Sepsis: The Road Ahead

  • Jianfeng Xie
  • Craig M. Coopersmith


  • Remarkable progress has been made in understanding the pathophysiology of sepsis.

  • New insights into sepsis have not been associated with new treatments for sepsis.

  • The road ahead will include improved recognition of sepsis.

  • The road ahead will include improved compliance with evidence-based management of sepsis.

  • The road ahead will lead to an increased understanding of the global burden of sepsis.

  • The road ahead will have increased screening and better methods for identifying sepsis.

  • The road ahead will lead to include precision medicine approaches for entry into clinical trials as well as new trial designs for sepsis.

  • The road ahead will lead to improvements in the diagnosis of both infection and sepsis.

  • The road ahead will lead to a more robust understanding of both organ dysfunction and the dysregulated host response in sepsis.

  • Although numerous pathways of discovery will be undertaken, especially promising routes include modulating both the microbiome and the immune system.


Sepsis Future Screening Identification Diagnosis Treatment Discovery Microbiome Immune system Precision medicine 


  1. 1.
    Marshall JC. Sepsis: rethinking the approach to clinical research. J Leukoc Biol. 2008;83(3):471–82.CrossRefGoogle Scholar
  2. 2.
    Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486–552.CrossRefGoogle Scholar
  3. 3.
    McDermott KW, Elixhauser A, Sun R. Trends in Hospital Inpatient Stays in the United States, 2005–2014. Healthcare cost and utilization project (HCUP) 2017;Available from:
  4. 4.
    Kaukonen KM, Bailey M, Suzuki S, et al. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA. 2014;311(13):1308–16.CrossRefGoogle Scholar
  5. 5.
    Levy MM, Rhodes A, Phillips GS, et al. Surviving sepsis campaign: association between performance metrics and outcomes in a 7.5-year study. Crit Care Med. 2015;43(1):3–12.CrossRefGoogle Scholar
  6. 6.
    Seymour CW, Rea TD, Kahn JM, et al. Severe sepsis in pre-hospital emergency care: analysis of incidence, care, and outcome. Am J Respir Crit Care Med. 2012;186(12):1264–71.CrossRefGoogle Scholar
  7. 7.
    Dellinger RP, Carlet JM, Masur H, et al. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32(3):858–73.CrossRefGoogle Scholar
  8. 8.
    Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296–327.CrossRefGoogle Scholar
  9. 9.
    Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580–637.CrossRefGoogle Scholar
  10. 10.
    Making health care safer—think sepsis. Time matters. https://www.cdcgov/vitalsigns/sepsis/2017. Accessed 1 Aug 2017.
  11. 11.
    Reinhart K, Daniels R, Kissoon N, et al. Recognizing sepsis as a global health priority—a WHO resolution. N Engl J Med. 2017;377:414–7.CrossRefGoogle Scholar
  12. 12.
    THRIVE. Society of Critical Care Medicine 2017. Available from: Accessed 1 Aug 2017.
  13. 13.
    Phua J, Koh Y, Du B, et al. Management of severe sepsis in patients admitted to Asian intensive care units: prospective cohort study. BMJ. 2011;342:d3245.CrossRefGoogle Scholar
  14. 14.
    Levy MM, Artigas A, Phillips GS, et al. Outcomes of the surviving sepsis campaign in intensive care units in the USA and Europe: a prospective cohort study. Lancet Infect Dis. 2012;12(12):919–24.CrossRefGoogle Scholar
  15. 15.
    Masoudi FA, Ponirakis A, de Lemos JA, et al. Executive summary: trends in U.S. cardiovascular care: 2016 report From 4 ACC national cardiovascular data registries. J Am Coll Cardiol. 2017;69(11):1424–6.CrossRefGoogle Scholar
