The immune system’s role in sepsis progression, resolution, and long-term outcome

Immunological Reviews

Volumn 274, Issue 1, 2016, Pages 330-353

  Delano, Matthew J ^a   Ward, Peter A ^b  

^a UNIVERSITY OF MICHIGAN   (United States)

^b UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

Author keywords

adaptive immune dysfunction; immune suppression sepsis; inflammation; innate immune dysfunction; sepsis

Indexed keywords

BIOLOGICAL MARKER; DRONABINOL; GAMMA INTERFERON; GRANULOCYTE COLONY STIMULATING FACTOR; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; INTERLEUKIN 15; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE 2; OXANDROLONE; POLY(ADENOSINE DIPHOSPHATE RIBOSE); PROGRAMMED DEATH 1 LIGAND 1; PROGRAMMED DEATH 1 RECEPTOR; PROPRANOLOL; RECOMBINANT INTERLEUKIN 3; RECOMBINANT INTERLEUKIN 7;

ADAPTIVE IMMUNITY; APOPTOSIS; B LYMPHOCYTE; CALCIUM HOMEOSTASIS; CELL SUBPOPULATION; COMPLEMENT ACTIVATION; DENDRITIC CELL; DISEASE COURSE; DISORDERS OF MITOCHONDRIAL FUNCTIONS; GAMMA DELTA T LYMPHOCYTE; HUMAN; IMMUNE RESPONSE; IMMUNE SYSTEM; IMMUNOMODULATION; INFLAMMATION; MACROPHAGE; METABOLIC REGULATION; MONOCYTE; MYELOPOIESIS; NATURAL KILLER CELL; NEUTROPHIL; OUTCOME ASSESSMENT; OXIDATION REDUCTION REACTION; PRIORITY JOURNAL; REVIEW; SEPSIS; SUPPRESSOR CELL; VAGUS NERVE; ANIMAL; IMMUNITY; IMMUNOLOGY; IMMUNOSUPPRESSIVE TREATMENT; SECONDARY PREVENTION; TIME FACTOR; TREATMENT OUTCOME;

ANIMALS; DISEASE PROGRESSION; HUMANS; IMMUNE SYSTEM; IMMUNITY; IMMUNOMODULATION; IMMUNOSUPPRESSION; INFLAMMATION; SECONDARY PREVENTION; SEPSIS; TIME FACTORS; TREATMENT OUTCOME;

EID: 84992446144     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/imr.12499     Document Type: Review

References (289)

1. Leadership Members. 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;20:864–874.
2. 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.
3. Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015;372:1629–1638.
4. 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.
5. Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013;41:1167–1174.
6. Mayr FB, Yende S, Angus DC. Epidemiology of severe sepsis. Virulence. 2014;5:4–11.
7. Coopersmith CM, Wunsch H, Fink MP, et al. A comparison of critical care research funding and the financial burden of critical illness in the United States. Crit Care Med. 2012;40:1072–1079.
8. Martin GS, Mannino DM, Moss M. The effect of age on the development and outcome of adult sepsis. Crit Care Med. 2006;34:15–21.
9. Kahn JM, Le T, Angus DC, et al. The epidemiology of chronic critical illness in the United States*. Crit Care Med. 2015;43:282–287.
10. Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014;20:195–203.
11. Deutschman CS, Tracey KJ. Sepsis: Current dogma and new perspectives. Immunity. 2014;40:463–475.
12. Ward PA, Bosmann M. A historical perspective on sepsis. Am J Pathol. 2012;181:2–7.
13. Tracey KJ, Fong Y, Hesse DG, et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987;330:662–664.
14. Schorr CA, Dellinger RP. The Surviving Sepsis Campaign: Past, present and future. Trends Mol Med. 2014;20:192–194.
15. Boomer JS, To K, Chang KC, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306:2594–2605.
16. Gentile LF, Cuenca AG, Efron PA, et al. Persistent inflammation and immunosuppression: A common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg. 2012;72:1491–1501.
17. Winters BD, Eberlein M, Leung J, Needham DM, Pronovost PJ, Sevransky JE. Long-term mortality and quality of life in sepsis: A systematic review. Crit Care Med. 2010;38:1276–1283.
18. Moore FA, Moore EE. Evolving concepts in the pathogenesis of postinjury multiple organ failure. Surg Clin North Am. 1995;75:257–277.
19. Delano MJ, Ward PA. Sepsis-induced immune dysfunction: Can immune therapies reduce mortality? J Clin Invest. 2016;126:23–31.
20. Needham DM, Davidson J, Cohen H, et al. Improving long-term outcomes after discharge from intensive care unit: Report from a stakeholders' conference. Crit Care Med. 2012;40:502–509.
21. Yende S, D'Angelo G, Kellum JA, et al. Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am J Respir Crit Care Med. 2008;177:1242–1247.
22. Elliott D, Davidson JE, Harvey MA, et al. Exploring the scope of post-intensive care syndrome therapy and care: Engagement of non-critical care providers and survivors in a second stakeholders meeting. Crit Care Med. 2014;42:2518–2526.
23. Annane D. What is the evidence for harm of neuromuscular blockade and corticosteroid use in the intensive care unit? Semin Respir Crit Care Med. 2016;37:51–56.
24. Hotchkiss RS, Moldawer LL. Parallels between cancer and infectious disease. N Engl J Med. 2014;371:380–383.
25. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: From cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13:862–874.
26. Delano MJ, Moldawer LL. Magic bullets and surrogate biomarkers circa 2009. Crit Care Med. 2009;37:1796–1798.
27. Bosmann M, Ward PA. The inflammatory response in sepsis. Trends Immunol. 2013;34:129–136.
28. Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA. The sepsis seesaw: Tilting toward immunosuppression. Nat Med. 2009;15:496–497.
29. Bone RC, Grodzin CJ, Balk RA. Sepsis: A new hypothesis for pathogenesis of the disease process. Chest. 1997;112:235–243.
30. Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol. 2008;8:776–787.
31. Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208:2581–2590.
32. Cuenca AG, Gentile LF, Lopez MC, et al. Development of a genomic metric that can be rapidly used to predict clinical outcome in severely injured trauma patients. Crit Care Med. 2013;41:1175–1185.
