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Recent developments in severe sepsis research: from bench to bedside and back

    Orhan Rasid

    Unit Cytokines & Inflammation, Institut Pasteur, 28 rue Dr. Roux, Paris, France

    &
    Jean-Marc Cavaillon

    *Author for correspondence:

    E-mail Address: jean-marc.cavaillon@pasteur.fr

    Unit Cytokines & Inflammation, Institut Pasteur, 28 rue Dr. Roux, Paris, France

    Published Online:https://doi.org/10.2217/fmb.15.133

    Severe sepsis remains a worldwide threat, not only in industrialized countries, due to their aging population, but also in developing countries where there still are numerous cases of neonatal and puerperal sepsis. Tools for early diagnosis, a prerequisite for rapid and appropriate antibiotic therapy, are still required. In this review, we highlight some recent developments in our understanding of the associated systemic inflammatory response that help deciphering pathophysiology (e.g., epigenetic, miRNA, regulatory loops, compartmentalization, apoptosis and synergy) and discuss some of the consequences of sepsis (e.g., immune status, neurological and muscular alterations). We also emphasize the challenge to better define animal models and discuss past failures in clinical investigations in order to define new efficient therapies.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet 365(9453), 63–78 (2005).
    • 2 Levy MM, Fink MP, Marshall JC et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit. Care Med. 31(4), 1250–1256 (2003).
    • 3 Seymour CW, Rea TD, Kahn JM, Walkey AJ, Yealy DM, Angus DC. Severe sepsis in pre-hospital emergency care: analysis of incidence, care, and outcome. Am. J. Respir. Crit. Care Med. 186(12), 1264–1271 (2012). • An important demonstration of the increased incidence of sepsis in emergency rooms.
    • 4 Rhee C, Gohil S, Klompas M. Regulatory mandates for sepsis care – reasons for caution. N. Engl. J. Med. 370(18), 1673–1676 (2014).
    • 5 Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 29(7), 1303–1310 (2001). •• Provides a comprehensive review on the epidemiology of sepsis.
    • 6 Vincent JL, Sakr Y, Sprung CL et al. Sepsis in European intensive care units: results of the SOAP study. Crit. Care Med. 34(2), 344–353 (2006).
    • 7 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 311(13), 1308–1316 (2014). • An interesting demonstration of the decreased mortality due to sepsis in the recent years.
    • 8 Quartin AA, Schein RM, Kett DH, Peduzzi PN. Magnitude and duration of the effect of sepsis on survival. Department of Veterans Affairs Systemic Sepsis Cooperative Studies Group. JAMA 277(13), 1058–1063 (1997).
    • 9 Yende S, D'angelo G, Kellum JA et al. Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am. J. Respir. Crit. Care Med. 177(11), 1242–1247 (2008).
    • 10 Cavassani KA, Carson WFT, Moreira AP et al. The post sepsis-induced expansion and enhanced function of regulatory T cells create an environment to potentiate tumor growth. Blood 115(22), 4403–4411 (2010).
    • 11 Kinney MV, Kerber KJ, Black RE et al. ub-Saharan Africa's mothers, newborns, and children: where and why do they die? PLoS Med. 7(6), e1000294 (2010).
    • 12 Seale AC, Blencowe H, Zaidi A et al. Neonatal severe bacterial infection impairment estimates in South Asia, sub-Saharan Africa, and Latin America for 2010. Pediatr. Res. 74(Suppl. 1), 73–85 (2013).
    • 13 Iwashyna TJ, Cooke CR, Wunsch H, Kahn JM. Population burden of long-term survivorship after severe sepsis in older Americans. J. Am. Geriatr. Soc. 60(6), 1070–1077 (2012).
    • 14 Global Sepsis Alliance. www.world-sepsis-day.org
    • 15 Kumar A, Roberts D, Wood KE et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit. Care Med. 34(6), 1589–1596 (2006). •• Provides the key demonstration on the importance of early antibiotic treatment.
    • 16 Valles J, Rello J, Ochagavia A, Garnacho J, Alcala MA. Community-acquired bloodstream infection in critically ill adult patients: impact of shock and inappropriate antibiotic therapy on survival. Chest 123(5), 1615–1624 (2003).
    • 17 Lim SH, Mix S, Xu Z et al. Colorimetric sensor array allows fast detection and simultaneous identification of sepsis-causing bacteria in spiked blood culture. J. Clin. Microbiol. 52(2), 592–598 (2014).
    • 18 Liesenfeld O, Lehman L, Hunfeld KP, Kost G. Molecular diagnosis of sepsis: new aspects and recent developments. Eur. J. Microbiol. Immunol. (Bp) 4(1), 1–25 (2014).
    • 19 Bonacorsi S, Bidet P, Bingen E. Méthodes diagnostiques rapides des sepsis sévères en réanimation. In: Infectiologie en Réanimation. Charbonneau P, Wolff M (Eds). Springer-Verlag, Paris, France (2013).