  16. 16.
    Seymour CW, Gesten F, Prescott HC, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med. 2017;376(23):2235–44.CrossRefGoogle Scholar
  17. 17.
    Rhee C, Gohil S, Klompas M. Regulatory mandates for sepsis care—reasons for caution. N Engl J Med. 2014;370(18):1673–6.CrossRefGoogle Scholar
  18. 18.
    Klompas M, Rhee C. The CMS sepsis mandate: right disease, wrong measure. Ann Intern Med. 2016;165(7):517–8.CrossRefGoogle Scholar
  19. 19.
    Shankar-Hari M, Phillips GS, Levy ML, 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. 2016;315(8):775–87.CrossRefGoogle Scholar
  20. 20.
    Torio CM, Andrews RM. National inpatient hospital costs: the most expensive conditions by payer, 2011. Statistical Brief #160. 2006 February.Google Scholar
  21. 21.
    Fleischmann C, Scherag A, Adhikari NK, et al. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med. 2016;193(3):259–72.CrossRefGoogle Scholar
  22. 22.
    Gaieski DF, Edwards JM, Kallan MJ, et al. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013;41(5):1167–74.CrossRefGoogle Scholar
  23. 23.
    Epstein L, Dantes R, Magill S, et al. Varying estimates of sepsis mortality using death certificates and administrative codes—United States, 1999–2014. MMWR Morb Mortal Wkly Rep. 2016;65(13):342–5.CrossRefGoogle Scholar
  24. 24.
    Kochanek KD, Murphy SL, Xu J, et al. Deaths: final data for 2014. Natl Vital Stat Rep. 2016;65(4):1–122.PubMedGoogle Scholar
  25. 25.
    Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303–10.CrossRefGoogle Scholar
  26. 26.
    Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348(16):1546–54.CrossRefGoogle Scholar
  27. 27.
    Dombrovskiy VY, Martin AA, Sunderram J, et al. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med. 2007;35(5):1244–50.CrossRefGoogle Scholar
  28. 28.
    Wang HE, Shapiro NI, Angus DC, et al. National estimates of severe sepsis in United States emergency departments. Crit Care Med. 2007;35(8):1928–36.CrossRefGoogle Scholar
  29. 29.
    Seymour CW, Coopersmith CM, Deutschman CS, et al. Application of a framework to assess the usefulness of alternative sepsis criteria. Crit Care Med. 2016;44(3):e122–30.CrossRefGoogle Scholar
  30. 30.
    Angus DC, Seymour CW, Coopersmith CM, et al. A framework for the development and interpretation of different sepsis definitions and clinical criteria. Crit Care Med. 2016;44(3):e113–21.CrossRefGoogle Scholar
  31. 31.
    Rhee C, Kadri S, Huang SS, et al. Objective sepsis surveillance using electronic clinical data. Infect Control Hosp Epidemiol. 2016;37(2):163–71.CrossRefGoogle Scholar
  32. 32.
    Bone RC, Balk RA, Cerra FB, 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. 1992;101(6):1644–55.CrossRefGoogle Scholar
  33. 33.
    Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):801–10.CrossRefGoogle Scholar
  34. 34.
    Frohlich S, Murphy N, Doolan A, et al. Acute respiratory distress syndrome: underrecognition by clinicians. J Crit Care. 2013;28(5):663–8.CrossRefGoogle Scholar
  35. 35.
    Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med. 2003;31(4):1250–6.CrossRefGoogle Scholar
  36. 36.
    Churpek MM, Zadravecz FJ, Winslow C, et al. Incidence and prognostic value of the systemic inflammatory response syndrome and organ dysfunctions in ward patients. Am J Respir Crit Care Med. 2015;192(8):958–64.CrossRefGoogle Scholar
  37. 37.
    Kaukonen KM, Bailey M, Pilcher D, et al. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015;372(17):1629–38.CrossRefGoogle Scholar