33. Hutchins NA, Unsinger J, Hotchkiss RS, Ayala A. The new normal: Immunomodulatory agents against sepsis immune suppression. Trends Mol Med. 2014;20:224–233.
34. Medzhitov R, Janeway C Jr. Innate immunity. N Engl J Med. 2000;343:338–344.
35. Goodwin AJ, Rice DA, Simpson KN, Ford DW. Frequency, cost, and risk factors of readmissions among severe sepsis survivors. Crit Care Med. 2015;43:738–746.
36. Gauglitz GG, Williams FN, Herndon DN, Jeschke MG. Burns: Where are we standing with propranolol, oxandrolone, recombinant human growth hormone, and the new incretin analogs? Curr Opin Clin Nutr Metab Care. 2011;14:176–181.
37. Norbury WB, Jeschke MG, Herndon DN. Metabolism modulators in sepsis: Propranolol. Crit Care Med. 2007;35:S616–620.
38. Jeschke MG, Finnerty CC, Suman OE, Kulp G, Mlcak RP, Herndon DN. The effect of oxandrolone on the endocrinologic, inflammatory, and hypermetabolic responses during the acute phase postburn. Ann Surg. 2007;246:351–360; discussion 360-352.
39. Goldszmid RS, Dzutsev A, Trinchieri G. Host immune response to infection and cancer: Unexpected commonalities. Cell Host Microbe. 2014;15:295–305.
40. Bohlius J, Herbst C, Reiser M, Schwarzer G, Engert A. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev. 2008;8:CD003189.
41. Smilek DE, Ehlers MR, Nepom GT. Restoring the balance: Immunotherapeutic combinations for autoimmune disease. Dis Model Mech. 2014;7:503–513.
42. Gilroy DW, Vallance P. Resolution for sepsis? Circulation. 2005;111:2–4.
43. Fullerton JN, Gilroy DW. Resolution of inflammation: A new therapeutic frontier. Nat Rev Drug Discov. 2016;15:551–567.
44. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510:92–101.
45. Buckley CD, Gilroy DW, Serhan CN. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity. 2014;40:315–327.
46. Venet F, Chung CS, Monneret G, et al. Regulatory T cell populations in sepsis and trauma. J Leukoc Biol. 2008;83:523–535.
47. Venet F, Chung CS, Kherouf H, et al. Increased circulating regulatory T cells (CD4(+)CD25 (+)CD127 (−)) contribute to lymphocyte anergy in septic shock patients. Intensive Care Med. 2009;35:678–686.
48. Brudecki L, Ferguson DA, McCall CE, El Gazzar M. Myeloid-derived suppressor cells evolve during sepsis and can enhance or attenuate the systemic inflammatory response. Infect Immun. 2012;80:2026–2034.
49. Dalli J, Chiang N, Serhan CN. Elucidation of novel 13-series resolvins that increase with atorvastatin and clear infections. Nat Med. 2015;21:1071–1075.
50. Lee CR, Zeldin DC. Resolvin infectious inflammation by targeting the host response. N Engl J Med. 2015;373:2183–2185.
51. Deshpande A, Pasupuleti V, Rothberg MB. Statin therapy and mortality from sepsis: A meta-analysis of randomized trials. Am J Med. 2015;128(410–417):e411.
52. Cummings CJ, Martin TR, Frevert CW, et al. Expression and function of the chemokine receptors CXCR1 and CXCR2 in sepsis. J Immunol. 1999;162:2341–2346.
53. Kovach MA, Standiford TJ. The function of neutrophils in sepsis. Curr Opin Infect Dis. 2012;25:321–327.
54. Grailer JJ, Kalbitz M, Zetoune FS, Ward PA. Persistent neutrophil dysfunction and suppression of acute lung injury in mice following cecal ligation and puncture sepsis. J Innate Immun. 2014;6:695–705.
55. Huber-Lang M, Sarma VJ, Lu KT, et al. Role of C5a in multiorgan failure during sepsis. J Immunol. 2001;166:1193–1199.
56. Cavaillon JM, Adib-Conquy M. Monocytes/macrophages and sepsis. Crit Care Med. 2005;33:S506–509.
57. Benjamim CF, Lundy SK, Lukacs NW, Hogaboam CM, Kunkel SL. Reversal of long-term sepsis-induced immunosuppression by dendritic cells. Blood. 2005;105:3588–3595.
58. Pene F, Zuber B, Courtine E, et al. Dendritic cells modulate lung response to Pseudomonas aeruginosa in a murine model of sepsis-induced immune dysfunction. J Immunol. 2008;181:8513–8520.
59. Grimaldi D, Llitjos JF, Pene F. Post-infectious immune suppression: A new paradigm of severe infections. Med Mal Infect. 2014;44:455–463.
60. Hotchkiss RS, Tinsley KW, Swanson PE, et al. Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol. 2002;168:2493–2500.
61. Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med. 1999;27:1230–1251.
62. Walton AH, Muenzer JT, Rasche D, et al. Reactivation of multiple viruses in patients with sepsis. PLoS ONE. 2014;9:e98819.
63. Drewry AM, Samra N, Skrupky LP, Fuller BM, Compton SM, Hotchkiss RS. Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock. 2014;42:383–391.
64. 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.
65. Prescott HC, Langa KM, Iwashyna TJ. Readmission diagnoses after hospitalization for severe sepsis and other acute medical conditions. JAMA. 2015;313:1055–1057.
66. Jones TK, Fuchs BD, Small DS, et al. Post-acute care use and hospital readmission after sepsis. Ann Am Thorac Soc. 2015;12:904–913.
67. Chang DW, Tseng CH, Shapiro MF. Rehospitalizations following sepsis: Common and costly. Crit Care Med. 2015;43:2085–2093.
68. Jensen US, Knudsen JD, Wehberg S, Gregson DB, Laupland KB. Risk factors for recurrence and death after bacteraemia: A population-based study. Clin Microbiol Infect. 2011;17:1148–1154.
69. Prescott HC, Dickson RP, Rogers MA, Langa KM, Iwashyna TJ. Hospitalization type and subsequent severe sepsis. Am J Respir Crit Care Med. 2015;192:581–588.
