Balance between Hyperinflammation and Immunosuppression in Sepsis

Hemang Yadav; Rodrigo Cartin-Ceba

doi:10.1055/s-0035-1570356

Seminars in Respiratory and Critical Care Medicine, Table of Contents

Semin Respir Crit Care Med 2016; 37(01): 042-050
DOI: 10.1055/s-0035-1570356

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Balance between Hyperinflammation and Immunosuppression in Sepsis

Hemang Yadav

¹Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota

,

Rodrigo Cartin-Ceba

¹Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota

› Author Affiliations

Abstract

Sepsis is a major cause of morbidity and mortality among hospitalized patients and the leading cause of death among patients admitted to intensive care units. The immune response in sepsis is characterized by the activation of both proinflammatory and anti-inflammatory pathways. These pathways are concurrent, starting early in the course of sepsis. Given the high burden of morbidity and mortality associated with sepsis, there is an increasing interest in immunomodulatory therapies targeted at improving outcomes in sepsis. This review will summarize current understanding about the balance between hyperinflammation and immunosuppression in sepsis and discuss the role of potential therapies to modulate these responses.

Keywords

sepsis - immunology - immunosuppression - glucocorticoid

Full Text

References

References
1 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 (5) 1167-1174
2 Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348 (16) 1546-1554
3 Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA 2014; 311 (13) 1308-1316
4 Miller III RR, Dong L, Nelson NC , et al; Intermountain Healthcare Intensive Medicine Clinical Program. Multicenter implementation of a severe sepsis and septic shock treatment bundle. Am J Respir Crit Care Med 2013; 188 (1) 77-82
5 Lagu T, Rothberg MB, Shieh MS, Pekow PS, Steingrub JS, Lindenauer PK. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med 2012; 40 (3) 754-761
6 Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 2013; 13 (12) 862-874
7 Maslove DM, Tang BM, McLean AS. Identification of sepsis subtypes in critically ill adults using gene expression profiling. Crit Care 2012; 16 (5) R183
8 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 (5) 509-517
9 Crouser ED, Julian MW, Blaho DV, Pfeiffer DR. Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med 2002; 30 (2) 276-284
10 Rosser DM, Stidwill RP, Jacobson D, Singer M. Cardiorespiratory and tissue oxygen dose response to rat endotoxemia. Am J Physiol 1996; 271 (3, Pt 2) H891-H895
11 Kirschenbaum LA, Aziz M, Astiz ME, Saha DC, Rackow EC. Influence of rheologic changes and platelet-neutrophil interactions on cell filtration in sepsis. Am J Respir Crit Care Med 2000; 161 (5) 1602-1607
12 Piagnerelli M, Boudjeltia KZ, Brohee D, Vincent JL, Vanhaeverbeek M. Modifications of red blood cell shape and glycoproteins membrane content in septic patients. Adv Exp Med Biol 2003; 510: 109-114
13 Coopersmith CM, Stromberg PE, Dunne WM , et al. Inhibition of intestinal epithelial apoptosis and survival in a murine model of pneumonia-induced sepsis. JAMA 2002; 287 (13) 1716-1721
14 Vincent JL, Zhang H, Szabo C, Preiser JC. Effects of nitric oxide in septic shock. Am J Respir Crit Care Med 2000; 161 (6) 1781-1785
15 Sharshar T, Gray F, Lorin de la Grandmaison G , et al. Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 2003; 362 (9398) 1799-1805
16 Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano Y, Boyle III WA. Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit Care Med 2001; 29 (3) 487-493
17 Landry DW, Levin HR, Gallant EM , et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95 (5) 1122-1125
18 Hoffmann JN, Werdan K, Hartl WH, Jochum M, Faist E, Inthorn D. Hemofiltrate from patients with severe sepsis and depressed left ventricular contractility contains cardiotoxic compounds. Shock 1999; 12 (3) 174-180
19 Boomer JS, Green JM, Hotchkiss RS. The changing immune system in sepsis: is individualized immuno-modulatory therapy the answer?. Virulence 2014; 5 (1) 45-56
20 Casey LC. Immunologic response to infection and its role in septic shock. Crit Care Clin 2000; 16 (2) 193-213
21 Suffredini AF, Fromm RE, Parker MM , et al. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989; 321 (5) 280-287
22 Guidet B, Barakett V, Vassal T, Petit JC, Offenstadt G. Endotoxemia and bacteremia in patients with sepsis syndrome in the intensive care unit. Chest 1994; 106 (4) 1194-1201
