237)
• 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 (PMID: 9620656)
• 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 (PMID: 2456628)
• 46 Plata-Salamán CR. 1998 Curt P. Richter Award. Brain mechanisms in cytokine-induced anorexia. Psychoneuroendocrinology 1999; 24: 25-41 DOI: 10.1016/s0306-4530(98)00045-6. (PMID: 10098218)
• 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 DOI: 10.1080/13813450802181047. (PMID: 18629684)
• 48 Ming WJ, Bersani L, Mantovani A. Tumor necrosis factor is chemotactic for monocytes and polymorphonuclear leukocytes. J Immunol 1987; 138: 1469-1474 (PMID: 3805724)
• 49 Morgan BP. The membrane attack complex as an inflammatory trigger. Immunobiology 2016; 221: 747-751 DOI: 10.1016/j.imbio.2015.04.006. (PMID: 25956457)
• 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 DOI: 10.1111/j.1432-1033.1986.tb09460.x. (PMID: 3081348)
• 51 Ward PA. The harmful role of c5a on innate immunity in sepsis. J Innate Immun 2010; 2: 439-445 DOI: 10.1159/000317194. (PMID: 20588003)
• 52 Simmons J, Pittet JF. The coagulopathy of acute sepsis. Curr Opin Anaesthesiol 2015; 28: 227-236 DOI: 10.1097/aco.0000000000000163. (PMID: 25590467)
• 53 Oikonomopoulou K, Ricklin D, Ward PA. et al. Interactions between coagulation and complement – their role in inflammation. Semin Immunopathol 2012; 34: 151-165 DOI: 10.1007/s00281-011-0280-x. (PMID: 21811895)
• 54 Miyake K. Roles for accessory molecules in microbial recognition by Toll-like receptors. J Endotoxin Res 2006; 12: 195-204 DOI: 10.1179/096805106x118807. (PMID: 16953972)
• 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 DOI: 10.1038/ni.2426. (PMID: 23023391)
• 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 DOI: 10.1126/science.1240988. (PMID: 24031018)
• 57 von Moltke J, Ayres JS, Kofoed EM. et al. Recognition of bacteria by inflammasomes. Annu Rev Immunol 2013; 31: 73-106 DOI: 10.1146/annurev-immunol-032712-095944. (PMID: 23215645)
• 58 Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 2015; 21: 677-687 DOI: 10.1038/nm.3893. (PMID: 26121197)
• 59 Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140: 821-832 DOI: 10.1016/j.cell.2010.01.040. (PMID: 20303873)
• 60 Liu X, Zhang Z, Ruan J. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 2016; 535: 153-158 DOI: 10.1038/nature18629. (PMID: 27383986)
• 61 Wei Y, Kim J, Ernits H. et al. The septic neutrophil – friend or foe. Shock 2021; 55: 147-155 DOI: 10.1097/shk.0000000000001620. (PMID: 32769816)
• 62 Kaplan MJ, Radic M. Neutrophil extracellular traps: double-edged swords of innate immunity. J Immunol 2012; 189: 2689-2695 DOI: 10.4049/jimmunol.1201719. (PMID: 22956760)
• 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 DOI: 10.1016/j.coi.2006.03.010. (PMID: 16616476)
• 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 DOI: 10.1073/pnas.97.24.12950. (PMID: 11087850)
• 65 Li Q, Zhang Q, Wang C. et al. Disruption of tight junctions during polymicrobial sepsis in vivo. J Pathol 2009; 218: 210-221 DOI: 10.1002/path.2525.
• 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 DOI: 10.1038/sj.bjp.0707147. (PMID: 17279089)
• 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 DOI: 10.1084/jem.20051207. (PMID: 16380509)
• 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 DOI: 10.1016/j.jcrc.2012.02.007. (PMID: 22591569)
• 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 DOI: 10.1007/s10877-019-00423-8.