70. Prescott HC. Toward a nuanced understanding of the role of infection in readmissions after sepsis. Crit Care Med. 2016;44:634–635.
71. Sun A, Netzer G, Small DS, et al. Association between index hospitalization and hospital readmission in sepsis survivors. Crit Care Med. 2016;44:478–487.
72. Leibovici L. Long-term consequences of severe infections. Clin Microbiol Infect. 2013;19:510–512.
73. van Vught LA, Klein Klouwenberg PM, Spitoni C, et al. Incidence, risk factors, and attributable mortality of secondary infections in the intensive care unit after admission for sepsis. JAMA. 2016;315:1469–1479.
74. Wang T, Derhovanessian A, De Cruz S, Belperio JA, Deng JC, Hoo GS. Subsequent infections in survivors of sepsis: Epidemiology and outcomes. J Intensive Care Med. 2014;29:87–95.
75. Sogaard M, Thomsen RW, Bang RB, Schonheyder HC, Norgaard M. Trends in length of stay, mortality and readmission among patients with community-acquired bacteraemia. Clin Microbiol Infect. 2015;21(789):e781–787.
76. Suzuki K, Inoue S, Kametani Y, et al. Reduced immunocompetent B cells and increased secondary infection in elderly patients with severe sepsis. Shock. 2016;46:270–278.
77. Martin GS. Sepsis, severe sepsis and septic shock: Changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther. 2012;10:701–706.
78. Unnewehr H, Rittirsch D, Sarma JV, et al. Changes and regulation of the C5a receptor on neutrophils during septic shock in humans. J Immunol. 2013;190:4215–4225.
79. Czermak BJ, Sarma V, Pierson CL, et al. Protective effects of C5a blockade in sepsis. Nat Med. 1999;5:788–792.
80. Huber-Lang MS, Sarma JV, McGuire SR, et al. Protective effects of anti-C5a peptide antibodies in experimental sepsis. FASEB J. 2001;15:568–570.
81. Huber-Lang M, Sarma JV, Zetoune FS, et al. Generation of C5a in the absence of C3: A new complement activation pathway. Nat Med. 2006;12:682–687.
82. Ward PA. The harmful role of c5a on innate immunity in sepsis. J Innate Immun. 2010;2:439–445.
83. Melis JP, Strumane K, Ruuls SR, Beurskens FJ, Schuurman J, Parren PW. Complement in therapy and disease: Regulating the complement system with antibody-based therapeutics. Mol Immunol. 2015;67:117–130.
84. Ogilvie AC, Groeneveld AB, Straub JP, Thijs LG. Plasma lipid peroxides and antioxidants in human septic shock. Intensive Care Med. 1991;17:40–44.
85. Cowley HC, Bacon PJ, Goode HF, Webster NR, Jones JG, Menon DK. Plasma antioxidant potential in severe sepsis: A comparison of survivors and nonsurvivors. Crit Care Med. 1996;24:1179–1183.
86. Santos SS, Brunialti MK, Rigato O, Machado FR, Silva E, Salomao R. Generation of nitric oxide and reactive oxygen species by neutrophils and monocytes from septic patients and association with outcomes. Shock. 2012;38:18–23.
87. Andrades ME, Morina A, Spasic S, Spasojevic I. Bench-to-bedside review: Sepsis – From the redox point of view. Crit Care. 2011;15:230.
88. Ojeda Ojeda M, Larrondo Muguercia H, Magdariaga Figuerola A, et al. Temporal trends of circulating nitric oxide and pro-inflammatory cytokine responses ex vivo in intra-abdominal sepsis: Results from a cohort study. Inflamm Res. 2011;60:289–297.
89. Dare AJ, Phillips AR, Hickey AJ, et al. A systematic review of experimental treatments for mitochondrial dysfunction in sepsis and multiple organ dysfunction syndrome. Free Radic Biol Med. 2009;47:1517–1525.
90. Mishra V. Oxidative stress and role of antioxidant supplementation in critical illness. Clin Lab. 2007;53:199–209.
91. Muller B, Becker KL, Kranzlin M, et al. Disordered calcium homeostasis of sepsis: Association with calcitonin precursors. Eur J Clin Invest. 2000;30:823–831.
92. Zivin JR, Gooley T, Zager RA, Ryan MJ. Hypocalcemia: A pervasive metabolic abnormality in the critically ill. Am J Kidney Dis. 2001;37:689–698.
93. Desai TK, Carlson RW, Geheb MA. Prevalence and clinical implications of hypocalcemia in acutely ill patients in a medical intensive care setting. Am J Med. 1988;84:209–214.
94. 2+. Arch Surg. 2000;135:1432–1442.
95. Zaloga GP, Washburn D, Black KW, Prielipp R. Human sepsis increases lymphocyte intracellular calcium. Crit Care Med. 1993;21:196–202.
96. Thompson M, Kliewer A, Maass D, et al. Increased cardiomyocyte intracellular calcium during endotoxin-induced cardiac dysfunction in guinea pigs. Pediatr Res. 2000;47:669–676.
97. 2+: A critical link in the pathophysiology of sepsis? Proc Natl Acad Sci USA. 1993;90:3933–3937.
98. Collage RD, Howell GM, Zhang X, et al. Calcium supplementation during sepsis exacerbates organ failure and mortality via calcium/calmodulin-dependent protein kinase kinase signaling. Crit Care Med. 2013;41:e352–360.
99. Ba X, Garg NJ. Signaling mechanism of poly(ADP-ribose) polymerase-1 (PARP-1) in inflammatory diseases. Am J Pathol. 2011;178:946–955.
100. Liaudet L, Oddo M. Role of poly(adenosine diphosphate-ribose) polymerase 1 in septic peritonitis. Curr Opin Crit Care. 2003;9:152–158.
101. Wongsrichanalai C, Namsiripongpun V, Pornsilapatip J, Kyle DE, Wilde H. Sensitivity of QBC malaria test. Lancet. 1992;340:792–793.