23 Frantz S, Ertl G, Bauersachs J. Mechanisms of disease: Toll-like receptors in cardiovascular disease. Nat Clin Pract Cardiovasc Med 2007; 4 (8) 444-454
24 Hutchins NA, Unsinger J, Hotchkiss RS, Ayala A. The new normal: immunomodulatory agents against sepsis immune suppression. Trends Mol Med 2014; 20 (4) 224-233
25 Ritter C, Andrades M, Frota Júnior ML , et al. Oxidative parameters and mortality in sepsis induced by cecal ligation and perforation. Intensive Care Med 2003; 29 (10) 1782-1789
26 Gao XP, Standiford TJ, Rahman A , et al. Role of NADPH oxidase in the mechanism of lung neutrophil sequestration and microvessel injury induced by Gram-negative sepsis: studies in p47phox-/- and gp91phox-/- mice. J Immunol 2002; 168 (8) 3974-3982
27 Goode HF, Cowley HC, Walker BE, Howdle PD, Webster NR. Decreased antioxidant status and increased lipid peroxidation in patients with septic shock and secondary organ dysfunction. Crit Care Med 1995; 23 (4) 646-651
28 Long CL, Maull KI, Krishnan RS , et al. Ascorbic acid dynamics in the seriously ill and injured. J Surg Res 2003; 109 (2) 144-148
29 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 (7) 1179-1183
30 Galley HF, Webster NR. Elevated serum bleomycin-detectable iron concentrations in patients with sepsis syndrome. Intensive Care Med 1996; 22 (3) 226-229
31 Yin H, Jin XB, Gong Q , et al. Fructose-1,6-diphosphate attenuates acute lung injury induced by lipopolysaccharide in mice. Int Immunopharmacol 2008; 8 (13–14) 1842-1847
32 Nunes FB, Simões Pires MG, Alves Filho JC, Wächter PH, Rodrigues De Oliveira J. Physiopathological studies in septic rats and the use of fructose 1,6-bisphosphate as cellular protection. Crit Care Med 2002; 30 (9) 2069-2074
33 Xie K, Yu Y, Pei Y , et al. Protective effects of hydrogen gas on murine polymicrobial sepsis via reducing oxidative stress and HMGB1 release. Shock 2010; 34 (1) 90-97
34 Angstwurm MW, Engelmann L, Zimmermann T , et al. Selenium in Intensive Care (SIC): results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock. Crit Care Med 2007; 35 (1) 118-126
35 Nathens AB, Neff MJ, Jurkovich GJ , et al. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg 2002; 236 (6) 814-822
36 Seok J, Warren HS, Cuenca AG , et al; Inflammation and Host Response to Injury, Large Scale Collaborative Research Program. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 2013; 110 (9) 3507-3512
37 Meagher LC, Cousin JM, Seckl JR, Haslett C. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J Immunol 1996; 156 (11) 4422-4428
38 Rinehart JJ, Sagone AL, Balcerzak SP, Ackerman GA, LoBuglio AF. Effects of corticosteroid therapy on human monocyte function. N Engl J Med 1975; 292 (5) 236-241
39 Borson DB, Gruenert DC. Glucocorticoids induce neutral endopeptidase in transformed human tracheal epithelial cells. Am J Physiol 1991; 260 (2, Pt 1) L83-L89
40 Slade JD, Hepburn B. Prednisone-induced alterations of circulating human lymphocyte subsets. J Lab Clin Med 1983; 101 (3) 479-487
41 Visser J, van Boxel-Dezaire A, Methorst D, Brunt T, de Kloet ER, Nagelkerken L. Differential regulation of interleukin-10 (IL-10) and IL-12 by glucocorticoids in vitro. Blood 1998; 91 (11) 4255-4264
42 Settipane GA, Pudupakkam RK, McGowan JH. Corticosteroid effect on immunoglobulins. J Allergy Clin Immunol 1978; 62 (3) 162-166
43 Winston DJ, Ho WG, Schiffman G, Champlin RE, Feig SA, Gale RP. Pneumococcal vaccination of recipients of bone marrow transplants. Arch Intern Med 1983; 143 (9) 1735-1737
44 Roquilly A, Mahe PJ, Seguin P , et al. Hydrocortisone therapy for patients with multiple trauma: the randomized controlled HYPOLYTE study. JAMA 2011; 305 (12) 1201-1209
45 Blum CA, Nigro N, Briel M , et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015; 385 (9977) 1511-1518
46 Torres A, Sibila O, Ferrer M , et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA 2015; 313 (7) 677-686
47 Siraux V, De Backer D, Yalavatti G , et al. Relative adrenal insufficiency in patients with septic shock: comparison of low-dose and conventional corticotropin tests. Crit Care Med 2005; 33 (11) 2479-2486
48 Annane D, Sébille V, Charpentier C , et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288 (7) 862-871
49 Beigel J, Eichacker P. Hydrocortisone and fludrocortisone improved 28-day survival in septic shock and adrenal insufficiency. ACP J Club 2003; 138 (2) 44
50 Sprung CL, Annane D, Keh D , et al; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008; 358 (2) 111-124