  38. 38.
    Vincent JL. Dear SIRS, I’m sorry to say that I don’t like you. Crit Care Med. 1997;25(2):372–4.CrossRefGoogle Scholar
  39. 39.
    Seymour CW, Liu VX, Iwashyna TJ, et al. Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):762–74.CrossRefGoogle Scholar
  40. 40.
    Sprung CL, Schein RM, Balk RA. The new sepsis consensus definitions: the good, the bad and the ugly. Intensive Care Med. 2016;42(12):2024–6.CrossRefGoogle Scholar
  41. 41.
    Simpson SQ. New sepsis criteria: a change we should not make. Chest. 2016;149(5):1117–8.CrossRefGoogle Scholar
  42. 42.
    Bhattacharjee P, Edelson DP, Churpek MM. Identifying patients with sepsis on the hospital wards. Chest. 2017;151(4):898–907.CrossRefGoogle Scholar
  43. 43.
    Abraham E. New definitions for sepsis and septic shock: continuing evolution but with much still to be done. JAMA. 2016;315(8):757–9.CrossRefGoogle Scholar
  44. 44.
    Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22(7):707–10.CrossRefGoogle Scholar
  45. 45.
    de Grooth HJ, Geenen IL, Girbes AR, et al. SOFA and mortality endpoints in randomized controlled trials: a systematic review and meta-regression analysis. Crit Care. 2017;21(1):38.CrossRefGoogle Scholar
  46. 46.
    Raith EP, Udy AA, Bailey M, et al. Prognostic accuracy of the SOFA score, SIRS criteria, and qSOFA score for in-hospital mortality among adults with suspected infection admitted to the intensive care unit. JAMA. 2017;317(3):290–300.CrossRefGoogle Scholar
  47. 47.
    Freund Y, Lemachatti N, Krastinova E, et al. Prognostic accuracy of sepsis-3 criteria for in-hospital mortality among patients with suspected infection presenting to the emergency department. JAMA. 2017;317(3):301–8.CrossRefGoogle Scholar
  48. 48.
    Churpek MM, Snyder A, Han X, et al. Quick sepsis-related organ failure assessment, systemic inflammatory response syndrome, and early warning scores for detecting clinical deterioration in infected patients outside the intensive care unit. Am J Respir Crit Care Med. 2017;195(7):906–11.CrossRefGoogle Scholar
  49. 49.
    Forward E, Konecny P, Burston J, et al. Predictive validity of the qSOFA criteria for sepsis in non-ICU inpatients. Intensive Care Med. 2017;43(6):945–6.CrossRefGoogle Scholar
  50. 50.
    Finkelsztein EJ, Jones DS, Ma KC, et al. Comparison of qSOFA and SIRS for predicting adverse outcomes of patients with suspicion of sepsis outside the intensive care unit. Crit Care. 2017;21(1):73.CrossRefGoogle Scholar
  51. 51.
    Donnelly JP, Safford MM, Shapiro NI, et al. Application of the third international consensus definitions for sepsis (sepsis-3) classification: a retrospective population-based cohort study. Lancet Infect Dis. 2017;17(6):661–70.CrossRefGoogle Scholar
  52. 52.
    Liang Z, Xie Y, Dominguez JA, et al. Intestine-specific deletion of microsomal triglyceride transfer protein increases mortality in aged mice. PLoS One. 2014;9(7):e101828.CrossRefGoogle Scholar
  53. 53.
    Dominguez JA, Xie Y, Dunne WM, et al. Intestine-specific Mttp deletion decreases mortality and prevents sepsis-induced intestinal injury in a murine model of Pseudomonas aeruginosa pneumonia. PLoS One. 2012;7(11):e49159.CrossRefGoogle Scholar
  54. 54.
    Csoka B, Nemeth ZH, Mukhopadhyay P, et al. CB2 cannabinoid receptors contribute to bacterial invasion and mortality in polymicrobial sepsis. PLoS One. 2009;4(7):e6409.CrossRefGoogle Scholar
  55. 55.