    • 20 Fitting C, Parlato M, Adib-Conquy M et al. DNAemia detection by multiplex PCR and biomarkers for infection in systemic inflammatory response syndrome patients. PLoS ONE 7(6), e38916 (2012).
    • 21 Parlato M, Cavaillon JM. Host response biomarkers in the diagnosis of sepsis: a general overview. Methods Mol. Biol. 1237, 149–211 (2015).
    • 22 Sandquist M, Wong HR. Biomarkers of sepsis and their potential value in diagnosis, prognosis and treatment. Expert Rev. Clin. Immunol. 10(10), 1349–1356 (2014).
    • 23 Adib-Conquy M, Monchi M, Goulenok C et al. Increased plasma levels of soluble triggering receptor expressed on myeloid cells 1 and procalcitonin after cardiac surgery and cardiac arrest without infection. Shock 28(4), 406–410 (2007).
    • 24 Luyt CE, Combes A, Reynaud C et al. Usefulness of procalcitonin for the diagnosis of ventilator-associated pneumonia. Intens. Care Med. 34(8), 1434–1440 (2008).
    • 25 Facy O, Paquette B, Orry D et al. Diagnostic accuracy of inflammatory markers as early predictors of infection after elective colorectal surgery: results from the IMACORS Study. Ann. Surg. doi:10.1097/SLA.0000000000001303 (2015) (Epub ahead of print).
    • 26 Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am. J. Respir. Crit. Care Med. 177(5), 498–505 (2008).
    • 27 Kjaergaard AG, Nielsen JS, Tonnesen E, Krog J. Expression of NK cell and monocyte receptors in critically ill patients-potential biomarkers of sepsis. Scand. J. Immunol. 81(4), 249–258 (2015).
    • 28 Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit. Care 14(1), R15 (2010).
    • 29 Messer J, Eyer D, Donato L, Gallati H, Matis J, Simeoni U. Evaluation of interleukin-6 and soluble receptors of tumor necrosis factor for early diagnosis of neonatal infection. J. Pediatr. 129(4), 574–580 (1996).
    • 30 Gibot S, Bene MC, Noel R et al. Combination biomarkers to diagnose sepsis in the critically ill patient. Am. J. Respir. Crit. Care Med. 186(1), 65–71 (2012). • Identifies an efficient combination proposed for diagnosis of sepsis.
    • 31 Dimoula A, Pradier O, Kassengera Z, Dalcomune D, Turkan H, Vincent JL. Serial determinations of neutrophil CD64 expression for the diagnosis and monitoring of sepsis in critically ill patients. Clin. Infect. Dis. 58(6), 820–829 (2014). • Provides a novel approach for diagnosis and monitoring of sepsis patients.
    • 32 Oved K, Cohen A, Boico O et al. A novel host-proteome signature for distinguishing between acute bacterial and viral infections. PLoS ONE 10(3), e0120012 (2015).
    • 33 Wong HR, Walley KR, Pettila V et al. Comparing the prognostic performance of ASSIST to interleukin-6 and procalcitonin in patients with severe sepsis or septic shock. Biomarkers 20(2), 132–135 (2015).
    • 34 Skibsted S, Bhasin MK, Aird WC, Shapiro NI. Bench-to-bedside review: future novel diagnostics for sepsis – a systems biology approach. Crit. Care 17(5), 231 (2013).
    • 35 Rogers AJ, Mcgeachie M, Baron RM et al. Metabolomic derangements are associated with mortality in critically ill adult patients. PLoS ONE 9(1), e87538 (2014).
    • 36 Langley RJ, Tsalik EL, Van Velkinburgh JC et al. An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci. Transl. Med. 5(195), 195ra195 (2013).
    • 37 Kamisoglu K, Haimovich B, Calvano SE et al. Human metabolic response to systemic inflammation: assessment of the concordance between experimental endotoxemia and clinical cases of sepsis/SIRS. Crit. Care 19, 71 (2015).
    • 38 Mickiewicz B, Tam P, Jenne CN et al. Integration of metabolic and inflammatory mediator profiles as a potential prognostic approach for septic shock in the intensive care unit. Crit. Care 19, 11 (2015).
    • 39 Pachot A, Lepape A, Vey S, Bienvenu J, Mougin B, Monneret G. Systemic transcriptional analysis in survivor and non-survivor septic shock patients: a preliminary study. Immunol. Lett. 106(1), 63–71 (2006).
    • 40 Ramilo O, Allman W, Chung W et al. Gene expression patterns in blood leukocytes discriminate patients with acute infections. Blood 109(5), 2066–2077 (2007).
    • 41 Tang BM, Mclean AS, Dawes IW, Huang SJ, Cowley MJ, Lin RC. Gene-expression profiling of gram-positive and gram-negative sepsis in critically ill patients. Crit. Care Med. 36(4), 1125–1128 (2008).
    • 42 Johnson SB, Lissauer M, Bochicchio GV, Moore R, Cross AS, Scalea TM. Gene expression profiles differentiate between sterile SIRS and early sepsis. Ann. Surg. 245(4), 611–621 (2007).
