J Pediatr Intensive Care 2019; 08(01): 025-031
DOI: 10.1055/s-0038-1675639
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Role of Damage-Associated Molecular Patterns and Uncontrolled Inflammation in Pediatric Sepsis-Induced Multiple Organ Dysfunction Syndrome

Alicia M. Alcamo
1   Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
2   Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
,
Diana Pang
3   Department of Critical Care Medicine, Children's Hospital of the King's Daughters, Norfolk, Virginia, United States
,
Dalia A. Bashir
4   Section of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine/Texas Children's Hospital, Houston, Texas, United States
5   Michael E. DeBakey Veteran Affairs Medical Center, Center for Translational Research on Inflammatory Diseases, Houston, Texas, United States
,
Joseph A. Carcillo
1   Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
2   Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
,
Trung C. Nguyen
4   Section of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine/Texas Children's Hospital, Houston, Texas, United States
5   Michael E. DeBakey Veteran Affairs Medical Center, Center for Translational Research on Inflammatory Diseases, Houston, Texas, United States
,
Rajesh K. Aneja
1   Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
2   Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
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Weitere Informationen

Publikationsverlauf

20. Februar 2018

19. März 2018

Publikationsdatum:
20. November 2018 (online)

Abstract

The incidence of multiple organ dysfunction syndrome (MODS) in sepsis varies from 17 to 73% and furthermore, increases the risk of death by 60% when controlled for the number of dysfunctional organs. Several MODS phenotypes exist, each unique in presentation and pathophysiology. Common to the phenotypes is the stimulation of the immune response by pathogen-associated molecular patterns (PAMPs), or danger-associated molecular patterns (DAMPs) causing an unremitting inflammation. Two of the MODS phenotypes are discussed in detail, thrombocytopenia-associated multiple organ failure (TAMOF) and the hyperinflammatory phenotype–macrophage activating syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH). In the end, we will briefly review the role of mitochondrial dysfunction as a significant contributor to the pathogenesis of MODS.