102. Soriano FG, Liaudet L, Szabo E, et al. Resistance to acute septic peritonitis in poly(ADP-ribose) polymerase-1-deficient mice. Shock. 2002;17:286–292.
103. Hotchkiss RS, Strasser A, McDunn JE, Swanson PE. Cell death. N Engl J Med. 2009;361:1570–1583.
104. Larsen FJ, Schiffer TA, Weitzberg E, Lundberg JO. Regulation of mitochondrial function and energetics by reactive nitrogen oxides. Free Radic Biol Med. 2012;53:1919–1928.
105. Szabo C, Modis K. Pathophysiological roles of peroxynitrite in circulatory shock. Shock. 2010;34(Suppl 1):4–14.
106. Brealey D, Brand M, Hargreaves I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002;360:219–223.
107. Srinivasan S, Avadhani NG. Cytochrome c oxidase dysfunction in oxidative stress. Free Radic Biol Med. 2012;53:1252–1263.
108. Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence. 2014;5:66–72.
109. Brealey D, Karyampudi S, Jacques TS, et al. Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol. 2004;286:R491–497.
110. Gentile LF, Nacionales DC, Lopez MC, et al. A better understanding of why murine models of trauma do not recapitulate the human syndrome. Crit Care Med. 2014;42:1406–1413.
111. Opitz B, Eitel J, Meixenberger K, Suttorp N. Role of Toll-like receptors, NOD-like receptors and RIG-I-like receptors in endothelial cells and systemic infections. Thromb Haemost. 2009;102:1103–1109.
112. Faure E, Equils O, Sieling PA, et al. Bacterial lipopolysaccharide activates NF-kappaB through toll-like receptor 4 (TLR-4) in cultured human dermal endothelial cells. Differential expression of TLR-4 and TLR-2 in endothelial cells. J Biol Chem. 2000;275:11058–11063.
113. Ince C, Mayeux PR, Nguyen T, et al. The endothelium in sepsis. Shock. 2016;45:259–270.
114. Colbert JF, Schmidt EP. Endothelial and microcirculatory function and dysfunction in sepsis. Clin Chest Med. 2016;37:263–275.
115. Mikacenic C, Hahn WO, Price BL, et al. Biomarkers of endothelial activation are associated with poor outcome in critical illness. PLoS ONE. 2015;10:e0141251.
116. van Ierssel SH, Van Craenenbroeck EM, Hoymans VY, Vrints CJ, Conraads VM, Jorens PG. Endothelium dependent vasomotion and in vitro markers of endothelial repair in patients with severe sepsis: An observational study. PLoS ONE. 2013;8:e69499.
117. Mostefai HA, Meziani F, Mastronardi ML, et al. Circulating microparticles from patients with septic shock exert protective role in vascular function. Am J Respir Crit Care Med. 2008;178:1148–1155.
118. Nathan C. Neutrophils and immunity: Challenges and opportunities. Nat Rev Immunol. 2006;6:173–182.
119. Link DC. Neutrophil homeostasis: A new role for stromal cell-derived factor-1. Immunol Res. 2005;32:169–178.
120. Hotchkiss RS, Nicholson DW. Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol. 2006;6:813–822.
121. Delano MJ, Thayer T, Gabrilovich S, et al. Sepsis induces early alterations in innate immunity that impact mortality to secondary infection. J Immunol. 2011;186:195–202.
122. Eash KJ, Greenbaum AM, Gopalan PK, Link DC. CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J Clin Invest. 2010;120:2423–2431.
123. Delano MJ, Kelly-Scumpia KM, Thayer TC, et al. Neutrophil mobilization from the bone marrow during polymicrobial sepsis is dependent on CXCL12 signaling. J Immunol. 2011;187:911–918.
124. Lerman YV, Lim K, Hyun YM, et al. Sepsis lethality via exacerbated tissue infiltration and TLR-induced cytokine production by neutrophils is integrin alpha3beta1-dependent. Blood. 2014;124:3515–3523.
125. Alves-Filho JC, Freitas A, Souto FO, et al. Regulation of chemokine receptor by Toll-like receptor 2 is critical to neutrophil migration and resistance to polymicrobial sepsis. Proc Natl Acad Sci USA. 2009;106:4018–4023.
126. Nacionales DC, Gentile LF, Vanzant E, et al. Aged mice are unable to mount an effective myeloid response to sepsis. J Immunol. 2014;192:612–622.
127. Delano MJ, Scumpia PO, Weinstein JS, et al. MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis. J Exp Med. 2007;204:1463–1474.
128. Davey MS, Morgan MP, Liuzzi AR, et al. Microbe-specific unconventional T cells induce human neutrophil differentiation into antigen cross-presenting cells. J Immunol. 2014;193:3704–3716.
129. Morris AC, Brittan M, Wilkinson TS, et al. C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients. Blood. 2011;117:5178–5188.
130. Wilkinson TS, Morris AC, Kefala K, et al. Ventilator-associated pneumonia is characterized by excessive release of neutrophil proteases in the lung. Chest. 2012;142:1425–1432.
131. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–1535.
132. Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science. 2015;349:316–320.
133. Sorensen OE, Borregaard N. Neutrophil extracellular traps – The dark side of neutrophils. J Clin Invest. 2016;126:1612–1620.
134. McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe. 2012;12:324–333.
135. Czaikoski PG, Mota JM, Nascimento DC, et al. Neutrophil extracellular traps induce organ damage during experimental and clinical sepsis. PLoS ONE. 2016;11:e0148142.
136. Cheadle WG, Wilson M, Hershman MJ, Bergamini D, Richardson JD, Polk HC Jr. Comparison of trauma assessment scores and their use in prediction of infection and death. Ann Surg. 1989;209:541–545; discussion 545-546.
137. Livingston DH, Appel SH, Wellhausen SR, Sonnenfeld G, Polk HC Jr. Depressed interferon gamma production and monocyte HLA-DR expression after severe injury. Arch Surg. 1988;123:1309–1312.
138. Munoz C, Carlet J, Fitting C, Misset B, Bleriot JP, Cavaillon JM. Dysregulation of in vitro cytokine production by monocytes during sepsis. J Clin Invest. 1991;88:1747–1754.