    • 43 Tang BM, Mclean AS, Dawes IW, Huang SJ, Lin RC. Gene-expression profiling of peripheral blood mononuclear cells in sepsis. Crit. Care Med. 37(3), 882–888 (2009).
    • 44 Tsalik EL, Langley RJ, Dinwiddie DL et al. An integrated transcriptome and expressed variant analysis of sepsis survival and death. Genome Med. 6(11), 111 (2014).
    • 45 Severino P, Silva E, Baggio-Zappia GL et al. Patterns of gene expression in peripheral blood mononuclear cells and outcomes from patients with sepsis secondary to community acquired pneumonia. PLoS ONE 9(3), e91886 (2014).
    • 46 Shanley TP, Cvijanovich N, Lin R et al. Genome-level longitudinal expression of signaling pathways and gene networks in pediatric septic shock. Mol. Med. 13(9–10), 495–508 (2007).
    • 47 Wynn JL, Cvijanovich NZ, Allen GL et al. The influence of developmental age on the early transcriptomic response of children with septic shock. Mol. Med. 17(11–12), 1146–1156 (2011).
    • 48 Almansa R, Heredia-Rodriguez M, Gomez-Sanchez E et al. Transcriptomic correlates of organ failure extent in sepsis. J. Infect. 70(5), 445–456 (2015).
    • 49 Tang BM, Mclean AS, Dawes IW, Huang SJ, Lin RC. The use of gene-expression profiling to identify candidate genes in human sepsis. Am. J. Respir. Crit. Care Med. 176(7), 676–684 (2007).
    • 50 Shalova IN, Lim JY, Chittezhath M et al. Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1alpha. Immunity 42(3), 484–498 (2015). • A further insight into the mechanisms of leukocyte reprogramming.
    • 51 Maier M, Wutzler S, Bauer M, Trendafilov P, Henrich D, Marzi I. Altered gene expression patterns in dendritic cells after severe trauma: implications for systemic inflammation and organ injury. Shock 30(4), 344–351 (2008).
    • 52 McHugh L, Seldon T, Brandon R et al. A molecular host response assay to discriminate between sepsis and systemic inflammatory response syndrome. PLoS Med. 12(12), e1001916 (2015).
    • 53 How CK, Hou SK, Shih HC et al. Expression profile of microRNAs in gram-negative bacterial sepsis. Shock 43(2), 121–127 (2015).
    • 54 Zhou J, Chaudhry H, Zhong Y et al. Dysregulation in microRNA expression in peripheral blood mononuclear cells of sepsis patients is associated with immunopathology. Cytokine 71(1), 89–100 (2015).
    • 55 Zhang AQ, Gu W, Zeng L et al. Genetic variants of microRNA sequences and susceptibility to sepsis in patients with major blunt trauma. Ann. Surg. 261(1), 189–196 (2015).
    • 56 Fink MP, Warren HS. Strategies to improve drug development for sepsis. Nat. Rev. Drug Discov. 13(10), 741–758 (2014).
    • 57 Seok J, Warren HS, Cuenca AG et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl Acad. Sci. USA 110(9), 3507–3512 (2013).
    • 58 Osuchowski MF, Remick DG, Lederer JA et al. Abandon the mouse research ship? Not just yet! Shock 41(6), 463–475 (2014).
    • 59 Takao K, Miyakawa T. Genomic responses in mouse models greatly mimic human inflammatory diseases. Proc. Natl Acad. Sci. USA 112(4), 1167–1172 (2015).
    • 60 Carninci P. Genomics: mice in the ENCODE spotlight. Nature 515(7527), 346–347 (2014).
    • 61 Lin S, Lin Y, Nery JR et al. Comparison of the transcriptional landscapes between human and mouse tissues. Proc. Natl Acad. Sci. USA 111(48), 17224–17229 (2014).
    • 62 Rongvaux A, Willinger T, Martinek J et al. Development and function of human innate immune cells in a humanized mouse model. Nat. Biotechnol. 32(4), 364–372 (2014).
    • 63 Warren HS, Fitting C, Hoff E et al. Resilience to bacterial infection: difference between species could be due to proteins in serum. J. Infect. Dis. 201(2), 223–232 (2010). •• Underlines key factors responsible for the difference in sensitivity to endotoxin between mice and humans.
    • 64 Ye C, Choi JG, Abraham S et al. Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model. Proc. Natl Acad. Sci. USA 109(51), 21052–21057 (2012).
    • 65 Melican K, Michea Veloso P, Martin T, Bruneval P, Dumenil G. Adhesion of Neisseria meningitidis to dermal vessels leads to local vascular damage and purpura in a humanized mouse model. PLoS Pathog. 9(1), e1003139 (2013). • Describes a novel humanized graft mouse model for investigating pathogenesis of human pathogens in the murine system.
    • 66 Dejager L, Pinheiro I, Dejonckheere E, Libert C. Cecal ligation and puncture: the gold standard model for polymicrobial sepsis? Trends Microbiol. 19(4), 198–208 (2011).
    • 67 Gentile LF, Nacionales DC, Cuenca AG et al. Identification and description of a novel murine model for polytrauma and shock. Crit. Care Med. 41(4), 1075–1085 (2013).