 
  • References

  • 1 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 1992; 20 (06) 864-874
  • 2 Proulx F, Fayon M, Farrell CA, Lacroix J, Gauthier M. Epidemiology of sepsis and multiple organ dysfunction syndrome in children. Chest 1996; 109 (04) 1033-1037
  • 3 Goh A, Lum L. Sepsis, severe sepsis and septic shock in paediatric multiple organ dysfunction syndrome. J Paediatr Child Health 1999; 35 (05) 488-492
  • 4 Kutko MC, Calarco MP, Flaherty MB. , et al. Mortality rates in pediatric septic shock with and without multiple organ system failure. Pediatr Crit Care Med 2003; 4 (03) 333-337
  • 5 Proulx F, Joyal JS, Mariscalco MM, Leteurtre S, Leclerc F, Lacroix J. The pediatric multiple organ dysfunction syndrome. Pediatr Crit Care Med 2009; 10 (01) 12-22
  • 6 Buras JA, Holzmann B, Sitkovsky M. Animal models of sepsis: setting the stage. Nat Rev Drug Discov 2005; 4 (10) 854-865
  • 7 Amoo-Lamptey A, Dickman P, Carcillo JA. Comparative pathology of children with sepsis and MOF, pneumonia without MOF, and MOF without infection. Pediatr Res 2001; 49: 46A
  • 8 Nguyen T, Hall M, Han Y. , et al. Microvascular thrombosis in pediatric multiple organ failure: is it a therapeutic target?. Pediatr Crit Care Med 2001; 2 (03) 187-196
  • 9 Nguyen TC, Han YY, Kiss JE. , et al. Intensive plasma exchange increases a disintegrin and metalloprotease with thrombospondin motifs-13 activity and reverses organ dysfunction in children with thrombocytopenia-associated multiple organ failure. Crit Care Med 2008; 36 (10) 2878-2887
  • 10 Nguyen TC, Han YY, Fortenberry JD, Zhou Z, Cruz MA, Carcillo Jr. JA. Thrombocytopenia-associated multiple organ failure syndrome. In: Wheeler DS, Wong HR, Shanley TP. , eds. Pediatric Critical Care Medicine: Basic Science and Clinical Evidence. Vol 3. 2nd ed. New York, NY: Springer; 2014: 481-492
  • 11 Hall MW, Knatz NL, Vetterly C. , et al. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med 2011; 37 (03) 525-532
  • 12 Hotchkiss RS, Tinsley KW, Swanson PE. , et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol 2001; 166 (11) 6952-6963
  • 13 Hotchkiss RS, Swanson PE, Freeman BD. , et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999; 27 (07) 1230-1251
  • 14 Hotchkiss RS, Swanson PE, Knudson CM. , et al. Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. J Immunol 1999; 162 (07) 4148-4156
  • 15 Doughty L, Clark RS, Kaplan SS, Sasser H, Carcillo J. sFas and sFas ligand and pediatric sepsis-induced multiple organ failure syndrome. Pediatr Res 2002; 52 (06) 922-927
  • 16 Matzinger P. An innate sense of danger. Semin Immunol 1998; 10 (05) 399-415
  • 17 Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004; 4 (07) 499-511
  • 18 Franchi L, McDonald C, Kanneganti TD, Amer A, Núñez G. Nucleotide-binding oligomerization domain-like receptors: intracellular pattern recognition molecules for pathogen detection and host defense. J Immunol 2006; 177 (06) 3507-3513
  • 19 Hotchkiss RS, Opal S. Immunotherapy for sepsis--a new approach against an ancient foe. N Engl J Med 2010; 363 (01) 87-89
  • 20 Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003; 348 (02) 138-150
  • 21 Abraham E, Glauser MP, Butler T. , et al. p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. Ro 45-2081 Study Group. JAMA 1997; 277 (19) 1531-1538
  • 22 Abraham E, Wunderink R, Silverman H. , et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA 1995; 273 (12) 934-941
  • 23 Bustin M. At the crossroads of necrosis and apoptosis: signaling to multiple cellular targets by HMGB1. Sci STKE 2002; 2002 (151) pe39
  • 24 Wang H, Yang H, Czura CJ, Sama AE, Tracey KJ. HMGB1 as a late mediator of lethal systemic inflammation. Am J Respir Crit Care Med 2001; 164 (10, Pt 1): 1768-1773
