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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
1   Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota
,
Rodrigo Cartin-Ceba
1   Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota
› Author Affiliations
Further Information

Publication History

Publication Date:
28 January 2016 (online)

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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
 

  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 6 Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 2013; 13 (12) 862-874
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 17 Landry DW, Levin HR, Gallant EM , et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95 (5) 1122-1125
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 20 Casey LC. Immunologic response to infection and its role in septic shock. Crit Care Clin 2000; 16 (2) 193-213
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 30 Galley HF, Webster NR. Elevated serum bleomycin-detectable iron concentrations in patients with sepsis syndrome. Intensive Care Med 1996; 22 (3) 226-229
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 40 Slade JD, Hepburn B. Prednisone-induced alterations of circulating human lymphocyte subsets. J Lab Clin Med 1983; 101 (3) 479-487
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 42 Settipane GA, Pudupakkam RK, McGowan JH. Corticosteroid effect on immunoglobulins. J Allergy Clin Immunol 1978; 62 (3) 162-166
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 59 Osawa R, Singh N. Cytomegalovirus infection in critically ill patients: a systematic review. Crit Care 2009; 13 (3) R68
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar