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Sepsis and septic shock

Nature Reviews Disease Primers volume 2, Article number: 16045 (2016) Cite this article

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Abstract

For more than two decades, sepsis was defined as a microbial infection that produces fever (or hypothermia), tachycardia, tachypnoea and blood leukocyte changes. Sepsis is now increasingly being considered a dysregulated systemic inflammatory and immune response to microbial invasion that produces organ injury for which mortality rates are declining to 15–25%. Septic shock remains defined as sepsis with hyperlactataemia and concurrent hypotension requiring vasopressor therapy, with in-hospital mortality rates approaching 30–50%. With earlier recognition and more compliance to best practices, sepsis has become less of an immediate life-threatening disorder and more of a long-term chronic critical illness, often associated with prolonged inflammation, immune suppression, organ injury and lean tissue wasting. Furthermore, patients who survive sepsis have continuing risk of mortality after discharge, as well as long-term cognitive and functional deficits. Earlier recognition and improved implementation of best practices have reduced in-hospital mortality, but results from the use of immunomodulatory agents to date have been disappointing. Similarly, no biomarker can definitely diagnose sepsis or predict its clinical outcome. Because of its complexity, improvements in sepsis outcomes are likely to continue to be slow and incremental.

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Figure 1: Cell-surface and intracellular receptors that are responsible for the recognition of microbial products and endogenous danger signals (alarmins).
Figure 2: Current conceptual model of outcomes of sepsis.
Figure 3: The late immunosuppressive effects of sepsis.
Figure 4: Changes in the vascular endothelium in response to inflammatory stimuli during sepsis.
Figure 5: Interaction between coagulation and inflammation.

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References

  1. Majno, G. The ancient riddle of σηψιζ (sepsis). J. Infect. Dis. 163, 937–945 (1991).

    Article  CAS  PubMed  Google Scholar 

  2. Bone, R. C., Sibbald, W. J. & Sprung, C. L. The ACCP-SCCM consensus conference on sepsis and organ failure. Chest 101, 1481–1483 (1992). This paper has laid the ground for our current understanding of sepsis by underlining the crucial role of the host response to infection for which the term SIRS was coined. Furthermore, it was pointed out that SIRS can also result from non-infectious causes.

    Article  CAS  PubMed  Google Scholar 

  3. Levy, M. M. et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit. Care Med. 31, 1250–1256 (2003).

    Article  PubMed  Google Scholar 

  4. Singer, M. et al. The third international consensus conference on sepsis and septic shock (Sepsis-3). JAMA 315, 801–810 (2016). The third consensus update of the definitions and clinical criteria for sepsis and septic shock. Although there has been an important effort to improve the understanding of sepsis, controversy remains as to whether these new criteria will be useful or practical as early warning signs, especially in low-income and middle-income countries where it is often difficult to obtain the required measures of organ injury.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Le, J. M. & Vilcek, J. Interleukin 6: a multifunctional cytokine regulating immune reactions and the acute phase protein response. Lab. Invest. 61, 588–602 (1989).

    CAS  PubMed  Google Scholar 

  6. Dinarello, C. A. Interleukin-1. Rev. Infect. Dis. 6, 51–95 (1984).

    Article  CAS  PubMed  Google Scholar 

  7. Beutler, B. & Cerami, A. The biology of cachectin/TNF — a primary mediator of the host response. Annu. Rev. Immunol. 7, 625–655 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Deutschman, C. S. & Tracey, K. J. Sepsis: current dogma and new perspectives. Immunity 40, 463–475 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Levi, M., Schultz, M. & van der Poll, T. Sepsis and thrombosis. Semin. Thromb. Hemost. 39, 559–566 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Opal, S. M. & van der Poll, T. Endothelial barrier dysfunction in septic shock. J. Intern. Med. 277, 277–293 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. White, L. E. et al. Acute kidney injury is surprisingly common and a powerful predictor of mortality in surgical sepsis. J. Trauma Acute Care Surg. 75, 432–438 (2013).

    Article  PubMed  Google Scholar 

  13. Kaukonen, K. M., 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 311, 1308–1316 (2014). This is a retrospective analysis of an administrative database from >100,000 patients with recorded sepsis or septic shock. Mortality significantly improved in patients with both severe sepsis and septic shock, but did so at rates that were comparable to other diagnoses.

    Article  CAS  PubMed  Google Scholar 

  14. Ferrer, R. et al. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA 299, 2294–2303 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Levy, M. M. et al. Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. Crit. Care Med. 43, 3–12 (2015). This is one of many papers to demonstrate that increasing awareness for sepsis and the initiation of quality improvement initiatives in the field of sepsis can improve patient survival.

    Article  PubMed  Google Scholar 

  16. Fleischmann, C. et al. Assessment of global incidence and mortality of hospital-treated sepsis — current estimates and limitations. Am. J. Respir. Crit. Care Med. 193, 259–272 (2016). This population-level epidemiological data from 15 international databases over the past 36 years demonstrate a high level of sepsis incidence in developed countries. By contrast, the study emphasizes the paucity of sepsis data from the developing world.

    Article  CAS  PubMed  Google Scholar 

  17. Jawad, I., Luksic, I. & Rafnsson, S. B. Assessing available information on the burden of sepsis: global estimates of incidence, prevalence and mortality. J. Glob. Health 2, 010404 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Becker, J. U., Theodosis, C., Jacob, S. T., Wira, C. R. & Groce, N. E. Surviving sepsis in low-income and middle-income countries: new directions for care and research. Lancet Infect. Dis. 9, 577–582 (2009).

    Article  PubMed  Google Scholar 

  19. Murray, C. J. & Lopez, A. D. Measuring the global burden of disease. N. Engl. J. Med. 369, 448–457 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Mayanja, B. N. et al. Septicaemia in a population-based HIV clinical cohort in rural Uganda, 1996–2007: incidence, aetiology, antimicrobial drug resistance and impact of antiretroviral therapy. Trop. Med. Int. Health 15, 697–705 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Gordon, M. A. et al. Bacteraemia and mortality among adult medical admissions in Malawi — predominance of non-typhi salmonellae and Streptococcus pneumoniae. J. Infect. 42, 44–49 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 386, 743–800 (2015).