  • 25 Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007; 81 (01) 1-5
  • 26 Castiglioni A, Canti V, Rovere-Querini P, Manfredi AA. High-mobility group box 1 (HMGB1) as a master regulator of innate immunity. Cell Tissue Res 2011; 343 (01) 189-199
  • 27 Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr Opin Immunol 2001; 13 (01) 114-119
  • 28 Yang H, Ochani M, Li J. , et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci U S A 2004; 101 (01) 296-301
  • 29 Wang H, Bloom O, Zhang M. , et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999; 285 (5425) 248-251
  • 30 Park JS, Svetkauskaite D, He Q. , et al. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 2004; 279 (09) 7370-7377
  • 31 Yu M, Wang H, Ding A. , et al. HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock 2006; 26 (02) 174-179
  • 32 Pedrazzi M, Patrone M, Passalacqua M. , et al. Selective proinflammatory activation of astrocytes by high-mobility group box 1 protein signaling. J Immunol 2007; 179 (12) 8525-8532
  • 33 Angus DC, Yang L, Kong L. , et al; GenIMS Investigators Circulating high-mobility group box 1 (HMGB1) concentrations are elevated in both uncomplicated pneumonia and pneumonia with severe sepsis. Crit Care Med 2007; 35 (04) 1061-1067
  • 34 Sundén-Cullberg J, Norrby-Teglund A, Rouhiainen A. , et al. Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med 2005; 33 (03) 564-573
  • 35 Aneja R, Killeen M, Bayir H. , et al. High Mobility Group Box 1 (HMGB1) clearance with plasma exchange in pediatric patients with sepsis and thrombocytopenia-associated with multiple organ failure. Crit Care Med 2007; 35 (12) A264 . Available at: https://journals.lww.com/ccmjournal/Citation/2007/12001/Abstracts.1.aspx
  • 36 Gaïni S, Pedersen SS, Koldkjaer OG, Pedersen C, Møller HJ. High mobility group box-1 protein in patients with suspected community-acquired infections and sepsis: a prospective study. Crit Care 2007; 11 (02) R32
  • 37 Gibot S, Massin F, Cravoisy A. , et al. High-mobility group box 1 protein plasma concentrations during septic shock. Intensive Care Med 2007; 33 (08) 1347-1353
  • 38 Pang D, Bola R, Au A. , et al. Plasma high mobility group box-1 (HMGB1) concentration in pediatric sepsis and multi-organ failure. Crit Car Med 2014; 42 (12) A1386 . Available at: https://journals.lww.com/ccmjournal/Fulltext/2014/12001/109___PLASMA_HIGH_MOBILITY_GROUP_BOX_1__HMGB1_.76.aspx
  • 39 Wiesner RJ, Rüegg JC, Morano I. Counting target molecules by exponential polymerase chain reaction: copy number of mitochondrial DNA in rat tissues. Biochem Biophys Res Commun 1992; 183 (02) 553-559
  • 40 Taanman JW. The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta 1999; 1410 (02) 103-123
  • 41 Andersson SG, Karlberg O, Canbäck B, Kurland CG. On the origin of mitochondria: a genomics perspective. Philos Trans R Soc Lond B Biol Sci 2003; 358 (1429): 165-177 , discussion 177–179
  • 42 West AP, Koblansky AA, Ghosh S. Recognition and signaling by toll-like receptors. Annu Rev Cell Dev Biol 2006; 22: 409-437
  • 43 Zhang Q, Raoof M, Chen Y. , et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010; 464 (7285): 104-107
  • 44 West AP, Shadel GS, Ghosh S. Mitochondria in innate immune responses. Nat Rev Immunol 2011; 11 (06) 389-402
  • 45 Zhang Q, Itagaki K, Hauser CJ. Mitochondrial DNA is released by shock and activates neutrophils via p38 map kinase. Shock 2010; 34 (01) 55-59
  • 46 Di Caro V, Walko III TD, Bola RA. , et al. Plasma mitochondrial DNA--a novel DAMP in pediatric sepsis. Shock 2016; 45 (05) 506-511
  • 47 Schäfer ST, Franken L, Adamzik M. , et al. Mitochondrial DNA: an endogenous trigger for immune paralysis. Anesthesiology 2016; 124 (04) 923-933