139. Docke WD, Randow F, Syrbe U, et al. Monocyte deactivation in septic patients: Restoration by IFN-gamma treatment. Nat Med. 1997;3:678–681.
140. Cazalis MA, Friggeri A, Cave L, et al. Decreased HLA-DR antigen-associated invariant chain (CD74) mRNA expression predicts mortality after septic shock. Crit Care. 2013;17:R287.
141. Cheron A, Floccard B, Allaouchiche B, et al. Lack of recovery in monocyte human leukocyte antigen-DR expression is independently associated with the development of sepsis after major trauma. Crit Care. 2010;14:R208.
142. Landelle C, Lepape A, Voirin N, et al. Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med. 2010;36:1859–1866.
143. + regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J Immunol. 2006;177:6540–6547.
144. Monneret G, Venet F, Pachot A, Lepape A. Monitoring immune dysfunctions in the septic patient: A new skin for the old ceremony. Mol Med. 2008;14:64–78.
145. Carson WF, Cavassani KA, Dou Y, Kunkel SL. Epigenetic regulation of immune cell functions during post-septic immunosuppression. Epigenetics. 2011;6:273–283.
146. Ishii M, Wen H, Corsa CA, et al. Epigenetic regulation of the alternatively activated macrophage phenotype. Blood. 2009;114:3244–3254.
147. Saeed S, Quintin J, Kerstens HH, et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science. 2014;345:1251086.
148. Poli A, Michel T, Theresine M, Andres E, Hentges F, Zimmer J. CD56bright natural killer (NK) cells: An important NK cell subset. Immunology. 2009;126:458–465.
149. Halstead ES, Carcillo JA, Schilling B, Greiner RJ, Whiteside TL. Reduced frequency of CD56 dim CD16 pos natural killer cells in pediatric systemic inflammatory response syndrome/sepsis patients. Pediatr Res. 2013;74:427–432.
150. Giamarellos-Bourboulis EJ, Tsaganos T, Spyridaki E, et al. Early changes of CD4-positive lymphocytes and NK cells in patients with severe Gram-negative sepsis. Crit Care. 2006;10:R166.
151. Souza-Fonseca-Guimaraes F, Parlato M, Philippart F, et al. Toll-like receptors expression and interferon-gamma production by NK cells in human sepsis. Crit Care. 2012;16:R206.
152. Chiche L, Forel JM, Thomas G, et al. Interferon-gamma production by natural killer cells and cytomegalovirus in critically ill patients. Crit Care Med. 2012;40:3162–3169.
153. Limaye AP, Kirby KA, Rubenfeld GD, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008;300:413–422.
154. Giamarellos-Bourboulis EJ. Natural killer cells in sepsis: Detrimental role for final outcome. Crit Care Med. 2014;42:1579–1580.
155. Broquet A, Roquilly A, Jacqueline C, Potel G, Caillon J, Asehnoune K. Depletion of natural killer cells increases mice susceptibility in a Pseudomonas aeruginosa pneumonia model. Crit Care Med. 2014;42:e441–450.
156. Grimaldi D, Louis S, Pene F, et al. Profound and persistent decrease of circulating dendritic cells is associated with ICU-acquired infection in patients with septic shock. Intensive Care Med. 2011;37:1438–1446.
157. Pastille E, Didovic S, Brauckmann D, et al. Modulation of dendritic cell differentiation in the bone marrow mediates sustained immunosuppression after polymicrobial sepsis. J Immunol. 2011;186:977–986.
158. Efron PA, Martins A, Minnich D, et al. Characterization of the systemic loss of dendritic cells in murine lymph nodes during polymicrobial sepsis. J Immunol. 2004;173:3035–3043.
159. + dendritic cells are required for survival in murine polymicrobial sepsis. J Immunol. 2005;175:3282–3286.
160. Toliver-Kinsky TE, Lin CY, Herndon DN, Sherwood ER. Stimulation of hematopoiesis by the Fms-like tyrosine kinase 3 ligand restores bacterial induction of Th1 cytokines in thermally injured mice. Infect Immun. 2003;71:3058–3067.
161. Ochoa JB, Bernard AC, O'Brien WE, et al. Arginase I expression and activity in human mononuclear cells after injury. Ann Surg. 2001;233:393–399.
162. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12:253–268.
163. 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.
164. + myeloid suppressor cells cause T cell dysfunction after traumatic stress. J Immunol. 2006;176:2085–2094.
165. Kelly-Scumpia KM, Scumpia PO, Delano MJ, et al. Type I interferon signaling in hematopoietic cells is required for survival in mouse polymicrobial sepsis by regulating CXCL10. J Exp Med. 2010;207:319–326.
166. Scumpia PO, Kelly-Scumpia KM, Delano MJ, et al. Cutting edge: Bacterial infection induces hematopoietic stem and progenitor cell expansion in the absence of TLR signaling. J Immunol. 2010;184:2247–2251.
167. Cartwright GE, Athens JW, Wintrobe MM. The kinetics of granulopoiesis in normal man. Blood. 1964;24:780–803.
168. McCabe A, Zhang Y, Thai V, Jones M, Jordan MB, MacNamara KC. Macrophage-lineage cells negatively regulate the hematopoietic stem cell pool in response to interferon gamma at steady state and during infection. Stem Cells. 2015;33:2294–2305.
169. Mathias B, Delmas AL, Ozrazgat-Baslanti T, et al. Human myeloid-derived suppressor cells are associated with chronic immune suppression after severe sepsis/septic shock. Ann Surg. 2016 May 9. Epub ahead of print.
170. Terashima A, Okamoto K, Nakashima T, Akira S, Ikuta K, Takayanagi H. Sepsis-induced osteoblast ablation causes immunodeficiency. Immunity. 2016;44:1434–1443.
171. Hotchkiss RS, Coopersmith CM, Karl IE. Prevention of lymphocyte apoptosis–a potential treatment of sepsis? Clin Infect Dis. 2005;41(Suppl 7):S465–469.
172. Lang JD, Matute-Bello G. Lymphocytes, apoptosis and sepsis: Making the jump from mice to humans. Crit Care. 2009;13:109.