    Article  PubMed Central  Google Scholar 

  23. van den Boogaard, W., Manzi, M., Harries, A. D. & Reid, A. J. Causes of pediatric mortality and case-fatality rates in eight Medecins Sans Frontieres-supported hospitals in Africa. Public Health Action 2, 117–121 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sundararajan, V., Macisaac, C. M., Presneill, J. J., Cade, J. F. & Visvanathan, K. Epidemiology of sepsis in Victoria, Australia. Crit. Care Med. 33, 71–80 (2005).

    Article  PubMed  Google Scholar 

  25. Seymour, C. W., Iwashyna, T. J., Cooke, C. R., Hough, C. L. & Martin, G. S. Marital status and the epidemiology and outcomes of sepsis. Chest 137, 1289–1296 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Fleischmann, C. et al. Hospital incidence and mortality rates of sepsis. Dtsch. Arztebl. Int. 113, 159–166 (2016).

    PubMed  PubMed Central  Google Scholar 

  27. Dombrovskiy, V. Y., Martin, A. A., Sunderram, J. & Paz, H. L. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit. Care Med. 35, 1244–1250 (2007).

    Article  PubMed  Google Scholar 

  28. Martin, G. S., Mannino, D. M., Eaton, S. & Moss, M. The epidemiology of sepsis in the United States from 1979 through 2000. N. Engl. J. Med. 348, 1546–1554 (2003).

    Article  PubMed  Google Scholar 

  29. Liu, V. et al. Hospital deaths in patients with sepsis from 2 independent cohorts. JAMA 312, 90–92 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Lagu, T. et al. What is the best method for estimating the burden of severe sepsis in the United States? J. Crit. Care 27, 414.e1–414.e9 (2012).

    Article  Google Scholar 

  31. Gaieski, D. F., Edwards, J. M., Kallan, M. J. & Carr, B. G. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit. Care Med. 41, 1167–1174 (2013). The incidence and outcome of sepsis were estimated using four different published methods; depending on the methods of data abstraction, the incidence of sepsis in the United States could vary as much as 3.5-fold.

    Article  PubMed  Google Scholar 

  32. Rhee, C., Gohil, S. & Klompas, M. Regulatory mandates for sepsis care — reasons for caution. N. Engl. J. Med. 370, 1673–1676 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Whittaker, S. A. et al. Severe sepsis cohorts derived from claims-based strategies appear to be biased toward a more severely ill patient population. Crit. Care Med. 41, 945–953 (2013).

    Article  PubMed  Google Scholar 

  34. Iwashyna, T. J. & Angus, D. C. Declining case fatality rates for severe sepsis: good data bring good news with ambiguous implications. JAMA 311, 1295–1297 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. McPherson, D. et al. Sepsis-associated mortality in England: an analysis of multiple cause of death data from 2001 to 2010. BMJ Open 3, e002586 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Vincent, J. L. et al. Sepsis in European intensive care units: results of the SOAP study. Crit. Care Med. 34, 344–353 (2006).

    Article  PubMed  Google Scholar 

  37. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Tang, D., Kang, R., Coyne, C. B., Zeh, H. J. & Lotze, M. T. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol. Rev. 249, 158–175 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bierhaus, A. & Nawroth, P. P. Modulation of the vascular endothelium during infection — the role of NF-kappa B activation. Contrib. Microbiol. 10, 86–105 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Parikh, S. M. Dysregulation of the angiopoietin–Tie-2 axis in sepsis and ARDS. Virulence 4, 517–524 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Guo, R. F. & Ward, P. A. Role of C5a in inflammatory responses. Annu. Rev. Immunol. 23, 821–852 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Ward, P. A. The harmful role of C5a on innate immunity in sepsis. J. Innate Immun. 2, 439–445 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Stevens, J. H. et al. Effects of anti-C5a antibodies on the adult respiratory distress syndrome in septic primates. J. Clin. Invest. 77, 1812–1816 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Czermak, B. J. et al. Protective effects of C5a blockade in sepsis. Nat. Med. 5, 788–792 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Rittirsch, D. et al. Functional roles for C5a receptors in sepsis. Nat. Med. 14, 551–557 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Garcia, C. C. et al. Complement C5 activation during influenza A infection in mice contributes to neutrophil recruitment and lung injury. PLoS ONE 8, e64443 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sun, S. et al. Inhibition of complement activation alleviates acute lung injury induced by highly pathogenic avian influenza H5N1 virus infection. Am. J. Respir. Cell. Mol. Biol. 49, 221–230 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Sun, S. et al. Treatment with anti-C5a antibody improves the outcome of H7N9 virus infection in African green monkeys. Clin. Infect. Dis. 60, 586–595 (2015). This paper demonstrates the potential beneficial effects of complement inhibition in a clinically relevant monkey model of viral infection.

    Article  CAS  PubMed  Google Scholar 

  49. US National Library of Medicine. Studying complement inhibition in early, newly developing septic organ dysfunction (SCIENS). ClinicalTrials.govhttp://clinicaltrials.gov/ct2/show/NCT02246595 (2014).

  50. Gentile, L. F. et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J. Trauma Acute Care Surg. 72, 1491–1501 (2012). This paper provides a description of a phenotype of individuals who survived sepsis or critical illness who exhibit PICS. The authors propose that as early treatments for sepsis and trauma improve, this phenotype will predominate in survivors, especially the elderly.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hu, D. et al. Persistent inflammation–immunosuppression catabolism syndrome, a common manifestation of patients with enterocutaneous fistula in intensive care unit. J. Trauma Acute Care Surg. 76, 725–729 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Vanzant, E. L. et al. Persistent inflammation, immunosuppression, and catabolism syndrome after severe blunt trauma. J. Trauma Acute Care Surg. 76, 21–29; discussion 29–30 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Rubartelli, A. & Lotze, M. T. Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol. 28, 429–436 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Walton, A. H. et al. Reactivation of multiple viruses in patients with sepsis. PLoS ONE 9, e98819 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Kollef, K. E. et al. Predictors of 30-day mortality and hospital costs in patients with ventilator-associated pneumonia attributed to potentially antibiotic-resistant Gram-negative bacteria. Chest 134, 281–287 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Otto, G. P. et al. The late phase of sepsis is characterized by an increased microbiological burden and death rate. Crit. Care 15, R183 (2011). An important publication that documents that the majority of patients with protracted sepsis develop infections with ‘opportunistic-type pathogens’, thereby strongly supporting the concept of sepsis progressing to an immunosuppressive disorder.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Torgersen, C. et al. Macroscopic postmortem findings in 235 surgical intensive care patients with sepsis. Anesth. Analg. 108, 1841–1847 (2009).