    Tschop J, Kasten KR, Nogueiras R, et al. The cannabinoid receptor 2 is critical for the host response to sepsis. J Immunol. 2009;183(1):499–505.CrossRefGoogle Scholar
  56. 56.
    Rios-Santos F, Benjamim CF, Zavery D, et al. A critical role of leukotriene B4 in neutrophil migration to infectious focus in cecal ligation and puncture sepsis. Shock. 2003;19(1):61–5.CrossRefGoogle Scholar
  57. 57.
    Eichacker PQ, Parent C, Kalil A, et al. Risk and the efficacy of antiinflammatory agents: retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med. 2002;166(9):1197–205.CrossRefGoogle Scholar
  58. 58.
    Grunwell JR, Weiss SL, Cvijanovich NZ, et al. Differential expression of the Nrf2-linked genes in pediatric septic shock. Crit Care. 2015;19:327.CrossRefGoogle Scholar
  59. 59.
    Wong HR, Cvijanovich NZ, Anas N, et al. Developing a clinically feasible personalized medicine approach to pediatric septic shock. Am J Respir Crit Care Med. 2015;191(3):309–15.CrossRefGoogle Scholar
  60. 60.
    Wong HR, Cvijanovich NZ, Anas N, et al. Prospective testing and redesign of a temporal biomarker based risk model for patients with septic shock: implications for septic shock biology. EBioMedicine. 2015;2(12):2087–93.CrossRefGoogle Scholar
  61. 61.
    Shakoory B, Carcillo JA, Chatham WW, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med. 2016;44(2):275–81.CrossRefGoogle Scholar
  62. 62.
    Buchman TG, Billiar TR, Elster E, et al. Precision medicine for critical illness and injury. Crit Care Med. 2016;44(9):1635–8.CrossRefGoogle Scholar
  63. 63.
    Perner A, Gordon AC, Angus DC, et al. The intensive care medicine research agenda on septic shock. Intensive Care Med. 2017;43:1294–305.CrossRefGoogle Scholar
  64. 64.
    Shankar-Hari M, Rubenfeld GD. The use of enrichment to reduce statistically indeterminate or negative trials in critical care. Anaesthesia. 2017;72(5):560–5.CrossRefGoogle Scholar
  65. 65.
    Yende S, Austin S, Rhodes A, et al. Long-term quality of life among survivors of severe sepsis: analyses of two international trials. Crit Care Med. 2016;44(8):1461–7.CrossRefGoogle Scholar
  66. 66.
    Annane D, Sharshar T. Cognitive decline after sepsis. Lancet Respir Med. 2015;3(1):61–9.CrossRefGoogle Scholar
  67. 67.
    Heming N, Mazeraud A, Verdonk F, et al. Neuroanatomy of sepsis-associated encephalopathy. Crit Care. 2017;21(1):65.CrossRefGoogle Scholar
  68. 68.
    Goodwin AJ, Rice DA, Simpson KN, et al. Frequency, cost, and risk factors of readmissions among severe sepsis survivors. Crit Care Med. 2015;43(4):738–46.CrossRefGoogle Scholar
  69. 69.
    Prescott HC, Langa KM, Liu V, et al. Increased 1-year healthcare use in survivors of severe sepsis. Am J Respir Crit Care Med. 2014;190(1):62–9.CrossRefGoogle Scholar
  70. 70.
    Bochud PY, Bonten M, Marchetti O, et al. Antimicrobial therapy for patients with severe sepsis and septic shock: an evidence-based review. Crit Care Med. 2004;32(11 Suppl):S495–512.CrossRefGoogle Scholar
  71. 71.
    Gupta S, Sakhuja A, Kumar G, et al. Culture-negative severe sepsis: nationwide trends and outcomes. Chest. 2016;150(6):1251–9.CrossRefGoogle Scholar
  72. 72.
    Vincent JL, Brealey D, Libert N, et al. Rapid diagnosis of infection in the critically Ill, a multicenter study of molecular detection in bloodstream infections, pneumonia, and sterile site infections. Crit Care Med. 2015;43(11):2283–91.CrossRefGoogle Scholar
  73. 73.
    Clerc O, Prod’hom G, Vogne C, et al. Impact of matrix-assisted laser desorption ionization time-of-flight mass spectrometry on the clinical management of patients with Gram-negative bacteremia: a prospective observational study. Clin Infect Dis. 2013;56(8):1101–7.CrossRefGoogle Scholar