173. Hotchkiss RS, Swanson PE, Cobb JP, Jacobson A, Buchman TG, Karl IE. Apoptosis in lymphoid and parenchymal cells during sepsis: Findings in normal and T- and B-cell-deficient mice. Crit Care Med. 1997;25:1298–1307.
174. Hotchkiss RS, Osmon SB, Chang KC, Wagner TH, Coopersmith CM, Karl IE. Accelerated lymphocyte death in sepsis occurs by both the death receptor and mitochondrial pathways. J Immunol. 2005;174:5110–5118.
175. Liu ZG, Ni SY, Chen GM, et al. Histones-mediated lymphocyte apoptosis during sepsis is dependent on p38 phosphorylation and mitochondrial permeability transition. PLoS ONE. 2013;8:e77131.
176. Grailer JJ, Fattahi F, Dick RS, Zetoune FS, Ward PA. Cutting edge: Critical role for C5aRs in the development of septic lymphopenia in mice. J Immunol. 2015;194:868–872.
177. Unsinger J, McGlynn M, Kasten KR, et al. IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol. 2010;184:3768–3779.
178. Brahmamdam P, Inoue S, Unsinger J, Chang KC, McDunn JE, Hotchkiss RS. Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J Leukoc Biol. 2010;88:233–240.
179. Holtmeier W, Kabelitz D. gammadelta T cells link innate and adaptive immune responses. Chem Immunol Allergy. 2005;86:151–183.
180. Andreu-Ballester JC, Tormo-Calandin C, Garcia-Ballesteros C, et al. Association of gammadelta T cells with disease severity and mortality in septic patients. Clin Vaccine Immunol. 2013;20:738–746.
181. Grimaldi D, Le Bourhis L, Sauneuf B, et al. Specific MAIT cell behaviour among innate-like T lymphocytes in critically ill patients with severe infections. Intensive Care Med. 2014;40:192–201.
182. Tomasello E, Bedoui S. Intestinal innate immune cells in gut homeostasis and immunosurveillance. Immunol Cell Biol. 2013;91:201–203.
183. Szabo PA, Anantha RV, Shaler CR, McCormick JK, Haeryfar SM. CD1d- and MR1-restricted T cells in sepsis. Front Immunol. 2015;6:401.
184. Gutcher I, Becher B. APC-derived cytokines and T cell polarization in autoimmune inflammation. J Clin Invest. 2007;117:1119–1127.
185. + T lymphocytes in humans. J Immunol. 2001;166:6952–6963.
186. O’sullivan ST, Lederer JA, Horgan AF, Chin DH, Mannick JA, Rodrick ML. Major injury leads to predominance of the T helper-2 lymphocyte phenotype and diminished interleukin-12 production associated with decreased resistance to infection. Ann Surg. 1995;222:482–490; discussion 490-482.
187. Pachot A, Monneret G, Voirin N, et al. Longitudinal study of cytokine and immune transcription factor mRNA expression in septic shock. Clin Immunol. 2005;114:61–69.
188. Romani L. Immunity to fungal infections. Nat Rev Immunol. 2011;11:275–288.
189. Wu HP, Chung K, Lin CY, Jiang BY, Chuang DY, Liu YC. Associations of T helper 1, 2, 17 and regulatory T lymphocytes with mortality in severe sepsis. Inflamm Res. 2013;62:751–763.
190. Smeekens SP, Ng A, Kumar V, et al. Functional genomics identifies type I interferon pathway as central for host defense against Candida albicans. Nat Commun. 2013;4:1342.
191. Spec A, Shindo Y, Burnham CA, et al. T cells from patients with Candida sepsis display a suppressive immunophenotype. Crit Care. 2016;20:15.
192. + regulatory T cell function via innate TLR2 signaling. J Clin Invest. 2006;116:2022–2032.
193. + regulatory T cells and their suppressor activity do not contribute to mortality in murine polymicrobial sepsis. J Immunol. 2006;177:7943–7949.
194. Scumpia PO, Delano MJ, Kelly-Scumpia KM, et al. Treatment with GITR agonistic antibody corrects adaptive immune dysfunction in sepsis. Blood. 2007;110:3673–3681.
195. Cavassani KA, Carson W, Moreira AP, et al. The post sepsis-induced expansion and enhanced function of regulatory T cells create an environment to potentiate tumor growth. Blood. 2010;115:4403–4411.
196. Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol. 2012;30:221–241.
197. Monserrat J, de Pablo R, Diaz-Martin D, et al. Early alterations of B cells in patients with septic shock. Crit Care. 2013;17:R105.
198. Kelly-Scumpia KM, Scumpia PO, Weinstein JS, et al. B cells enhance early innate immune responses during bacterial sepsis. J Exp Med. 2011;208:1673–1682.
199. Rauch PJ, Chudnovskiy A, Robbins CS, et al. Innate response activator B cells protect against microbial sepsis. Science. 2012;335:597–601.
200. 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.
201. Hotchkiss RS, Sherwood ER. Immunology. Getting sepsis therapy right. Science. 2015;347:1201–1202.
202. Lieschke GJ, Grail D, Hodgson G, et al. Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood. 1994;84:1737–1746.
203. Petit I, Szyper-Kravitz M, Nagler A, et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol. 2002;3:687–694.
204. Nelson S, Belknap SM, Carlson RW, et al. A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia. CAP Study Group. J Infect Dis. 1998;178:1075–1080.
205. Root RK, Lodato RF, Patrick W, et al. Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis. Crit Care Med. 2003;31:367–373.
206. Francisco-Cruz A, Aguilar-Santelises M, Ramos-Espinosa O, et al. Granulocyte-macrophage colony-stimulating factor: Not just another haematopoietic growth factor. Med Oncol. 2014;31:774.
207. Paine R 3rd, 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;40:90–97.
208. 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;180:640–648.
209. Hall MW, Knatz NL, Vetterly C, et al. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med. 2011;37:525–532.
210. Bo L, Wang F, Zhu J, Li J, Deng X. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: A meta-analysis. Crit Care. 2011;15:R58.
211. Mathias B, Szpila BE, Moore FA, Efron PA, Moldawer LL. A review of GM-CSF therapy in sepsis. Medicine (Baltimore). 2015;94:e2044.
