J Pediatr Intensive Care 2019; 08(01): 042-050
DOI: 10.1055/s-0038-1676607
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Immune Modulation in Pediatric Sepsis

Mark W. Hall
1   Division of Critical Care Medicine, Nationwide Children's Hospital, Columbus, Ohio, United States
2   The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
› Author Affiliations
Further Information

Publication History

30 October 2018

02 November 2018

Publication Date:
02 January 2019 (online)

Abstract

The initial host immune response to sepsis in children is characterized by a proinflammatory surge that can be associated with fever, capillary leak, and organ dysfunction. There is, however, a concurrent anti-inflammatory response that results in hyporesponsiveness of innate and adaptive immune cells. When severe, this response is termed immunoparalysis and is known to be associated with prolonged organ dysfunction, increased risk for nosocomial infection, and death in septic adults and children. Sepsis-induced immune suppression can be defined in the laboratory by reduced whole blood ex vivo-stimulated cytokine production capacities, reduced expression of human leukocyte antigen (HLA)-DR on circulating monocytes, and reduced absolute cell counts. While anti-inflammatory therapies have largely been unsuccessful at improving outcomes from adult and pediatric sepsis, the use of immunostimulatory therapies such as granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with sepsis-induced immunoparalysis shows promise. A greater understanding of the risk factors for immunoparalysis along with the development and execution of immunophenotype-specific clinical trials of strategies to optimize innate and adaptive immune function are needed to further improve outcomes in septic children.