    • 68 Gentile LF, Nacionales DC, Lopez MC et al. Host responses to sepsis vary in different low-lethality murine models. PLoS ONE 9(5), e94404 (2014).
    • 69 Von Kockritz-Blickwede M, Rohde M, Oehmcke S et al. Immunological mechanisms underlying the genetic predisposition to severe Staphylococcus aureus infection in the mouse model. Am. J. Pathol. 173(6), 1657–1668 (2008).
    • 70 De Albuquerque N, Baig E, Ma X et al. Murine hepatitis virus strain 1 produces a clinically relevant model of severe acute respiratory syndrome in A/J mice. J. Virol. 80, 10382–10394 (2006).
    • 71 Mostafavi S, Ortiz-Lopez A, Bogue MA et al. Variation and genetic control of gene expression in primary immunocytes across inbred mouse strains. J. Immunol. 193(9), 4485–4496 (2014).
    • 72 Wells CA, Ravasi T, Faulkner GJ et al. Genetic control of the innate immune response. BMC Immunol. 4, 5 (2003).
    • 73 Rivera J, Tessarollo L. Genetic background and the dilemma of translating mouse studies to humans. Immunity 28(1), 1–4 (2008).
    • 74 Hultgren O, Kopf M, Tarkowski A. Outcome of Staphylococcus aureus-triggered sepsis and arthritis in IL-4-deficient mice depends on the genetic background of the host. Eur. J. Immunol. 29(8), 2400–2405 (1999).
    • 75 Wei XQ, Niedbala W, Xu D, Luo ZX, Pollock KG, Brewer JM. Host genetic background determines whether IL-18 deficiency results in increased susceptibility or resistance to murine Leishmania major infection. Immunol. Lett. 94(1–2), 35–37 (2004).
    • 76 Tschop J, Kasten KR, Nogueiras R et al. The cannabinoid receptor 2 is critical for the host response to sepsis. J. Immunol. 183(1), 499–505 (2009).
    • 77 Csoka B, Nemeth ZH, Mukhopadhyay P et al. CB2 cannabinoid receptors contribute to bacterial invasion and mortality in polymicrobial sepsis. PLoS ONE 4(7), e6409 (2009).
    • 78 Vanden Berghe T, Hulpiau P, Martens L et al. Passenger mutations confound interpretation of all genetically modified congenic mice. Immunity 43(1), 200–209 (2015). •• An important issue regarding the relevance of all conclusions drawn from KO mice.
    • 79 Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172(5), 2731–2738 (2004).
    • 80 Drewry AM, Fuller BM, Skrupky LP, Hotchkiss RS. The presence of hypothermia within 24 hours of sepsis diagnosis predicts persistent lymphopenia. Crit. Care Med. 43(6), 1165–1169 (2015).
    • 81 Karp CL. Unstressing intemperate models: how cold stress undermines mouse modeling. J. Exp. Med. 209(6), 1069–1074 (2012). •• Reviews key aspects about thermoneutrality in the mouse and its influence on results obtained using murine models.
    • 82 Jiang Q, Cross AS, Singh IS, Chen TT, Viscardi RM, Hasday JD. Febrile core temperature is essential for optimal host defense in bacterial peritonitis. Infect. Immun. 68(3), 1265–1270 (2000).
    • 83 Moragues V, Pinkerton H. Variation in morbidity and mortality of murine typhus infection in mice with changes in the environmental temperature. J. Exp. Med. 79(1), 41–43 (1944).
    • 84 Gordon C. Thermal physiology of laboratory mice: defining thermoneutrality. J. Thermal Biol. 37, 654–685 (2012).
    • 85 Martin B, Ji S, Maudsley S, Mattson MP. “Control” laboratory rodents are metabolically morbid: why it matters. Proc. Natl Acad. Sci. USA 107(14), 6127–6133 (2010).
    • 86 Saito H, Sherwood ER, Varma TK, Evers BM. Effects of aging on mortality, hypothermia, and cytokine induction in mice with endotoxemia or sepsis. Mech. Ageing Dev. 124(10–12), 1047–1058 (2003).
    • 87 Nacionales DC, Szpila B, Ungaro R et al. A detailed characterization of the dysfunctional immunity and abnormal myelopoiesis induced by severe shock and trauma in the aged. J. Immunol. 195(5), 2396–2407 (2015). • An elegant insight into the differences between young and aged mice.
    • 88 Efron PA, Mohr AM, Moore FA, Moldawer LL. The future of murine sepsis and trauma research models. J. Leukoc. Biol. 98(6), 945–952 (2015).
    • 89 Fairbairn L, Kapetanovic R, Beraldi D et al. Comparative analysis of monocyte subsets in the pig. J. Immunol. 190(12), 6389–6396 (2013).
    • 90 Salgado-Pabon W, Breshears L, Spaulding AR et al. Superantigens are critical for Staphylococcus aureus infective endocarditis, sepsis, and acute kidney injury. mBio 4(4), pii: e00494–e00513 (2013).