• 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 DOI: 10.1097/QCO.0b013e328344c078. (PMID: 21330919)
• 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 DOI: 10.1186/s13613-019-0499-6. (PMID: 30701381)
• 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 DOI: 10.1016/j.jss.2009.04.034. (PMID: 19560161)
• 73 Uchimido R, Schmidt EP, Shapiro NI. The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit Care 2019; 23: 16 DOI: 10.1186/s13054-018-2292-6. (PMID: 30654825)
• 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 DOI: 10.1097/ccm.0000000000000742. (PMID: 25479113)
• 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 DOI: 10.1186/cc10332. (PMID: 21798063)
• 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 DOI: 10.1016/j.jcrc.2007.11.008. (PMID: 19056016)
• 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 DOI: 10.1111/j.1365-2567.2010.03281.x. (PMID: 20406299)
• 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 DOI: 10.1038/nm.1929. (PMID: 19234462)
• 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 DOI: 10.1111/j.1600-065X.2008.00635.x. (PMID: 18613832)
• 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 DOI: 10.1016/j.coph.2009.04.008. (PMID: 19481975)
• 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 DOI: 10.1097/00003246-199707000-00010. (PMID: 9233735)
• 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 DOI: 10.1371/journal.pone.0131645. (PMID: 26135738)
• 83 Zhan C, Patskovsky Y, Yan Q. et al. Decoy strategies: the structure of TL1A: DcR3 complex. Structure 2011; 19: 162-171 DOI: 10.1016/j.str.2010.12.004. (PMID: 21300286)
• 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 DOI: 10.1097/01.Ccm.0000069345.78884.0f. (PMID: 12847405)
• 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 DOI: 10.2119/molmed.2010.00178. (PMID: 21085745)
• 86 Hotchkiss RS, Nicholson DW. Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol 2006; 6: 813-822 DOI: 10.1038/nri1943. (PMID: 17039247)
• 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 DOI: 10.1186/s13054-015-0796-x. (PMID: 25888255)
• 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 DOI: 10.1016/j.jss.2007.07.014. (PMID: 17981300)
• 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 DOI: 10.1097/EJA.0b013e328329afca. (PMID: 18226173)
• 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 (PMID: 7858264)
• 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 DOI: 10.1186/1471-2334-10-240. (PMID: 20707930)
• 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 DOI: 10.3389/fimmu.2018.02705. (PMID: 30515175)
• 93 Lin GL, McGinley JP, Drysdale SB. et al. Epidemiology and immune pathogenesis of viral sepsis. Front Immunol 2018; 9: 2147 DOI: 10.3389/fimmu.2018.02147. (PMID: 30319615)
• 94 Gu X, Zhou F, Wang Y. et al. Respiratory viral sepsis: epidemiology, pathophysiology, diagnosis and treatment. Eur Respir Rev 2020; 29: 200038 DOI: 10.1183/16000617.0038-2020. (PMID: 32699026)
• 95 Ravindranath TM. Viral sepsis: underrated and underdiagnosed entity in clinical arena. Future Virology 2022; 17: 197-199 DOI: 10.2217/fvl-2021-0189.
• 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 DOI: 10.1097/ccm.0000000000005195. (PMID: 34259663)
• 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 DOI: 10.1016/j.bcp.2021.114847. (PMID: 34801526)
• 98 Gupta A, Madhavan MV, Sehgal K. et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020; 26: 1017-1032 DOI: 10.1038/s41591-020-0968-3. (PMID: 32651579)
• 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 DOI: 10.1038/s41586-020-2600-6. (PMID: 32726800)
• 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 DOI: 10.1016/j.cytogfr.2020.12.001. (PMID: 33558131)
• 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 DOI: 10.1186/s12985-022-01814-1. (PMID: 35619180)
• 102 Hu B, Huang S, Yin L. The cytokine storm and COVID-19. J Med Virol 2021; 93: 250-256 DOI: 10.1002/jmv.26232. (PMID: 32592501)
• 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 DOI: 10.1186/s13054-020-02950-2. (PMID: 32430052)
• 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 DOI: 10.1001/jama.2019.5791. (PMID: 31104070)
• 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 DOI: 10.1097/ccm.0000000000003084. (PMID: 29537985)