  • 48 Burke AP, Mont E, Kolodgie F, Virmani R. Thrombotic thrombocytopenic purpura causing rapid unexpected death: value of CD61 immunohistochemical staining in diagnosis. Cardiovasc Pathol 2005; 14 (03) 150-155
  • 49 Hosler GA, Cusumano AM, Hutchins GM. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. A review of 56 autopsy cases. Arch Pathol Lab Med 2003; 127 (07) 834-839
  • 50 Levy GG, Nichols WC, Lian EC. , et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413 (6855): 488-494
  • 51 Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339 (22) 1585-1594
  • 52 Zhou Z, Han H, Cruz MA, López JA, Dong JF, Guchhait P. Haemoglobin blocks von Willebrand factor proteolysis by ADAMTS-13: a mechanism associated with sickle cell disease. Thromb Haemost 2009; 101 (06) 1070-1077
  • 53 Ono T, Mimuro J, Madoiwa S. , et al. Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. Blood 2006; 107 (02) 528-534
  • 54 Studt JD, Kremer Hovinga JA, Antoine G. , et al. Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin. Blood 2005; 105 (02) 542-544
  • 55 Crawley JT, Lam JK, Rance JB, Mollica LR, O'Donnell JS, Lane DA. Proteolytic inactivation of ADAMTS13 by thrombin and plasmin. Blood 2005; 105 (03) 1085-1093
  • 56 Mannucci PM, Capoferri C, Canciani MT. Plasma levels of von Willebrand factor regulate ADAMTS-13, its major cleaving protease. Br J Haematol 2004; 126 (02) 213-218
  • 57 Bernardo A, Ball C, Nolasco L, Moake JF, Dong JF. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 2004; 104 (01) 100-106
  • 58 Wong HR, Cvijanovich NZ, Anas N. , et al. Pediatric sepsis biomarker risk model-ii: redefining the pediatric sepsis biomarker risk model with septic shock phenotype. Crit Care Med 2016; 44 (11) 2010-2017
  • 59 Claushuis TA, van Vught LA, Scicluna BP. , et al; Molecular Diagnosis and Risk Stratification of Sepsis Consortium Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients. Blood 2016; 127 (24) 3062-3072
  • 60 Hashimoto S, Kobayashi A, Kooguchi K, Kitamura Y, Onodera H, Nakajima H. Upregulation of two death pathways of perforin/granzyme and FasL/Fas in septic acute respiratory distress syndrome. Am J Respir Crit Care Med 2000; 161 (01) 237-243
  • 61 Emmenegger U, Zehnder R, Frey U, Reimers A, Spaeth PJ, Neftel KA. Elevation of soluble Fas and soluble Fas ligand in reactive macrophage activation syndromes. Am J Hematol 2000; 64 (02) 116-119
  • 62 Hori Y, Wada H, Mori Y. , et al. Plasma sFas and sFas ligand levels in patients with thrombotic thrombocytopenic purpura and in those with disseminated intravascular coagulation. Am J Hematol 1999; 61 (01) 21-25
  • 63 Takada H, Nomura A, Ohga S, Hara T. Interleukin-18 in hemophagocytic lymphohistiocytosis. Leuk Lymphoma 2001; 42 (1-2) 21-28
  • 64 Allen CE, McClain KL. Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis. Hematology (Am Soc Hematol Educ Program) 2015; 2015 (01) 177-182
  • 65 Castillo L, Carcillo J. Secondary hemophagocytic lymphohistiocytosis and severe sepsis/systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation. Pediatr Crit Care Med 2009; 10 (03) 387-392
  • 66 Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood 2011; 118 (15) 4041-4052
  • 67 Zhang K, Jordan MB, Marsh RA. , et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood 2011; 118 (22) 5794-5798
  • 68 Zhang M, Behrens EM, Atkinson TP, Shakoory B, Grom AA, Cron RQ. Genetic defects in cytolysis in macrophage activation syndrome. Curr Rheumatol Rep 2014; 16 (09) 439
  • 69 Kaufman KM, Linghu B, Szustakowski JD. , et al. Whole-exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis. Arthritis Rheumatol 2014; 66 (12) 3486-3495
  • 70 Carcillo JA, Sward K, Halstead ES. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network Investigators. A systemic inflammation mortality risk assessment contingency table for severe sepsis. Pediatr Crit Care Med 2017; 18 (02) 143-150