 
  • References

  • 1 Uematsu S, Akira S. Toll-like receptors (TLRs) and their ligands. Handb Exp Pharmacol 2008; (183) 1-20
  • 2 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
  • 3 Volk HD, Reinke P, Krausch D. , et al. Monocyte deactivation–rationale for a new therapeutic strategy in sepsis. Intensive Care Med 1996; 22 (Suppl. 04) S474-S481
  • 4 Monneret G, Lepape A, Voirin N. , et al. Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med 2006; 32 (08) 1175-1183
  • 5 Döcke WD, Höflich C, Davis KA. , et al. Monitoring temporary immunodepression by flow cytometric measurement of monocytic HLA-DR expression: a multicenter standardized study. Clin Chem 2005; 51 (12) 2341-2347
  • 6 Meisel C, Schefold JC, Pschowski R. , et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med 2009; 180 (07) 640-648
  • 7 Manzoli TF, Troster EJ, Ferranti JF, Sales MM. Prolonged suppression of monocytic human leukocyte antigen-DR expression correlates with mortality in pediatric septic patients in a pediatric tertiary intensive care unit. J Crit Care 2016; 33: 84-89
  • 8 Hall MW, Geyer SM, Guo CY. , et al; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network PICFlu Study Investigators. Innate immune function and mortality in critically ill children with influenza: a multicenter study. Crit Care Med 2013; 41 (01) 224-236
  • 9 Muszynski JA, Nofziger R, Moore-Clingenpeel M. , et al. Early immune function and duration of organ dysfunction in critically III children with sepsis. Am J Respir Crit Care Med 2018; 198 (03) 361-369
  • 10 Felmet KA, Hall MW, Clark RS, Jaffe R, Carcillo JA. Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. J Immunol 2005; 174 (06) 3765-3772
  • 11 Boomer JS, To K, Chang KC. , et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 2011; 306 (23) 2594-2605
  • 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 Wong HR, Cvijanovich NZ, Anas N. , et al. Developing a clinically feasible personalized medicine approach to pediatric septic shock. Am J Respir Crit Care Med 2015; 191 (03) 309-315
  • 14 Muszynski JA, Nofziger R, Greathouse K. , et al. Early adaptive immune suppression in children with septic shock: a prospective observational study. Crit Care 2014; 18 (04) R145
  • 15 Boomer JS, Shuherk-Shaffer J, Hotchkiss RS, Green JM. A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis. Crit Care 2012; 16 (03) R112
  • 16 Calandra T, Glauser MP, Schellekens J, Verhoef J. Treatment of gram-negative septic shock with human IgG antibody to Escherichia coli J5: a prospective, double-blind, randomized trial. J Infect Dis 1988; 158 (02) 312-319
  • 17 McCloskey RV, Straube RC, Sanders C, Smith SM, Smith CR. ; CHESS Trial Study Group. Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1994; 121 (01) 1-5
  • 18 Fisher Jr CJ, Dhainaut JF, Opal SM. , et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 1994; 271 (23) 1836-1843
  • 19 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 (07) 1115-1124
  • 20 Fisher Jr CJ, Agosti JM, Opal SM. , et al; The Soluble TNF Receptor Sepsis Study Group. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. N Engl J Med 1996; 334 (26) 1697-1702
  • 21 Abraham E, Anzueto A, Gutierrez G. , et al; NORASEPT II Study Group. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. Lancet 1998; 351 (9107): 929-933
  • 22 Fein AM, Bernard GR, Criner GJ. , et al. Treatment of severe systemic inflammatory response syndrome and sepsis with a novel bradykinin antagonist, deltibant (CP-0127). Results of a randomized, double-blind, placebo-controlled trial. CP-0127 SIRS and sepsis study group. JAMA 1997; 277 (06) 482-487
  • 23 Sprung CL, Caralis PV, Marcial EH. , et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med 1984; 311 (18) 1137-1143
  • 24 Panacek EA, Marshall JC, Albertson TE. , et al. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med 2004; 32 (11) 2173-2182
  • 25 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
  • 26 Teachey DT, Rheingold SR, Maude SL. , et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 2013; 121 (26) 5154-5157
  • 27 Fumeaux T, Pugin J. Role of interleukin-10 in the intracellular sequestration of human leukocyte antigen-DR in monocytes during septic shock. Am J Respir Crit Care Med 2002; 166 (11) 1475-1482
  • 28 Döcke WD, Randow F, Syrbe U. , et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 1997; 3 (06) 678-681
  • 29 Delsing CE, Gresnigt MS, Leentjens J. , et al. Interferon-gamma as adjunctive immunotherapy for invasive fungal infections: a case series. BMC Infect Dis 2014; 14: 166