212. Nalos M, Santner-Nanan B, Parnell G, Tang B, McLean AS, Nanan R. Immune effects of interferon gamma in persistent staphylococcal sepsis. Am J Respir Crit Care Med. 2012;185:110–112.
213. Dries DJ, Jurkovich GJ, Maier RV, et al. Effect of interferon gamma on infection-related death in patients with severe injuries. A randomized, double-blind, placebo-controlled trial. Arch Surg. 1994;129:1031–1041; discussion 1042.
214. Cheng SC, Scicluna BP, Arts RJ, et al. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat Immunol. 2016;17:406–413.
215. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227–242.
216. Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443:350–354.
217. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–2454.
218. Zhang Y, Li J, Lou J, et al. Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients. Crit Care. 2011;15:R70.
219. Wang JF, Li JB, Zhao YJ, et al. Up-regulation of programmed cell death 1 ligand 1 on neutrophils may be involved in sepsis-induced immunosuppression: An animal study and a prospective case-control study. Anesthesiology. 2015;122:852–863.
220. 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:R85.
221. Mackall CL, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol. 2011;11:330–342.
222. Perales MA, Goldberg JD, Yuan J, et al. Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation. Blood. 2012;120:4882–4891.
223. Demaret J, Dupont G, Venet F, et al. STAT5 phosphorylation in T cell subsets from septic patients in response to recombinant human interleukin-7: A pilot study. J Leukoc Biol. 2015;97:791–796.
224. Kinter AL, Godbout EJ, McNally JP, et al. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol. 2008;181:6738–6746.
225. Levy Y, Sereti I, Tambussi G, et al. Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: Results of a phase I/IIa randomized, placebo-controlled, multicenter study. Clin Infect Dis. 2012;55:291–300.
226. Pelletier M, Ratthe C, Girard D. Mechanisms involved in interleukin-15-induced suppression of human neutrophil apoptosis: Role of the anti-apoptotic Mcl-1 protein and several kinases including Janus kinase-2, p38 mitogen-activated protein kinase and extracellular signal-regulated kinases-1/2. FEBS Lett. 2002;532:164–170.
227. Inoue S, Unsinger J, Davis CG, et al. IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. J Immunol. 2010;184:1401–1409.
228. Tracey KJ. The inflammatory reflex. Nature. 2002;420:853–859.
229. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007;117:289–296.
230. Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–462.
231. Wang H, Liao H, Ochani M, et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med. 2004;10:1216–1221.
232. Ulloa L. The vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov. 2005;4:673–684.
233. Tracey KJ. Reflex control of immunity. Nat Rev Immunol. 2009;9:418–428.
234. Song XM, Li JG, Wang YL, et al. The protective effect of the cholinergic anti-inflammatory pathway against septic shock in rats. Shock. 2008;30:468–472.
235. van Westerloo DJ, Giebelen IA, Florquin S, et al. The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis. J Infect Dis. 2005;191:2138–2148.
236. Rosas-Ballina M, Tracey KJ. Cholinergic control of inflammation. J Intern Med. 2009;265:663–679.
237. Kox M, Pickkers P. Modulation of the innate immune response through the vagus nerve. Nephron. 2015;131:79–84.
238. Koopman FA, Chavan SS, Miljko S, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci USA. 2016;113:8284–8289.
239. Gabanyi I, Muller PA, Feighery L, Oliveira TY, Costa-Pinto FA, Mucida D. Neuro-immune interactions drive tissue programming in intestinal macrophages. Cell. 2016;164:378–391.
240. Tracey KJ. Reflexes in immunity. Cell. 2016;164:343–344.
241. Kempner W. The nature of leukemic blood cells as determined by their metabolism. J Clin Invest. 1939;18:291–300.
242. Newsholme P, Curi R, Gordon S, Newsholme EA. Metabolism of glucose, glutamine, long-chain fatty acids and ketone bodies by murine macrophages. Biochem J. 1986;239:121–125.
243. Newsholme P, Newsholme EA. Rates of utilization of glucose, glutamine and oleate and formation of end-products by mouse peritoneal macrophages in culture. Biochem J. 1989;261:211–218.
244. Oren R, Farnham AE, Saito K, Milofsky E, Karnovsky ML. Metabolic patterns in three types of phagocytizing cells. J Cell Biol. 1963;17:487–501.
245. Levene PA, Meyer GM. On the action of leucocytes on glucose. J Biol Chem. 1912;12:265–273.
246. Ardawi MS, Newsholme EA. Maximum activities of some enzymes of glycolysis, the tricarboxylic acid cycle and ketone-body and glutamine utilization pathways in lymphocytes of the rat. Biochem J. 1982;208:743–748.
247. Newsholme EA, Crabtree B, Ardawi MS. Glutamine metabolism in lymphocytes: Its biochemical, physiological and clinical importance. Q J Exp Physiol. 1985;70:473–489.
248. Vachharajani V, Liu T, McCall CE. Epigenetic coordination of acute systemic inflammation: Potential therapeutic targets. Expert Rev Clin Immunol. 2014;10:1141–1150.
249. Palsson-McDermott EM, O'Neill LA. The Warburg effect then and now: From cancer to inflammatory diseases. BioEssays. 2013;35:965–973.
250. Warburg O. On the origin of cancer cells. Science. 1956;123:309–314.
251. Lu H, Forbes RA, Verma A. Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem. 2002;277:23111–23115.
252. Sun Q, Chen X, Ma J, et al. Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci USA. 2011;108:4129–4134.
253. Cheng SC, Quintin J, Cramer RA, et al. mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. 2014;345:1250684.
254. Rodriguez-Prados JC, Traves PG, Cuenca J, et al. Substrate fate in activated macrophages: A comparison between innate, classic, and alternative activation. J Immunol. 2010;185:605–614.
255. Tannahill GM, Curtis AM, Adamik J, et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature. 2013;496:238–242.
256. Freemerman AJ, Johnson AR, Sacks GN, et al. Metabolic reprogramming of macrophages: Glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem. 2014;289:7884–7896.