    • 91 Barreiro LB, Marioni JC, Blekhman R, Stephens M, Gilad Y. Functional comparison of innate immune signaling pathways in primates. PLoS Genet. 6(12), e1001249 (2010).
    • 92 Souza-Fonseca-Guimaraes F, Cavaillon JM, Adib-Conquy M. Bench-to-bedside review: natural killer cells in sepsis – guilty or not guilty? Crit. Care 17(4), 235 (2013).
    • 93 Fan X, Liu Z, Jin H, Yan J, Liang HP. Alterations of dendritic cells in sepsis: featured role in immunoparalysis. BioMed. Res. Int. 2015, 903720 (2015).
    • 94 Garraud O, Hamzeh-Cognasse H, Pozzetto B, Cavaillon JM, Cognasse F. Bench-to-bedside review: platelets and active immune functions - new clues for immunopathology? Crit. Care 17(4), 236 (2013).
    • 95 Camicia G, Pozner R, De Larranaga G. Neutrophil extracellular traps in sepsis. Shock 42(4), 286–294 (2014).
    • 96 Cavaillon JM, Adib-Conquy M. Monocytes/macrophages and sepsis. Crit. Care Med. 33(12), S506–S509 (2005).
    • 97 Opal SM, Van Der Poll T. Endothelial barrier dysfunction in septic shock. J. Intern. Med. 277(3), 277–293 (2015).
    • 98 Yan Q, Sharma-Kuinkel BK, Deshmukh H et al. DUSP3 and PSME3 are associated with murine susceptibility to Staphylococcus aureus infection and human sepsis. PLoS Pathog. 10(6), e1004149 (2014).
    • 99 Singh P, Dejager L, Amand M et al. DUSP3 genetic deletion confers M2-like macrophage-dependent tolerance to septic shock. J. Immunol. 194(10), 4951–4962 (2015).
    • 100 Echtenacher B, Mannel DN, Hultner L. Critical protective role of mast cells in a model of acute septic peritonitis. Nature 381(6577), 75–77 (1996).
    • 101 Dahdah A, Gautier G, Attout T et al. Mast cells aggravate sepsis by inhibiting peritoneal macrophage phagocytosis. J. Clin. Invest. 124(10), 4577–4589 (2014).
    • 102 Weber GF, Chousterman BG, He S et al. Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis. Science 347(6227), 1260–1265 (2015). •• Describes the identification of a new partner within the cytokine network that contributes to deleterious events during sepsis.
    • 103 Venet F, Pachot A, Debard AL et al. Increased percentage of CD4+CD25+ regulatory T cells during septic shock is due to the decrease of CD4+CD25- lymphocytes. Crit. Care Med. 32(11), 2329–2331 (2004).
    • 104 Tang L, Bai J, Chung CS et al. Active players in resolution of shock/sepsis induced indirect lung injury: immunomodulatory effects of Tregs and PD-1. J. Leukoc. Biol. 96(5), 809–820 (2014). • Provides interesting experimental data on the effect of PD-1 in the suppressive mechanism of Tregs during lung injury.
    • 105 Tang L, Bai J, Chung CS et al. Programmed cell death receptor ligand 1 modulates the regulatory T cells’ capacity to repress shock/sepsis-induced indirect acute lung injury by recruiting phosphatase SRC homology region 2 domain-containing phosphatase 1. Shock 43(1), 47–54 (2015).
    • 106 Mirsoian A, Bouchlaka MN, Sckisel GD et al. Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice. J. Exp. Med. 211(12), 2373–2383 (2014). •• Makes an important demonstration on the role of adipose tissues in systemic inflammatory response syndrome.
    • 107 Starr ME, Saito M, Evers BM, Saito H. Age-associated increase in cytokine production during systemic inflammation-II: the role of IL-1beta in age-dependent IL-6 upregulation in adipose tissue. J. Gerontol. A Biol. Sci. Med. Sci. 70(12), 1508–1515 (2014).
    • 108 Waage A, Espevik T, Lamvik J. Detection of tumour necrosis factor-like cytotoxicity in serum from patients with septicaemia but not from untreated cancer patients. Scand. J. Immunol. 24(6), 739–743 (1986). •• Reports the first observation of a circulating cytokine in sepsis.
    • 109 Cavaillon JM, Adib-Conquy M, Fitting C, Adrie C, Payen D. Cytokine cascade in sepsis. Scand. J. Infect. Dis. 35(9), 535–544 (2003).
    • 110 Wang H, Ma S. The cytokine storm and factors determining the sequence and severity of organ dysfunction in multiple organ dysfunction syndrome. Am. J. Emerg. Med. 26(6), 711–715 (2008).
    • 111 Adib-Conquy M, Cavaillon JM. Stress molecules in sepsis and systemic inflammatory response syndrome. FEBS Lett. 581(19), 3723–3733 (2007).
    • 112 Jin L, Batra S, Douda DN, Palaniyar N, Jeyaseelan S. CXCL1 contributes to host defense in polymicrobial sepsis via modulating T cell and neutrophil functions. J. Immunol. 193(7), 3549–3558 (2014).