  74. 74.
    Clerc O, Prod’hom G, Senn L, et al. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry and PCR-based rapid diagnosis of Staphylococcus aureus bacteraemia. Clin Microbiol Infect. 2014;20(4):355–60.CrossRefGoogle Scholar
  75. 75.
    Huang AM, Newton D, Kunapuli A, et al. Impact of rapid organism identification via matrix-assisted laser desorption/ionization time-of-flight combined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. Clin Infect Dis. 2013;57(9):1237–45.CrossRefGoogle Scholar
  76. 76.
    Cambau E, Durand-Zaleski I, Bretagne S, et al. Performance and economic evaluation of the molecular detection of pathogens for patients with severe infections: the EVAMICA open-label, cluster-randomised, interventional crossover trial. Intensive Care Med. 2017;43(11):1616–25.CrossRefGoogle Scholar
  77. 77.
    Buehler SS, Madison B, Snyder SR, et al. Effectiveness of practices to increase timeliness of providing targeted therapy for inpatients with bloodstream infections: a laboratory medicine best practices systematic review and meta-analysis. Clin Microbiol Rev. 2016;29(1):59–103.CrossRefGoogle Scholar
  78. 78.
    Timbrook TT, Morton JB, McConeghy KW, et al. The effect of molecular rapid diagnostic testing on clinical outcomes in bloodstream infections: a systematic review and meta-analysis. Clin Infect Dis. 2017;64(1):15–23.CrossRefGoogle Scholar
  79. 79.
    Henry KE, Hager DN, Pronovost PJ, et al. A targeted real-time early warning score (TREWScore) for septic shock. Sci Transl Med. 2015;7(299):299ra122.CrossRefGoogle Scholar
  80. 80.
    Desautels T, Calvert J, Hoffman J, et al. Prediction of sepsis in the intensive care unit with minimal electronic health record data: a machine learning approach. JMIR Med Inform. 2016;4(3):e28.CrossRefGoogle Scholar
  81. 81.
    Hassan U, Ghonge T, Reddy B Jr, et al. A point-of-care microfluidic biochip for quantification of CD64 expression from whole blood for sepsis stratification. Nat Commun. 2017;8:15949.CrossRefGoogle Scholar
  82. 82.
    Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell. 2016;164(3):337–40.CrossRefGoogle Scholar
  83. 83.
    Hayakawa M, Asahara T, Henzan N, et al. Dramatic changes of the gut flora immediately after severe and sudden insults. Dig Dis Sci. 2011;56(8):2361–5.CrossRefGoogle Scholar
  84. 84.
    Krezalek MA, Defazio J, Zaborina O, et al. The shift of an intestinal “microbiome” to a “pathobiome” governs the course and outcome of sepsis following surgical injury. Shock. 2016;45(5):475–82.CrossRefGoogle Scholar
  85. 85.
    Alverdy JC, Krezalek MA. Collapse of the microbiome, emergence of the pathobiome, and the immunopathology of sepsis. Crit Care Med. 2017;45(2):337–47.CrossRefGoogle Scholar
  86. 86.
    McDonald D, Ackermann G, Khailova L, et al. Extreme dysbiosis of the microbiome in critical illness. mSphere. 2016;1(4):e00199-16.CrossRefGoogle Scholar
  87. 87.
    Lankelma JM, van Vught LA, Belzer C, et al. Critically ill patients demonstrate large interpersonal variation in intestinal microbiota dysregulation: a pilot study. Intensive Care Med. 2017;43:59–68.CrossRefGoogle Scholar
  88. 88.
    Price R, Maclennan G, Glen J. Selective digestive or oropharyngeal decontamination and topical oropharyngeal chlorhexidine for prevention of death in general intensive care: systematic review and network meta-analysis. BMJ. 2014;348:g2197.CrossRefGoogle Scholar