    Article  PubMed  Google Scholar 

  58. Delano, M. J. et al. MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis. J. Exp. Med. 204, 1463–1474 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Taneja, R., Sharma, A. P., Hallett, M. B., Findlay, G. P. & Morris, M. R. Immature circulating neutrophils in sepsis have impaired phagocytosis and calcium signaling. Shock 30, 618–622 (2008).

    Article  PubMed  Google Scholar 

  60. Munoz, C. et al. Dysregulation of in vitro cytokine production by monocytes during sepsis. J. Clin. Invest. 88, 1747–1754 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cuenca, A. G. et al. A paradoxical role for myeloid-derived suppressor cells in sepsis and trauma. Mol. Med. 17, 281–292 (2011). A study demonstrating that the expansion of MDSCs in sepsis can be associated with the preservation of innate immunity, even in the presence of adaptive immune suppression.

    Article  CAS  PubMed  Google Scholar 

  62. Drifte, G., Dunn-Siegrist, I., Tissieres, P. & Pugin, J. Innate immune functions of immature neutrophils in patients with sepsis and severe systemic inflammatory response syndrome. Crit. Care Med. 41, 820–832 (2013).

    Article  CAS  PubMed  Google Scholar 

  63. Hashiba, M. et al. Neutrophil extracellular traps in patients with sepsis. J. Surg. Res. 194, 248–254 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Hynninen, M. et al. Predictive value of monocyte histocompatibility leukocyte antigen-DR expression and plasma interleukin-4 and -10 levels in critically ill patients with sepsis. Shock 20, 1–4 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Boomer, J. S. et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 306, 2594–2605 (2011). This is the first study to show that immune effector cells in tissues from patients dying of sepsis have severe impairment of stimulated cytokine production. This study also demonstrated that ‘T cell exhaustion’ is a likely mechanism that contributes to immunosuppression in patients with sepsis, providing a rationale for the use of immune checkpoint inhibitors as a novel potential therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Meakins, J. L. et al. Delayed hypersensitivity: indicator of acquired failure of host defenses in sepsis and trauma. Ann. Surg. 186, 241–250 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hotchkiss, R. S. et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit. Care Med. 27, 1230–1251 (1999). This is the first study to show that patients with sepsis develop profound loss of immune effector cells via apoptosis, establishing that sepsis-induced apoptosis is a major immunosuppressive mechanism in sepsis.

    Article  CAS  PubMed  Google Scholar 

  68. Hotchkiss, R. S. et al. Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc. Natl Acad. Sci. USA 96, 14541–14546 (1999). This paper encourages more research on immune augmentatory approaches in sepsis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Drewry, A. M. et al. Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock 42, 383–391 (2014). This is a study that demonstrated that a sustained low total lymphocyte count was associated with increased mortality. Although the mechanisms are unclear, the data reveal that a commonly obtained clinical measurement can identify the severity of sepsis and organ failure.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Coopersmith, C. M. et al. Antibiotics improve survival and alter the inflammatory profile in a murine model of sepsis from Pseudomonas aeruginosa pneumonia. Shock 19, 408–414 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Bommhardt, U. et al. Akt decreases lymphocyte apoptosis and improves survival in sepsis. J. Immunol. 172, 7583–7591 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Hotchkiss, R. S. et al. Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat. Immunol. 1, 496–501 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Hotchkiss, R. S. et al. TAT-BH4 and TAT-Bcl-xL peptides protect against sepsis-induced lymphocyte apoptosis in vivo. J. Immunol. 176, 5471–5477 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Hotchkiss, R. S. et al. Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. J. Immunol. 162, 4148–4156 (1999).

    CAS  PubMed  Google Scholar 

  75. Schwulst, S. J. et al. Agonistic monoclonal antibody against CD40 receptor decreases lymphocyte apoptosis and improves survival in sepsis. J. Immunol. 177, 557–565 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Schwulst, S. J. et al. Bim siRNA decreases lymphocyte apoptosis and improves survival in sepsis. Shock 30, 127–134 (2008).

    CAS  PubMed  Google Scholar 

  77. Angus, D. C. & van der Poll, T. Severe sepsis and septic shock. N. Engl. J. Med. 369, 840–851 (2013). This review provides a concise update of what was known at the time and what has become a very prescient appraisal of the future of sepsis research.

    Article  CAS  PubMed  Google Scholar 

  78. Chelazzi, C., Villa, G., Mancinelli, P., De Gaudio, A. R. & Adembri, C. Glycocalyx and sepsis-induced alterations in vascular permeability. Crit. Care 19, 26 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  79. London, N. R. et al. Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Sci. Transl Med. 2, 23ra19 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Karpman, D. et al. Complement interactions with blood cells, endothelial cells and microvesicles in thrombotic and inflammatory conditions. Adv. Exp. Med. Biol. 865, 19–42 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. Zecher, D., Cumpelik, A. & Schifferli, J. A. Erythrocyte-derived microvesicles amplify systemic inflammation by thrombin-dependent activation of complement. Arterioscler. Thromb. Vasc. Biol. 34, 313–320 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Riewald, M. & Ruf, W. Science review: role of coagulation protease cascades in sepsis. Crit. Care 7, 123–129 (2003).