51 Annane D, Bellissant E, Bollaert PE , et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA 2009; 301 (22) 2362-2375
52 Minneci PC, Deans KJ, Eichacker PQ, Natanson C. The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis. Clin Microbiol Infect 2009; 15 (4) 308-318
53 Sligl WI, Milner Jr DA, Sundar S, Mphatswe W, Majumdar SR. Safety and efficacy of corticosteroids for the treatment of septic shock: a systematic review and meta-analysis. Clin Infect Dis 2009; 49 (1) 93-101
54 Torgersen C, Moser P, Luckner G , et al. Macroscopic postmortem findings in 235 surgical intensive care patients with sepsis. Anesth Analg 2009; 108 (6) 1841-1847
55 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 (3) 260-268
56 Kollef KE, Schramm GE, Wills AR, Reichley RM, Micek ST, Kollef MH. Predictors of 30-day mortality and hospital costs in patients with ventilator-associated pneumonia attributed to potentially antibiotic-resistant gram-negative bacteria. Chest 2008; 134 (2) 281-287
57 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 (4) R183
58 Luyt CE, Combes A, Deback C , et al. Herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation. Am J Respir Crit Care Med 2007; 175 (9) 935-942
59 Osawa R, Singh N. Cytomegalovirus infection in critically ill patients: a systematic review. Crit Care 2009; 13 (3) R68
60 Ziemann M, Sedemund-Adib B, Reiland P, Schmucker P, Hennig H. Increased mortality in long-term intensive care patients with active cytomegalovirus infection. Crit Care Med 2008; 36 (12) 3145-3150
61 Jaber S, Chanques G, Borry J , et al. Cytomegalovirus infection in critically ill patients: associated factors and consequences. Chest 2005; 127 (1) 233-241
62 Meakins JL, Pietsch JB, Bubenick O , et al. Delayed hypersensitivity: indicator of acquired failure of host defenses in sepsis and trauma. Ann Surg 1977; 186 (3) 241-250
63 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 (7) 1230-1251
64 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
65 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 (6) 3765-3772
66 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
67 Döcke WD, Randow F, Syrbe U , et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 1997; 3 (6) 678-681
68 Wasserman D, Ioannovich JD, Hinzmann RD, Deichsel G, Steinmann GG. The Severe Burns Study Group. Interferon-gamma in the prevention of severe burn-related infections: a European phase III multicenter trial. Crit Care Med 1998; 26 (3) 434-439
69 Polk Jr HC, Cheadle WG, Livingston DH , et al. A randomized prospective clinical trial to determine the efficacy of interferon-gamma in severely injured patients. Am J Surg 1992; 163 (2) 191-196
70 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 (10) 1031-1041 , discussion 1042
71 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 (7) 3768-3779
72 Rosenberg SA, Sportès C, Ahmadzadeh M , et al. IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells. J Immunother 2006; 29 (3) 313-319
73 Venet F, Foray AP, Villars-Méchin A , et al. IL-7 restores lymphocyte functions in septic patients. J Immunol 2012; 189 (10) 5073-5081
74 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 (4) 606-616
75 Lévy 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 (2) 291-300
76 Willis CR, Seamons A, Maxwell J , et al. Interleukin-7 receptor blockade suppresses adaptive and innate inflammatory responses in experimental colitis. J Inflamm (Lond) 2012; 9 (1) 39
77 Hartgring SA, Willis CR, Alcorn D , et al. Blockade of the interleukin-7 receptor inhibits collagen-induced arthritis and is associated with reduction of T cell activity and proinflammatory mediators. Arthritis Rheum 2010; 62 (9) 2716-2725
78 Bozinovski S, Jones JE, Vlahos R, Hamilton JA, Anderson GP. Granulocyte/macrophage-colony-stimulating factor (GM-CSF) regulates lung innate immunity to lipopolysaccharide through Akt/Erk activation of NFkappa B and AP-1 in vivo. J Biol Chem 2002; 277 (45) 42808-42814
79 Nelson S, Heyder AM, Stone J , et al. A randomized controlled trial of filgrastim for the treatment of hospitalized patients with multilobar pneumonia. J Infect Dis 2000; 182 (3) 970-973
80 Root RK, Lodato RF, Patrick W , et al; Pneumonia Sepsis Study Group. Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis. Crit Care Med 2003; 31 (2) 367-373
81 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 (7) 640-648
82 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 (1) R58