257. Davenport EE, Burnham KL, Radhakrishnan J, et al. Genomic landscape of the individual host response and outcomes in sepsis: A prospective cohort study. Lancet Respir Med. 2016;4:259–271.
258. Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve–an integrative interface between two supersystems: The brain and the immune system. Pharmacol Rev. 2000;52:595–638.
259. Muthu K, Deng J, Romano F, et al. Thermal injury and sepsis modulates beta-adrenergic receptors and cAMP responses in monocyte-committed bone marrow cells. J Neuroimmunol. 2005;165:129–138.
260. Cohen MJ, Shankar R, Stevenson J, Fernandez R, Gamelli RL, Jones SB. Bone marrow norepinephrine mediates development of functionally different macrophages after thermal injury and sepsis. Ann Surg. 2004;240:132–141.
261. Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med. 2007;35:1599–1608.
262. Rudiger A. Beta-block the septic heart. Crit Care Med. 2010;38:S608–612.
263. Evans DG, Miles AA, Niven JS. The enhancement of bacterial infections by adrenaline. Br J Exp Pathol. 1948;29:20–39.
264. Lyte M, Freestone PP, Neal CP, et al. Stimulation of Staphylococcus epidermidis growth and biofilm formation by catecholamine inotropes. Lancet. 2003;361:130–135.
265. Freestone PP, Haigh RD, Lyte M. Specificity of catecholamine-induced growth in Escherichia coli O157:H7, Salmonella enterica and Yersinia enterocolitica. FEMS Microbiol Lett. 2007;269:221–228.
266. Freestone PP, Lyte M, Neal CP, Maggs AF, Haigh RD, Williams PH. The mammalian neuroendocrine hormone norepinephrine supplies iron for bacterial growth in the presence of transferrin or lactoferrin. J Bacteriol. 2000;182:6091–6098.
267. Ohtsuka T, Hamada M, Hiasa G, et al. Effect of beta-blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy. J Am Coll Cardiol. 2001;37:412–417.
268. Friese RS, Barber R, McBride D, Bender J, Gentilello LM. Could Beta blockade improve outcome after injury by modulating inflammatory profiles? J Trauma. 2008;64:1061–1068.
269. Tian X, Zhang L, Hou Y, et al. Effects of cAMP and beta-adrenergic receptor antagonists on the function of peripheral T helper lymphocytes in patients with heart failure. NeuroImmunoModulation. 2011;18:73–78.
270. Bergmann M, Gornikiewicz A, Sautner T, et al. Attenuation of catecholamine-induced immunosuppression in whole blood from patients with sepsis. Shock. 1999;12:421–427.
271. Christensen S, Johansen MB, Tonnesen E, et al. Preadmission beta-blocker use and 30-day mortality among patients in intensive care: A cohort study. Crit Care. 2011;15:R87.
272. Herndon DN, Rodriguez NA, Diaz EC, et al. Long-term propranolol use in severely burned pediatric patients: A randomized controlled study. Ann Surg. 2012;256:402–411.
273. Arbabi S, Campion EM, Hemmila MR, et al. Beta-blocker use is associated with improved outcomes in adult trauma patients. J Trauma. 2007;62:56–61; discussion 61-52.
274. Hart DW, Wolf SE, Ramzy PI, et al. Anabolic effects of oxandrolone after severe burn. Ann Surg. 2001;233:556–564.
275. Demling RH, Orgill DP. The anticatabolic and wound healing effects of the testosterone analog oxandrolone after severe burn injury. J Crit Care. 2000;15:12–17.
276. Wolf SE, Edelman LS, Kemalyan N, et al. Effects of oxandrolone on outcome measures in the severely burned: A multicenter prospective randomized double-blind trial. J Burn Care Res. 2006;27:131–139; discussion 140-131.
277. Delano MJ, Moldawer LL. The origins of cachexia in acute and chronic inflammatory diseases. Nutr Clin Pract. 2006;21:68–81.
278. Haney M, Gunderson EW, Rabkin J, et al. Dronabinol and marijuana in HIV-positive marijuana smokers. Caloric intake, mood, and sleep. J Acquir Immune Defic Syndr. 2007;45:545–554.
279. Li YY, Li YN, Ni JB, et al. Involvement of cannabinoid-1 and cannabinoid-2 receptors in septic ileus. Neurogastroenterol Motil. 2010;22:350–e388.
280. Gallily R, Yamin A, Waksmann Y, et al. Protection against septic shock and suppression of tumor necrosis factor alpha and nitric oxide production by dexanabinol (HU-211), a nonpsychotropic cannabinoid. J Pharmacol Exp Ther. 1997;283:918–924.
281. Pierrakos C, Vincent JL. Sepsis biomarkers: A review. Crit Care. 2010;14:R15.
282. Monneret G, Venet F. Monocyte HLA-DR in sepsis: Shall we stop following the flow? Crit Care. 2014;18:102.
283. Monneret G, Venet F. Sepsis-induced immune alterations monitoring by flow cytometry as a promising tool for individualized therapy. Cytometry B Clin Cytom. 2015;90:376–386.
284. Shao R, Fang Y, Yu H, Zhao L, Jiang Z, Li CS. Monocyte programmed death ligand-1 expression after 3-4 days of sepsis is associated with risk stratification and mortality in septic patients: A prospective cohort study. Crit Care. 2016;20:124.
285. Sironi M, Cagliani R, Forni D, Clerici M. Evolutionary insights into host-pathogen interactions from mammalian sequence data. Nat Rev Genet. 2015;16:224–236.
286. Opal SM, Dellinger RP, Vincent JL, Masur H, Angus DC. The next generation of sepsis clinical trial designs: What is next after the demise of recombinant human activated protein C?*. Crit Care Med. 2014;42:1714–1721.
287. Coffey CS, Kairalla JA. Adaptive clinical trials: Progress and challenges. Drugs in R&D. 2008;9:229–242.
288. Press WH. Bandit solutions provide unified ethical models for randomized clinical trials and comparative effectiveness research. Proc the Natl Acad Sci USA. 2009;106:22387–22392.
289. Petroni GR, Wages NA, Paux G, Dubois F. Implementation of adaptive methods in early-phase clinical trials. Stat Med. 2016: Feb 29. Epub ahead of print.