    Article  PubMed  Google Scholar 

  83. Shorr, A. F. et al. Protein C concentrations in severe sepsis: an early directional change in plasma levels predicts outcome. Crit. Care 10, R92 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Matsumoto, H. et al. Enhanced expression of cell-specific surface antigens on endothelial microparticles in sepsis-induced disseminated intravascular coagulation. Shock 43, 443–449 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Aird, W. C. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101, 3765–3777 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Levi, M. & van der Poll, T. Inflammation and coagulation. Crit. Care Med. 38, S26–34 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Sato, R. & Nasu, M. A review of sepsis-induced cardiomyopathy. J. Intensive Care 3, 48 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Galley, H. F. Oxidative stress and mitochondrial dysfunction in sepsis. Br. J. Anaesth. 107, 57–64 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Nizet, V. & Johnson, R. S. Interdependence of hypoxic and innate immune responses. Nat. Rev. Immunol. 9, 609–617 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ricci, Z., Polito, A., Polito, A. & Ronco, C. The implications and management of septic acute kidney injury. Nat. Rev. Nephrol. 7, 218–225 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Angus, D. C. et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 29, 1303–1310 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Watanabe, E. et al. Sepsis induces extensive autophagic vacuolization in hepatocytes: a clinical and laboratory-based study. Lab. Invest. 89, 549–561 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Scerbo, M. H. et al. Beyond blood culture and gram stain analysis: a review of molecular techniques for the early detection of bacteremia in surgical patients. Surg. Infect. (Larchmt) 17, 294–302 (2016).

    Article  Google Scholar 

  94. Vincent, J. L., Opal, S. M., Marshall, J. C. & Tracey, K. J. Sepsis definitions: time for change. Lancet 381, 774–775 (2013). A plea to abandon the SIRS criteria and return to the meaning of ‘sepsis’ to common, everyday language — a ‘bad infection’ with some degree of organ dysfunction.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Seymour, C. W. et al. Assessment of clinical criteria for sepsis: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 762–774 (2016). This review of 1.3 million electronic health records and validation with another 700,000 records identified Sepsis-related Organ Failure Assessment (SOFA) and quick SOFA (qSOFA) scores as valuable tools to predict in-hospital mortality. The qSOFA was most predictive outside the ICU, suggesting that it might be useful as a ‘prompt’ to consider sepsis in early warning systems.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Shankar-Hari, M. et al. Developing a new definition and assessing new clinical criteria for septic shock: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 775–787 (2016). This systematic review of 166,479 patients with defined septic shock has revealed a working consensus definition of septic shock as hypotension requiring vasopressor support to maintain a mean arterial blood pressure of >65 mmHg and a plasma lactate level of >2 mmol per l with adequate resuscitation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Casserly, B. et al. Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit. Care Med. 43, 567–573 (2015).

    Article  CAS  PubMed  Google Scholar 

  98. Rowland, T., Hilliard, H. & Barlow, G. Procalcitonin: potential role in diagnosis and management of sepsis. Adv. Clin. Chem. 68, 71–86 (2015).

    Article  CAS  PubMed  Google Scholar 

  99. Bloos, F. & Reinhart, K. Rapid diagnosis of sepsis. Virulence 5, 154–160 (2014).

    Article  PubMed  Google Scholar 

  100. de Jong, E. et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect. Dis. http://dx.doi.org/10.1016/S1473-3099(16)00053-0 (2016). This randomized controlled trial from 15 institutions in the Netherlands demonstrated that using procalcitonin concentrations to dictate antibiotic cessation reduced antibiotic duration by 2 days and reduced in-hospital mortality.

  101. Westwood, M. et al. Procalcitonin testing to guide antibiotic therapy for the treatment of sepsis in intensive care settings and for suspected bacterial infection in emergency department settings: a systematic review and cost-effectiveness analysis. Health Technol. Assess. 19, 1–236 (2015).

    PubMed  PubMed Central  Google Scholar 

  102. Schuetz, P. et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst. Rev. 9, CD007498 (2012).

    Google Scholar 

  103. O'Grady, N. P. Guidelines for the prevention of intravascular catheter-related infections. Clin. Infect. Dis. 52, e162–e193 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Kumar, A. et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 136, 1237–1248 (2009).

    Article  PubMed  Google Scholar 

  105. Zahar, J. R. et al. Outcomes in severe sepsis and patients with septic shock: pathogen species and infection sites are not associated with mortality. Crit. Care Med. 39, 1886–1895 (2011).

    Article  PubMed  Google Scholar 

  106. Kumar, A. et al. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis. Crit. Care Med. 38, 1773–1785 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Micek, S. T. et al. Empiric combination antibiotic therapy is associated with improved outcome against sepsis due to Gram-negative bacteria: a retrospective analysis. Antimicrob. Agents Chemother. 54, 1742–1748 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sprung, C. L. et al. An evaluation of systemic inflammatory response syndrome signs in the Sepsis Occurrence In Acutely Ill Patients (SOAP) study. Intensive Care Med. 32, 421–427 (2006).

    Article  PubMed  Google Scholar 

  109. Vincent, J. L. et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 302, 2323–2329 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Heenen, S., Jacobs, F. & Vincent, J. L. Antibiotic strategies in severe nosocomial sepsis: why do we not de-escalate more often? Crit. Care Med. 40, 1404–1409 (2012).

    Article  CAS  PubMed  Google Scholar 

  111. Vincent, J. L. & De Backer, D. Circulatory shock. N. Engl. J. Med. 370, 583 (2014).

    CAS  PubMed  Google Scholar 

  112. Dellinger, R. P. et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 39, 165–228 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Rivers, E. et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N. Engl. J. Med. 345, 1368–1377 (2001). This seminal clinical trial demonstrates that EGDT bundles could significantly reduce mortality in patients with severe sepsis or septic shock. This study played a major supportive part in the use of standardized treatment bundles.

    Article  CAS  PubMed  Google Scholar 

  114. ProCESS Investigators et al. A randomized trial of protocol-based care for early septic shock. N. Engl. J. Med. 370, 1683–1693 (2014). This is an important and somewhat controversial study showing that EGDT did not improve 60-day survival in patients with severe sepsis and septic shock. These data were inconsistent with results by Rivers et al. (reference 113) found 13 years earlier; the explanation is thought to do with the better management of the control groups receiving standard care.