  • 30 Bilgin K, Yaramiş A, Haspolat K, Taş MA, Günbey S, Derman O. A randomized trial of granulocyte-macrophage colony-stimulating factor in neonates with sepsis and neutropenia. Pediatrics 2001; 107 (01) 36-41
  • 31 Drossou-Agakidou V, Kanakoudi-Tsakalidou F, Sarafidis K. , et al. In vivo effect of rhGM-CSF And rhG-CSF on monocyte HLA-DR expression of septic neonates. Cytokine 2002; 18 (05) 260-265
  • 32 Presneill JJ, Harris T, Stewart AG, Cade JF, Wilson JW. A randomized phase II trial of granulocyte-macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction. Am J Respir Crit Care Med 2002; 166 (02) 138-143
  • 33 Nierhaus A, Montag B, Timmler N. , et al. Reversal of immunoparalysis by recombinant human granulocyte-macrophage colony-stimulating factor in patients with severe sepsis. Intensive Care Med 2003; 29 (04) 646-651
  • 34 Rosenbloom AJ, Linden PK, Dorrance A, Penkosky N, Cohen-Melamed MH, Pinsky MR. Effect of granulocyte-monocyte colony-stimulating factor therapy on leukocyte function and clearance of serious infection in nonneutropenic patients. Chest 2005; 127 (06) 2139-2150
  • 35 Orozco H, Arch J, Medina-Franco H. , et al. Molgramostim (GM-CSF) associated with antibiotic treatment in nontraumatic abdominal sepsis: a randomized, double-blind, placebo-controlled clinical trial. Arch Surg 2006; 141 (02) 150-153 , discussion 154
  • 36 Paine III R, Standiford TJ, Dechert RE. , et al. A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury. Crit Care Med 2012; 40 (01) 90-97
  • 37 Venet F, Foray AP, Villars-Méchin A. , et al. IL-7 restores lymphocyte functions in septic patients. J Immunol 2012; 189 (10) 5073-5081
  • 38 Thampy LK, Remy KE, Walton AH. , et al. Restoration of T Cell function in multi-drug resistant bacterial sepsis after interleukin-7, anti-PD-L1, and OX-40 administration. PLoS One 2018; 13 (06) e0199497
  • 39 Chang K, Svabek C, Vazquez-Guillamet C. , et al. Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis. Crit Care 2014; 18 (01) R3
  • 40 Unsinger J, Burnham CA, McDonough J. , et al. Interleukin-7 ameliorates immune dysfunction and improves survival in a 2-hit model of fungal sepsis. J Infect Dis 2012; 206 (04) 606-616
  • 41 Chang KC, Burnham CA, Compton SM. , et al. Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis. Crit Care 2013; 17 (03) R85
  • 42 Shindo Y, Unsinger J, Burnham CA, Green JM, Hotchkiss RS. Interleukin-7 and anti-programmed cell death 1 antibody have differing effects to reverse sepsis-induced immunosuppression. Shock 2015; 43 (04) 334-343
  • 43 Muszynski J, Nateri J, Nicol K, Greathouse K, Hanson L, Hall M. Immunosuppressive effects of red blood cells on monocytes are related to both storage time and storage solution. Transfusion 2012; 52 (04) 794-802
  • 44 Muszynski JA, Frazier E, Nofziger R. , et al. Pediatric Critical Care Blood Research Network (Blood Net) subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI). Red blood cell transfusion and immune function in critically ill children: a prospective observational study. Transfusion 2015; 55 (04) 766-774
  • 45 Hildebrand F, van Griensven M, Giannoudis P. , et al. Impact of hypothermia on the immunologic response after trauma and elective surgery. Surg TechnolInt 2005; 14: 41-50
  • 46 Muszynski JA, Spinella PC, Cholette JM. , et al; Pediatric Critical Care Blood Research Network (Blood Net). Transfusion-related immunomodulation: review of the literature and implications for pediatric critical illness. Transfusion 2017; 57 (01) 195-206
  • 47 Labro MT. Antibacterial agents--phagocytes: new concepts for old in immunomodulation. Int J Antimicrob Agents 1998; 10 (01) 11-21
  • 48 Tamaoki J, Kadota J, Takizawa H. Clinical implications of the immunomodulatory effects of macrolides. Am J Med 2004; 117 (Suppl 9A): 5S-11S
  • 49 Zavala F. Benzodiazepines, anxiety and immunity. Pharmacol Ther 1997; 75 (03) 199-216
  • 50 Stolk RF, van der Poll T, Angus DC, van der Hoeven JG, Pickkers P, Kox M. Potentially inadvertent immunomodulation: norepinephrine use in sepsis. Am J Respir Crit Care Med 2016; 194 (05) 550-558
  • 51 Yu-Lee LY. Molecular actions of prolactin in the immune system. Proc Soc Exp Biol Med 1997; 215 (01) 35-52
  • 52 Yuengsrigul A, Chin TW, Nussbaum E. Immunosuppressive and cytotoxic effects of furosemide on human peripheral blood mononuclear cells. Ann Allergy Asthma Immunol 1999; 83 (6,Pt 1): 559-566
  • 53 Dandona P, Aljada A, Mohanty P. , et al. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect?. J Clin Endocrinol Metab 2001; 86 (07) 3257-3265
  • 54 Bhat RS, Bhaskaran M, Mongia A, Hitosugi N, Singhal PC. Morphine-induced macrophage apoptosis: oxidative stress and strategies for modulation. J Leukoc Biol 2004; 75 (06) 1131-1138