  89. 89.
    Manzanares W, Lemieux M, Langlois PL, et al. Probiotic and synbiotic therapy in critical illness: a systematic review and meta-analysis. Crit Care. 2016;19:262.CrossRefGoogle Scholar
  90. 90.
    Li Q, Wang C, Tang C, et al. Successful treatment of severe sepsis and diarrhea after vagotomy utilizing fecal microbiota transplantation: a case report. Crit Care. 2015;19:37.CrossRefGoogle Scholar
  91. 91.
    Wei Y, Yang J, Wang J, et al. Successful treatment with fecal microbiota transplantation in patients with multiple organ dysfunction syndrome and diarrhea following severe sepsis. Crit Care. 2016;20(1):332.CrossRefGoogle Scholar
  92. 92.
    Fay KT, Ford ML, Coopersmith CM. The intestinal microenvironment in sepsis. Biochim Biophys Acta. 2017;1863:2574–83.CrossRefGoogle Scholar
  93. 93.
    Klingensmith NJ, Coopersmith CM. The gut as the motor of multiple organ dysfunction in critical illness. Crit Care Clin. 2016;32(2):203–12.CrossRefGoogle Scholar
  94. 94.
    Meng M, Klingensmith NJ, Coopersmith CM. New insights into the gut as the driver of critical illness and organ failure. Curr Opin Crit Care. 2017;23(2):143–8.CrossRefGoogle Scholar
  95. 95.
    Lyons JD, Coopersmith CM. Pathophysiology of the gut and the microbiome in the host response. Pediatr Crit Care Med, 2017. 18(3_suppl Suppl 1):S46–9.CrossRefGoogle Scholar
  96. 96.
    Stortz JA, Raymond SL, Mira JC, et al. Murine models of sepsis and trauma: can we bridge the gap? ILAR J. 2017;58:1–16.CrossRefGoogle Scholar
  97. 97.
    Boomer JS, Shuherk-Shaffer J, Hotchkiss RS, et al. A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis. Crit Care. 2012;16(3):R112.CrossRefGoogle Scholar
  98. 98.
    Brahmamdam P, Inoue S, Unsinger J, et al. Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J Leukoc Biol. 2010;88(2):233–40.CrossRefGoogle Scholar
  99. 99.
    Chang K, Svabek C, Vazquez-Guillamet C, et al. Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis. Crit Care. 2014;18(1):R3.CrossRefGoogle Scholar
  100. 100.
    Chang KC, Burnham CA, Compton SM, et al. Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis. Crit Care. 2013;17(3):R85.CrossRefGoogle Scholar
  101. 101.
    Shubin NJ, Chung CS, Heffernan DS, et al. BTLA expression contributes to septic morbidity and mortality by inducing innate inflammatory cell dysfunction. J Leukoc Biol. 2012;92(3):593–603.CrossRefGoogle Scholar
  102. 102.
    Shubin NJ, Monaghan SF, Heffernan DS, et al. B and T lymphocyte attenuator expression on CD4+ T-cells associates with sepsis and subsequent infections in ICU patients. Crit Care. 2013;17(6):R276.CrossRefGoogle Scholar
  103. 103.
    Chen CW, Mittal R, Klingensmith NJ, et al. Cutting edge: 2B4-mediated coinhibition of CD4+ T cells underlies mortality in experimental sepsis. J Immunol. 2017;199:1961–6.CrossRefGoogle Scholar
  104. 104.
    Delano MJ, Ward PA. Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest. 2016;126(1):23–31.CrossRefGoogle Scholar
  105. 105.
    van Vught LA, Klein Klouwenberg PM, Spitoni C, et al. Incidence, risk factors, and attributable mortality of secondary infections in the intensive care unit after admission for sepsis. JAMA. 2016;315(14):1469–79.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Critical Care MedicineZhongda Hospital, School of Medicine, Southeast UniversityNanjingChina
  2. 2.Department of Surgery and Emory Critical Care CenterEmory University School of MedicineAtlantaUSA

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