    Article  CAS  Google Scholar 

  115. Weil, M. H. & Shubin, H. The “VIP” approach to the bedside management of shock. JAMA 207, 337–340 (1969).

    Article  CAS  PubMed  Google Scholar 

  116. Reinhart, K. et al. Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients. Intensive Care Med. 38, 368–383 (2012).

    Article  CAS  PubMed  Google Scholar 

  117. Myburgh, J. A. Fluid resuscitation in acute medicine: what is the current situation? J. Intern. Med. 277, 58–68 (2015).

    Article  CAS  PubMed  Google Scholar 

  118. De Backer, D., Aldecoa, C., Njimi, H. & Vincent, J. L. Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis. Crit. Care Med. 40, 725–730 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. De Backer, D. et al. Comparison of dopamine and norepinephrine in the treatment of shock. N. Engl. J. Med. 362, 779–789 (2010).

    Article  CAS  PubMed  Google Scholar 

  120. Jones, A. E. et al. Lactate clearance versus central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 303, 739–746 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. He, X. et al. A selective V1A receptor agonist, selepressin, is superior to arginine vasopressin and to norepinephrine in ovine septic shock. Crit. Care Med. 44, 23–31 (2016).

    Article  CAS  PubMed  Google Scholar 

  122. Marshall, J. C. Why have clinical trials in sepsis failed? Trends Mol. Med. 20, 195–203 (2014).

    Article  PubMed  Google Scholar 

  123. Alejandria, M. M., Lansang, M. A., Dans, L. F. & Mantaring, J. B. 3rd. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst. Rev. 9, CD001090 (2013).

    Google Scholar 

  124. Fisher, C. J. Jr et al. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N. Engl. J. Med. 334, 1697–1702 (1996).

    Article  CAS  PubMed  Google Scholar 

  125. Qiu, P. et al. The evolving experience with therapeutic TNF inhibition in sepsis: considering the potential influence of risk of death. Expert Opin. Investig. Drugs 20, 1555–1564 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Cross, G. et al. The epidemiology of sepsis during rapid response team reviews in a teaching hospital. Anaesth. Intensive Care 43, 193–198 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Lehman, K. D. & Thiessen, K. Sepsis guidelines: clinical practice implications. Nurse Pract. 40, 1–6 (2015).

    Article  PubMed  Google Scholar 

  128. Zubrow, M. T. et al. Improving care of the sepsis patient. Jt. Comm. J. Qual. Patient Saf. 34, 187–191 (2008).

    Article  PubMed  Google Scholar 

  129. Dowdy, D. W. et al. Quality of life in adult survivors of critical illness: a systematic review of the literature. Intensive Care Med. 31, 611–620 (2005).

    Article  PubMed  Google Scholar 

  130. Prescott, H. C., Langa, K. M., Liu, V., Escobar, G. J. & Iwashyna, T. J. Increased 1-year healthcare use in survivors of severe sepsis. Am. J. Respir. Crit. Care Med. 190, 62–69 (2014). Using an administrative database, the authors demonstrate that individuals in hospital who survived severe sepsis spent considerable time rehospitalized and had high out-of-hospital mortality rates in the year following sepsis survival.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Nelson, J. E. et al. The symptom burden of chronic critical illness. Crit. Care Med. 32, 1527–1534 (2004).

    Article  PubMed  Google Scholar 

  132. Baldwin, M. R. Measuring and predicting long-term outcomes in older survivors of critical illness. Minerva Anestesiol. 81, 650–661 (2015).

    CAS  PubMed  Google Scholar 

  133. Kaarlola, A., Tallgren, M. & Pettila, V. Long-term survival, quality of life, and quality-adjusted life-years among critically ill elderly patients. Crit. Care Med. 34, 2120–2126 (2006).

    Article  PubMed  Google Scholar 

  134. Mehlhorn, J. et al. Rehabilitation interventions for postintensive care syndrome: a systematic review. Crit. Care Med. 42, 1263–1271 (2014).

    Article  PubMed  Google Scholar 

  135. Battle, C. E., Davies, G. & Evans, P. A. Long term health-related quality of life in survivors of sepsis in South West Wales: an epidemiological study. PLoS ONE 9, e116304 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Semmler, A. et al. Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors. J. Neurol. Neurosurg. Psychiatry 84, 62–69 (2013).

    Article  PubMed  Google Scholar 

  137. Parker, A. M. et al. Posttraumatic stress disorder in critical illness survivors: a metaanalysis. Crit. Care Med. 43, 1121–1129 (2015).

    Article  PubMed  Google Scholar 

  138. Hofhuis, J. G. et al. The impact of critical illness on perceived health-related quality of life during ICU treatment, hospital stay, and after hospital discharge: a long-term follow-up study. Chest 133, 377–385 (2008).

    Article  PubMed  Google Scholar 

  139. Poulsen, J. B., Moller, K., Kehlet, H. & Perner, A. Long-term physical outcome in patients with septic shock. Acta Anaesthesiol. Scand. 53, 724–730 (2009).

    Article  CAS  PubMed  Google Scholar 

  140. Dellinger, R. P. et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit. Care Med. 32, 858–873 (2004).

    Article  PubMed  Google Scholar 

  141. Bernard, G. R. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 344, 699–709 (2001).

    Article  CAS  PubMed  Google Scholar 

  142. Lai, P. S. & Thompson, B. T. Why activated protein C was not successful in severe sepsis and septic shock: are we still tilting at windmills? Curr. Infect. Dis. Rep. 15, 407–412 (2013).

    Article  PubMed  Google Scholar 

  143. Blum, C. A. et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 385, 1511–1518 (2015).

    Article  CAS  PubMed  Google Scholar 

  144. Torres, A. 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 313, 677–686 (2015).

    Article  CAS  PubMed  Google Scholar 

  145. Kang, J. H. et al. An extracorporeal blood-cleansing device for sepsis therapy. Nat. Med. 20, 1211–1216 (2014).

    Article  CAS  PubMed  Google Scholar 

  146. Hutchins, N. A., Unsinger, J., Hotchkiss, R. S. & Ayala, A. The new normal: immunomodulatory agents against sepsis immune suppression. Trends Mol. Med. 20, 224–233 (2014). This paper surmises that, after many unsuccessful attempts to decrease the inflammatory response in randomized controlled trials, the possible place of immunostimulating strategies in sepsis is a reasonable option.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Meisel, C. 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. 180, 640–648 (2009).