    • 113 Vanden Berghe T, Demon D, Bogaert P et al. Simultaneous targeting of IL-1 and IL-18 is required for protection against inflammatory and septic shock. Am. J. Respir. Crit. Care Med. 189(3), 282–291 (2014).
    • 114 Bang BR, Kim SJ, Yagita H, Croft M, Kang YJ. Inhibition of 4–1BBL-regulated TLR response in macrophages ameliorates endotoxin-induced sepsis in mice. Eur. J. Immunol. 45(3), 886–892 (2015).
    • 115 Cavaillon JM, Fitting C, David B. Presence of interleukin 3-like activity in the supernatants of lipopolysaccharide-stimulated mouse splenocytes. Biochem. Biophys. Res. Commun. 138(3), 1322–1327 (1986).
    • 116 Cavaillon JM, Vidard L, Boudaly S et al. Induction of interleukin-3 by interleukin-1 in the absence of other exogenous stimuli. Cell. Immunol. 129(1), 176–188 (1990).
    • 117 Cohen L, David B, Cavaillon JM. Interleukin-3 enhances cytokine production by LPS-stimulated macrophages. Immunol. Lett. 28(2), 121–126 (1991).
    • 118 Li XJ, Fu HY, Yi WJ et al. Dual role of leukotriene B4 receptor type 1 in experimental sepsis. J. Surg. Res. 193(2), 902–908 (2015).
    • 119 Riedemann NC, Guo RF, Neff TA et al. Increased C5a receptor expression in sepsis. J. Clin. Invest. 110(1), 101–108 (2002).
    • 120 Cavaillon JM. “Septic Plasma”: an immunosuppressive milieu. Am. J. Respir. Crit. Care Med. 166(11), 1417–1418 (2002).
    • 121 Gopinathan U, Brusletto BS, Olstad OK et al. IL-10 immunodepletion from meningococcal sepsis plasma induces extensive changes in gene expression and cytokine release in stimulated human monocytes. Innate Immun. 21(4), 429–449 (2015).
    • 122 Song Z, Zhang J, Zhang X et al. Interleukin 4 deficiency reverses development of secondary Pseudomonas aeruginosa pneumonia during sepsis-associated immunosuppression. J. Infect. Dis. 211(10), 1616–1627 (2015).
    • 123 Ward PA. An endogenous factor mediates shock-induced injury. Nat. Med. 19(11), 1368–1369 (2013).
    • 124 Qiang X, Yang WL, Wu R et al. Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat. Med. 19(11), 1489–1495 (2013).
    • 125 Kang J, Kim S, Cho H, Lee S. DAMPs activating innate immune responses in sepsis. Age. Res. Rev. 24(Pt A), 54–65 (2015).
    • 126 Lima CX, Souza DG, Amaral FA et al. Therapeutic effects of treatment with anti-TLR2 and anti-TLR4 monoclonal antibodies in polymicrobial sepsis. PLoS ONE 10(7), e0132336 (2015).
    • 127 Opal SM, Laterre PF, Francois B et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 309(11), 1154–1162 (2013).
    • 128 Warren HS, Amato SF, Fitting C et al. Assessment of ability of murine and human anti-lipid A monoclonal antibodies to bind and neutralize lipopolysaccharide. J. Exp. Med. 177(1), 89–97 (1993).
    • 129 Hu D, Yang X, Xiang Y et al. Inhibition of Toll-like receptor 9 attenuates sepsis-induced mortality through suppressing excessive inflammatory response. Cell. Immunol. 295(2), 92–98 (2015).
    • 130 Cavaillon JM, Adib-Conquy M. Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis. Crit. Care 10(5), 233 (2006).
    • 131 Zhu J, Duan G, Lang L et al. The bacterial component flagellin induces anti-sepsis protection through TLR-5, IL-1RN and VCAN during polymicrobial sepsis in mice. Cell. Physiol. Biochem. 36(2), 446–456 (2015).
    • 132 Cuenca AG, Joiner DN, Gentile LF et al. TRIF-dependent innate immune activation is critical for survival to neonatal gram-negative sepsis. J. Immunol. 194(3), 1169–1177 (2015).
    • 133 Santana PT, Benjamim CF, Martinez CG, Kurtenbach E, Takiya CM, Coutinho-Silva R. The P2X7 receptor contributes to the development of the exacerbated inflammatory response associated with sepsis. J. Innate Immun. 7(4), 417–427 (2015).
    • 134 Csoka B, Nemeth ZH, Toro G et al. CD39 improves survival in microbial sepsis by attenuating systemic inflammation. FASEB J. 29(1), 25–36 (2015). • Demonstrates the involvement of CD39 in controlling evolution of sepsis.
    • 135 Cohen HB, Briggs KT, Marino JP, Ravid K, Robson SC, Mosser DM. TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses. Blood 122(11), 1935–1945 (2013).
    • 136 Christaki E, Opal SM, Keith JC et al. A monoclonal antibody against RAGE alters gene expression and is protective in experimental models of sepsis and pneumococcal pneumonia. Shock 35(5), 492–498 (2011).