  • 71 Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008; 50 (06) 1227-1235
  • 72 Lehmberg K, McClain KL, Janka GE, Allen CE. Determination of an appropriate cut-off value for ferritin in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2014; 61 (11) 2101-2103
  • 73 Shakoory B, Carcillo JA, Chatham WW. , et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med 2016; 44 (02) 275-281
  • 74 Demirkol D, Yildizdas D, Bayrakci B. , et al; Turkish Secondary HLH/MAS Critical Care Study Group. Hyperferritinemia in the critically ill child with secondary HLH/sepsis/MODS/MAS: what is the treatment?. Crit Care 2012; 16 (02) R52
  • 75 Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence 2014; 5 (01) 66-72
  • 76 Takasu O, Gaut JP, Watanabe E. , et al. Mechanisms of cardiac and renal dysfunction in patients dying of sepsis. Am J Respir Crit Care Med 2013; 187 (05) 509-517
  • 77 Larsen FJ, Schiffer TA, Weitzberg E, Lundberg JO. Regulation of mitochondrial function and energetics by reactive nitrogen oxides. Free Radic Biol Med 2012; 53 (10) 1919-1928
  • 78 Szabó C, Módis K. Pathophysiological roles of peroxynitrite in circulatory shock. Shock 2010; 34 (1, Suppl 1): 4-14
  • 79 Li JM, Shah AM. Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 2004; 287 (05) R1014-R1030
  • 80 Torres J, Darley-Usmar V, Wilson MT. Inhibition of cytochrome c oxidase in turnover by nitric oxide: mechanism and implications for control of respiration. Biochem J 1995; 312 (Pt 1): 169-173
  • 81 Li H, Hu J, Xin W, Zhao B. Production and interaction of oxygen and nitric oxide free radicals in PMA stimulated macrophages during the respiratory burst. Redox Rep 2000; 5 (06) 353-358
  • 82 Brealey D, Brand M, Hargreaves I. , et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002; 360 (9328): 219-223
  • 83 Boulos M, Astiz ME, Barua RS, Osman M. Impaired mitochondrial function induced by serum from septic shock patients is attenuated by inhibition of nitric oxide synthase and poly(ADP-ribose) synthase. Crit Care Med 2003; 31 (02) 353-358
  • 84 Porta F, Takala J, Weikert C. , et al. Effects of prolonged endotoxemia on liver, skeletal muscle and kidney mitochondrial function. Crit Care 2006; 10 (04) R118
  • 85 Sakaguchi S, Ibata H, Yokota K. Effect of calcium ion on lipid peroxide formation in endotoxemic mice. Microbiol Immunol 1989; 33 (02) 99-110
  • 86 Kudoh A, Kudoh E, Ishihara H, Matsuki A. ONO-5046, an elastase inhibitor, attenuates liver mitochondrial dysfunction after endotoxin. Crit Care Med 1998; 26 (01) 138-141
  • 87 Davies NA, Brealey DA, Stidwill R, Singer M, Svistunenko DA, Cooper CE. Nitrosyl heme production compared in endotoxemic and hemorrhagic shock. Free Radic Biol Med 2005; 38 (01) 41-49
  • 88 Garrabou G, Morén C, López S. , et al. The effects of sepsis on mitochondria. J Infect Dis 2012; 205 (03) 392-400
  • 89 Bouchier-Hayes L, Lartigue L, Newmeyer DD. Mitochondria: pharmacological manipulation of cell death. J Clin Invest 2005; 115 (10) 2640-2647
  • 90 Japiassú AM, Santiago AP, d'Avila JC. , et al. Bioenergetic failure of human peripheral blood monocytes in patients with septic shock is mediated by reduced F1Fo adenosine-5′-triphosphate synthase activity. Crit Care Med 2011; 39 (05) 1056-1063
  • 91 Sjövall F, Morota S, Persson J, Hansson MJ, Elmér E. Patients with sepsis exhibit increased mitochondrial respiratory capacity in peripheral blood immune cells. Crit Care 2013; 17 (04) R152
  • 92 Weiss SL, Selak MA, Tuluc F. , et al. Mitochondrial dysfunction in peripheral blood mononuclear cells in pediatric septic shock. Pediatr Crit Care Med 2015; 16 (01) e4-e12
  • 93 Singer M. Mitochondrial function in sepsis: acute phase versus multiple organ failure. Crit Care Med 2007; 35 (9, Suppl): S441-S448