    Article  CAS  PubMed  Google Scholar 

  148. US National Library of Medicine. Does GM-CSF restore neutrophil phagocytosis in critical illness? (GMCSF). ClinicalTrials.govhttp://clinicaltrials.gov/ct2/show/NCT01653665 (2012).

  149. US National Library of Medicine. The effects of interferon-gamma on sepsis-induced immunoparalysis. ClinicalTrials.govhttp://clinicaltrials.gov/ct2/show/NCT01649921 (2012).

  150. US National Library of Medicine. Safety, pharmacokinetics and pharmacodynamics of BMS-936559 in severe sepsis. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT02576457 (2015).

  151. Wu, J. et al. The efficacy of thymosin alpha 1 for severe sepsis (ETASS): a multicenter, single-blind, randomized and controlled trial. Crit. Care 17, R8 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Hotchkiss, R. S. & Moldawer, L. L. Parallels between cancer and infectious disease. N. Engl. J. Med. 371, 380–383 (2014). Sepsis and cancer have many features in common, including that both are heterogeneous conditions; the host response has an essential role in the evolution of the diseases.

    Article  CAS  PubMed  Google Scholar 

  153. Mackall, C. L., Fry, T. J. & Gress, R. E. Harnessing the biology of IL-7 for therapeutic application. Nat. Rev. Immunol. 11, 330–342 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. US National Library of Medicine. CYT107 after vaccine treatment (Provenge) in patients with metastatic hormone-resistant prostate cancer. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01881867 (2013).

  155. Levy, Y. 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. 55, 291–300 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Venet, F. et al. IL-7 restores lymphocyte functions in septic patients. J. Immunol. 189, 5073–5081 (2012).

    Article  CAS  PubMed  Google Scholar 

  157. Sweeney, T. E., Shidham, A., Wong, H. R. & Khatri, P. A comprehensive time-course-based multicohort analysis of sepsis and sterile inflammation reveals a robust diagnostic gene set. Sci. Transl Med. 7, 287ra71 (2015). Investigating a large number of publically available gene expression sets, the authors identify a pattern of gene expression that can be used to diagnose sepsis in a clear demonstration that ‘-omics’ is being used to diagnose and prognose sepsis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Maslove, D. M. & Wong, H. R. Gene expression profiling in sepsis: timing, tissue, and translational considerations. Trends Mol. Med. 20, 204–213 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Sutherland, A. et al. Development and validation of a novel molecular biomarker diagnostic test for the early detection of sepsis. Crit. Care 15, R149 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Davenport, E. E. et al. Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir. Med. 4, 259–271 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Chung, L. P. & Waterer, G. W. Genetic predisposition to respiratory infection and sepsis. Crit. Rev. Clin. Lab. Sci. 48, 250–268 (2011).

    Article  CAS  PubMed  Google Scholar 

  162. Bone, R. C. et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101, 1644–1655 (1992).

    Article  CAS  PubMed  Google Scholar 

  163. Teasdale, G. & Jennett, B. Assessment of coma and impaired consciousness. A practical scale. Lancet 2, 81–84 (1974).

    Article  CAS  PubMed  Google Scholar 

  164. Williams, M. D. et al. Hospitalized cancer patients with severe sepsis: analysis of incidence, mortality, and associated costs of care. Crit. Care 8, R291–R298 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Bone, R. C. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit. Care Med. 24, 1125–1128 (1996).

    Article  CAS  PubMed  Google Scholar 

  166. US National Library of Medicine. Trebananib in treating patients with persistent or recurrent endometrial cancer. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01210222 (2010).

  167. US National Library of Medicine. ACT-128800 in relapsing-remitting multiple sclerosis. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01006265 (2009).

  168. US National Library of Medicine. ACT-128800 in psoriasis. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT00852670 (2009).

  169. US National Library of Medicine. Efficacy of FX06 in the prevention of myocardial reperfusion injury. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT00326976 (2006).

  170. US National Library of Medicine. Safety study of PZ-128 in subjects with multiple coronary artery disease risk factors. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01806077 (2013).

  171. Thomas, G. et al. Statin therapy in critically-ill patients with severe sepsis: a review and meta-analysis of randomized clinical trials. Minerva Anestesiol. 81, 921–930 (2015).

    CAS  PubMed  Google Scholar 

  172. US National Library of Medicine. Selepressin evaluation programme for sepsis-induced shock — adaptive clinical trial (SEPSIS-ACT). ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT02508649 (2015).

  173. Wang, C. et al. Low-dose hydrocortisone therapy attenuates septic shock in adult patients but does not reduce 28-day mortality: a meta-analysis of randomized controlled trials. Anesth. Analg. 118, 346–357 (2014).

    Article  CAS  PubMed  Google Scholar 

  174. Annane, D. et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA 301, 2362–2375 (2009).

    Article  CAS  PubMed  Google Scholar 

  175. Russell, J. A. et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N. Engl. J. Med. 358, 877–887 (2008).

    Article  CAS  PubMed  Google Scholar 

  176. Angus, D. C. et al. E5 murine monoclonal antiendotoxin antibody in Gram-negative sepsis: a randomized controlled trial. E5 Study Investigators. JAMA 283, 1723–1730 (2000).

    Article  CAS  PubMed  Google Scholar 

  177. McCloskey, R. V., Straube, R. C., Sanders, C., Smith, S. M. & Smith, C. R. Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group. Ann. Intern. Med. 121, 1–5 (1994).

    Article  CAS  PubMed  Google Scholar 

  178. Dellinger, R. P. et al. Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial. Crit. Care Med. 37, 2929–2938 (2009).