    • 137 Vachharajani V, Liu T, Mccall CE. Epigenetic coordination of acute systemic inflammation: potential therapeutic targets. Expert Rev. Clin. Immunol. 10(9), 1141–1150 (2014). • Offers an important review addressing the major role of epigenetic regulation during sepsis.
    • 138 Weiterer S, Uhle F, Lichtenstern C et al. Sepsis induces specific changes in histone modification patterns in human monocytes. PLoS ONE 10(3), e0121748 (2015).
    • 139 Gao R, Ma Z, Hu Y, Chen J, Shetty S, Fu J. SIRT1 restrains lung inflammasome activation in a murine model of sepsis. Am. J. Physiol. Lung Cell Mol. Physiol. 308(8), L847–L853 (2015).
    • 140 Vachharajani VT, Liu T, Brown CM et al. SIRT1 inhibition during the hypoinflammatory phenotype of sepsis enhances immunity and improves outcome. J. Leukoc. Biol. 96(5), 785–796 (2014).
    • 141 Wu M, Gu JT, Yi B, Tang ZZ, Tao GC. microRNA-23b regulates the expression of inflammatory factors in vascular endothelial cells during sepsis. Exp. Ther. Med. 9(4), 1125–1132 (2015).
    • 142 Chatterjee V, Beard RS Jr, Reynolds JJ et al. MicroRNA-147b regulates vascular endothelial barrier function by targeting ADAM15 expression. PLoS ONE 9(10), e110286 (2014).
    • 143 Ying H, Kang Y, Zhang H et al. MiR-127 modulates macrophage polarization and promotes lung inflammation and injury by activating the JNK pathway. J. Immunol. 194(3), 1239–1251 (2015).
    • 144 Moon HG, Yang J, Zheng Y, Jin Y. miR-15a/16 regulates macrophage phagocytosis after bacterial infection. J. Immunol. 193(9), 4558–4567 (2014).
    • 145 Billeter AT, Hellmann J, Roberts H et al. MicroRNA-155 potentiates the inflammatory response in hypothermia by suppressing IL-10 production. FASEB J. 28(12), 5322–5336 (2014).
    • 146 Jiang Y, Zhou H, Ma D, Chen ZK, Cai X. MicroRNA-19a and CD22 comprise a feedback loop for B cell response in sepsis. Med. Sci. Monit. 21, 1548–1555 (2015).
    • 147 Puimege L, Van Hauwermeiren F, Steeland S et al. Glucocorticoid-induced microRNA-511 protects against TNF by down-regulating TNFR1. EMBO Mol. Med. 7(8), 1004–1017 (2015).
    • 148 Cavaillon JM. The fiendish behavior of TNF can be counteracted by microRNA. EMBO Mol. Med. 7(8), 989–991 (2015).
    • 149 Lavin Y, Winter D, Blecher-Gonen R et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159(6), 1312–1326 (2014). •• Provides a convincing demonstration of the concept of compartmentalization as observed from macrophage development in organ-specific environments.
    • 150 Bomsztyk K, Mar D, An D et al. Experimental acute lung injury induces multi-organ epigenetic modifications in key angiogenic genes implicated in sepsis-associated endothelial dysfunction. Crit. Care 19, 225 (2015).
    • 151 Blanchet C, Jouvion G, Fitting C, Cavaillon JM, Adib-Conquy M. Protective or deleterious role of scavenger receptors SR-A and CD36 on host resistance to Staphylococcus aureus depends on the site of infection. PLoS ONE 9(1), e87927 (2014).
    • 152 Raschke RA, Garcia-Orr R. Hemophagocytic lymphohistiocytosis: a potentially underrecognized association with systemic inflammatory response syndrome, severe sepsis, and septic shock in adults. Chest 140(4), 933–938 (2011).
    • 153 Shakoory B, Carcillo J, Win Chatham W et al. Interleukin-1 receptor antagonist reduces mortality in sepsis patients with features of macrophage activation syndrome. Crit. Care Med. doi:10.1097/CCM.000000000000140 (2015) (Epub ahead of print).
    • 154 Cavaillon JM, Eisen D, Annane D. Is boosting the immune system in sepsis appropriate? Crit. Care 18(1), 216 (2014).
    • 155 Parlato M, Souza-Fonseca-Guimaraes F, Philippart F et al. CD24-triggered caspase-dependent apoptosis via mitochondrial membrane depolarization and reactive oxygen species production of human neutrophils is impaired in sepsis. J. Immunol. 192(5), 2449–2459 (2014).
    • 156 Vaki I, Kranidioti H, Karagianni V et al. An early circulating factor in severe sepsis modulates apoptosis of monocytes and lymphocytes. J. Leukoc. Biol. 89(3), 343–349 (2011).
    • 157 Wu CL, Wu QY, Du JJ et al. Calcium-sensing receptor in the T lymphocyte enhanced the apoptosis and cytokine secretion in sepsis. Mol. Immunol. 63(2), 337–342 (2015).