    Article  CAS  PubMed  Google Scholar 

  179. Levin, M. et al. Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study Group. Lancet 356, 961–967 (2000).

    Article  CAS  PubMed  Google Scholar 

  180. Opal, S. M. et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 309, 1154–1162 (2013).

    Article  CAS  PubMed  Google Scholar 

  181. Rice, T. W. et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit. Care Med. 38, 1685–1694 (2010).

    Article  CAS  PubMed  Google Scholar 

  182. Axtelle, T. & Pribble, J. An overview of clinical studies in healthy subjects and patients with severe sepsis with IC14, a CD14-specific chimeric monoclonal antibody. J. Endotoxin Res. 9, 385–389 (2003).

    Article  CAS  PubMed  Google Scholar 

  183. Abraham, E. et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group. Lancet 351, 929–933 (1998).

    Article  CAS  PubMed  Google Scholar 

  184. Cohen, J. & Carlet, J. INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-α in patients with sepsis. International Sepsis Trial Study Group. Crit. Care Med. 24, 1431–1440 (1996).

    Article  CAS  PubMed  Google Scholar 

  185. Abraham, E. et al. Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients. Crit. Care Med. 29, 503–510 (2001).

    Article  CAS  PubMed  Google Scholar 

  186. Opal, S. M. 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. 25, 1115–1124 (1997).

    Article  CAS  PubMed  Google Scholar 

  187. Poeze, M., Froon, A. H., Ramsay, G., Buurman, W. A. & Greve, J. W. Decreased organ failure in patients with severe SIRS and septic shock treated with the platelet-activating factor antagonist TCV-309: a prospective, multicenter, double-blind, randomized phase II trial. TCV-309 Septic Shock Study Group. Shock 14, 421–428 (2000).

    Article  CAS  PubMed  Google Scholar 

  188. Suputtamongkol, Y. et al. A double-blind placebo-controlled study of an infusion of lexipafant (platelet-activating factor receptor antagonist) in patients with severe sepsis. Antimicrob. Agents Chemother. 44, 693–696 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Bernard, G. R. et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen Sepsis Study Group. N. Engl. J. Med. 336, 912–918 (1997).

    Article  CAS  PubMed  Google Scholar 

  190. Zeiher, B. G. et al. LY315920NA/S-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis. Crit. Care Med. 33, 1741–1748 (2005).

    Article  CAS  PubMed  Google Scholar 

  191. Bakker, J. et al. Administration of the nitric oxide synthase inhibitor NG-methyl-l-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144–002). Crit. Care Med. 32, 1–12 (2004).

    Article  CAS  PubMed  Google Scholar 

  192. Preiser, J. C. et al. Methylene blue administration in septic shock: a clinical trial. Crit. Care Med. 23, 259–264 (1995).

    Article  CAS  PubMed  Google Scholar 

  193. Annane, D. et al. Recombinant human activated protein C for adults with septic shock: a randomized controlled trial. Am. J. Respir. Crit. Care Med. 187, 1091–1097 (2013).

    Article  CAS  PubMed  Google Scholar 

  194. Abraham, E. et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 290, 238–247 (2003).

    Article  CAS  PubMed  Google Scholar 

  195. Warren, B. L. et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286, 1869–1878 (2001).

    Article  CAS  PubMed  Google Scholar 

  196. Morris, P. E. et al. A phase I study evaluating the pharmacokinetics, safety and tolerability of an antibody-based tissue factor antagonist in subjects with acute lung injury or acute respiratory distress syndrome. BMC Pulm. Med. 12, 5 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Zarychanski, R. et al. The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis. Crit. Care Med. 43, 511–518 (2015).

    Article  CAS  PubMed  Google Scholar 

  198. Vincent, J. L. et al. A randomized, double-blind, placebo-controlled, phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit. Care Med. 41, 2069–2079 (2013).

    Article  CAS  PubMed  Google Scholar 

  199. Kong, Z., Wang, F., Ji, S., Deng, X. & Xia, Z. Selenium supplementation for sepsis: a meta-analysis of randomized controlled trials. Am. J. Emerg. Med. 31, 1170–1175 (2013).

    Article  PubMed  Google Scholar 

  200. Fein, A. M. 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 277, 482–487 (1997).

    Article  CAS  PubMed  Google Scholar 

  201. Spapen, H. D., Diltoer, M. W., Nguyen, D. N., Hendrickx, I. & Huyghens, L. P. Effects of N-acetylcysteine on microalbuminuria and organ failure in acute severe sepsis: results of a pilot study. Chest 127, 1413–1419 (2005).

    CAS  PubMed  Google Scholar 

  202. Szakmany, T., Hauser, B. & Radermacher, P. N-acetylcysteine for sepsis and systemic inflammatory response in adults. Cochrane Database Syst. Rev. 9, CD006616 (2012).

    Google Scholar 

  203. Reinhart, K. et al. Open randomized phase II trial of an extracorporeal endotoxin adsorber in suspected Gram-negative sepsis. Crit. Care Med. 32, 1662–1668 (2004).

    Article  CAS  PubMed  Google Scholar 

  204. Flohe, S. et al. Effect of granulocyte–macrophage colony-stimulating factor on the immune response of circulating monocytes after severe trauma. Crit. Care Med. 31, 2462–2469 (2003).

    Article  CAS  PubMed  Google Scholar 

  205. Leentjens, J. et al. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am. J. Respir. Crit. Care Med. 186, 838–845 (2012).

    Article  CAS  PubMed  Google Scholar 

  206. Woods, D. R. & Mason, D. D. Six areas lead national early immunization drive. Public Health Rep. 107, 252–256 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Root, R. K. et al. Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis. Crit. Care Med. 31, 367–373 (2003).

    Article  CAS  PubMed  Google Scholar 

  208. Nelson, S. 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. 178, 1075–1080 (1998).

    Article  CAS  PubMed  Google Scholar 

  209. Dries, D. J. Interferon gamma in trauma-related infections. Intensive Care Med. 22, S462–S467 (1996).

    Article  PubMed  Google Scholar 

  210. Dries, D. J. et al. Effect of interferon gamma on infection-related death in patients with severe injuries. A randomized, double-blind, placebo-controlled trial. Arch. Surg. 129, 1031–1041; discussion 1042 (1994).

    Article  CAS  PubMed  Google Scholar 

  211. Kasten, K. R. et al. Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through γδ T-cell IL-17 production in a murine model of sepsis. Infect. Immun. 78, 4714–4722 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Unsinger, J. et al. Interleukin-7 ameliorates immune dysfunction and improves survival in a 2-hit model of fungal sepsis. J. Infect. Dis. 206, 606–616 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Inoue, S. et al. IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. J. Immunol. 184, 1401–1409 (2010).

    Article  CAS  PubMed  Google Scholar 

  214. 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, 38 mitogen-activated protein kinase and extracellular signal-regulated kinases-1/2. FEBS Lett. 532, 164–170 (2002).

    Article  CAS  PubMed  Google Scholar 

  215. Saikh, K. U., Kissner, T. L., Nystrom, S., Ruthel, G. & Ulrich, R. G. Interleukin-15 increases vaccine efficacy through a mechanism linked to dendritic cell maturation and enhanced antibody titers. Clin. Vaccine Immunol. 15, 131–137 (2008).

    Article  CAS  PubMed  Google Scholar 

  216. Chen, H., He, M. Y. & Li, Y. M. Treatment of patients with severe sepsis using ulinastatin and thymosin α1: a prospective, randomized, controlled pilot study. Chin. Med. J. (Engl.) 122, 883–888 (2009).

    CAS  Google Scholar 

  217. Chang, K. C. et al. Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis. Crit. Care 17, R85 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  218. Huang, X. et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc. Natl Acad. Sci. USA 106, 6303–6308 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. West, E. E. et al. PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. J. Clin. Invest. 123, 2604–2615 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Inoue, S. et al. Dose-dependent effect of anti-CTLA-4 on survival in sepsis. Shock 36, 38–44 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Yang, X. et al. T cell Ig mucin-3 promotes homeostasis of sepsis by negatively regulating the TLR response. J. Immunol. 190, 2068–2079 (2013).

    Article  CAS  PubMed  Google Scholar 

  222. Zhao, Z. et al. Blockade of the T cell immunoglobulin and mucin domain protein 3 pathway exacerbates sepsis-induced immune deviation and immunosuppression. Clin. Exp. Immunol. 178, 279–291 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Workman, C. J. et al. LAG-3 regulates plasmacytoid dendritic cell homeostasis. J. Immunol. 182, 1885–1891 (2009).

    Article  CAS  PubMed  Google Scholar 

  224. Durham, N. M. et al. Lymphocyte activation gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed in vivo. PLoS ONE 9, e109080 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This Primer does not promulgate the clinical use of a drug that is not approved by the US FDA or the off-label use of any FDA-approved drug.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Washington University of St. Louis, St. Louis, Missouri, USA

    Richard S. Hotchkiss & Isaiah R. Turnbull

  2. Department of Surgery, University of Florida College of Medicine, Shands Hospital, Room 6116, 1600 SW Archer Road, Gainesville, 32610-0019, Florida, USA

    Lyle L. Moldawer

  3. Department of Infectious Diseases and Medicine, Alpert Medical School of Brown University, Providence, Rhode Island, USA

    Steven M. Opal

  4. Department of Anesthesiology and Intensive Care, Jena University Hospital, Jena, Germany

    Konrad Reinhart

  5. Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium

    Jean-Louis Vincent

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  1. Richard S. Hotchkiss
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  2. Lyle L. Moldawer
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  3. Steven M. Opal
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  4. Konrad Reinhart
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  5. Isaiah R. Turnbull
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  6. Jean-Louis Vincent
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Authorship is ordered alphabetically. Introduction (L.L.M. and J.-L.V.); Epidemiology (J.-L.V., K.R. and S.M.O.); Mechanisms/pathophysiology (L.L.M., R.S.H., I.R.T. and K.R.); Diagnosis, screening and prevention (L.L.M., J.-L.V. and S.M.O.); Management (J.-L.V., S.M.O., R.S.H. and I.R.T.); Quality of life (L.L.M.); Outlook (all authors); Overview of the Primer (L.L.M.).

Corresponding author

Correspondence to Lyle L. Moldawer.

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Competing interests

R.S.H. has received no direct financial support, nor does he or his family hold patents or equity interest in any biotech or pharmaceutical company. He has received laboratory research support from Bristol-Myers Squibb, GlaxoSmithKline and Medimmune. He has served as a paid consultant to Bristol-Myers Squibb, GlaxoSmithKline, Medimmune and Merck. R.S.H. and Washington University in St Louis, Missouri, USA, have also received grant support from the US NIH, US Public Health Service for research investigations of sepsis. L.L.M. and the University of Florida College of Medicine, USA, have received financial support from the US National Institute of General Medical Sciences, US Public Health Service. No other financial support, patents or equity interest to him or his family are disclosed. S.M.O. has received no direct financial support, nor does he or his family hold patents or equity interest in any biotech or pharmaceutical company. S.M.O. and Brown University, Rhode Island, USA, have received preclinical grants in the past from the NIH, US Public Health Service, Atoxbio, GlaxoSmithKline and Arsanis, and have received financial support for assistance with clinical trial coordination from Asahi Kasei, Ferring, Cardeas and Biocartis. S.M.O. serves as a member of the Data Safety and Monitoring Board (DSMB) for Paratek (for Omadcycline), Acheogen (for Placomicin) and Bristol-Myers Squibb (anti-PDL1 monoclonal antibody). He also serves on the DSMB for two NIH-funded studies: one examining procalcitonin-guided antibiotic administration and the other investigating early intervention for community-acquired sepsis. S.M.O. serves as a paid consultant for BioAegis, Arsanis, Aridis, Batelle and Cyon on various biodefense and monoclonal antibody projects. He also receives royalty payments from Elsevier publishers for the textbook entitled, Infectious Diseases 4th edition. K.R. holds an equity interest in InflaRx and is a paid consultant for Adrenomed. J.-L.V. and I.R.T. declare no competing interests.

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Hotchkiss, R., Moldawer, L., Opal, S. et al. Sepsis and septic shock. Nat Rev Dis Primers 2, 16045 (2016). https://doi.org/10.1038/nrdp.2016.45

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