    • 158 Venet F, Davin F, Guignant C et al. Early assessment of leukocyte alterations at diagnosis of septic shock. Shock 34(4), 358–363 (2010).
    • 159 Guisset O, Dilhuydy MS, Thiebaut R et al. Decrease in circulating dendritic cells predicts fatal outcome in septic shock. Intens. Care Med. 33(1), 148–152 (2007).
    • 160 Drewry AM, Samra N, Skrupky LP, Fuller BM, Compton SM, Hotchkiss RS. Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock 42(5), 383–391 (2014).
    • 161 Zhao S, Wei Y, Xu D. Neutrophil gelatinase-associated lipocalin attenuates injury in the rat cecal ligation and puncture model of sepsis via apoptosis inhibition. Nephrology (Carlton) 20(9), 646–653 (2015).
    • 162 Zhang B, Liu Y, Zhang JS et al. Cortistatin protects myocardium from endoplasmic reticulum stress induced apoptosis during sepsis. Mol. Cell. Endocrinol. 406, 40–48 (2015).
    • 163 Fu H, Wang QS, Luo Q et al. Simvastatin inhibits apoptosis of endothelial cells induced by sepsis through upregulating the expression of Bcl-2 and downregulating Bax. World J. Emerg. Med. 5(4), 291–297 (2014).
    • 164 Liu J, Abdel-Razek O, Liu Z et al. Role of surfactant proteins A and D in sepsis-induced acute kidney injury. Shock 43(1), 31–38 (2015).
    • 165 Fang J, Lian Y, Xie K, Cai S, Wen P. Epigenetic modulation of neuronal apoptosis and cognitive functions in sepsis-associated encephalopathy. Neurol. Sci. 35(2), 283–288 (2014).
    • 166 Takebe M, Oishi H, Taguchi K et al. Inhibition of histone deacetylases protects septic mice from lung and splenic apoptosis. J. Surg. Res. 187(2), 559–570 (2014).
    • 167 Opal S, Van Der Poll T. Endothelial barrier dysfunction in septic shock. J. Intern. Med. 277, 277–295 (2015).
    • 168 Steinberg BE, Goldenberg NM, Lee WL. Do viral infections mimic bacterial sepsis? The role of microvascular permeability: a review of mechanisms and methods. Antiviral Res. 93(1), 2–15 (2012).
    • 169 London NR, Zhu W, Bozza FA et al. Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Sci. Transl. Med. 2(23), 23ra19 (2010).
    • 170 Han X, Fink MP, Uchiyama T, Yang R, Delude RL. Increased iNOS activity is essential for pulmonary epithelial tight junction dysfunction in endotoxemic mice. Am. J. Physiol. Lung Cell Mol. Physiol. 286(2), L259–L267 (2004).
    • 171 Yang R, Harada T, Mollen KP et al. Anti-HMGB1 neutralizing antibody ameliorates gut barrier dysfunction and improves survival after hemorrhagic shock. Mol. Med. 12(4–6), 105–114 (2006).
    • 172 Meng J, Yu H, Ma J et al. Morphine induces bacterial translocation in mice by compromising intestinal barrier function in a TLR-dependent manner. PLoS ONE 8(1), e54040 (2013).
    • 173 Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence 5(1), 66–72 (2014).
    • 174 Carchman EH, Whelan S, Loughran P et al. Experimental sepsis-induced mitochondrial biogenesis is dependent on autophagy, TLR4, and TLR9 signaling in liver. FASEB J. 27(12), 4703–4711 (2013).
    • 175 Quoilin C, Mouithys-Mickalad A, Lecart S, Fontaine-Aupart MP, Hoebeke M. Evidence of oxidative stress and mitochondrial respiratory chain dysfunction in an in vitro model of sepsis-induced kidney injury. Biochim. Biophys. Acta 1837(10), 1790–1800 (2014).
    • 176 Ledderose C, Bao Y, Ledderose S et al. Mitochondrial dysfunction, depleted purinergic signaling, and defective T cell vigilance and immune defense. J. Infect. Dis. 213(3), 456–464 (2016).
    • 177 Lowes DA, Webster NR, Murphy MP, Galley HF. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Br. J. Anaesth. 110(3), 472–480 (2013).
    • 178 Patil NK, Parajuli N, Macmillan-Crow LA, Mayeux PR. Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury. Am. J. Physiol. Renal Physiol. 306(7), F734–F743 (2014).
    • 179 Baudouin SV, Saunders D, Tiangyou W et al. Mitochondrial DNA and survival after sepsis: a prospective study. Lancet 366(9503), 2118–2121 (2005).
    • 180 Adib-Conquy M, Cavaillon JM. Compensatory anti-inflammatory response syndrome. Thromb. Haemost. 101(1), 36–47 (2009).
    • 181 Walton AH, Muenzer JT, Rasche D et al. Reactivation of multiple viruses in patients with sepsis. PLoS ONE 9(2), e98819 (2014).
    • 182 Heininger A, Haeberle H, Fischer I et al. Cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis. Crit. Care 15(2), R77 (2011).
    • 183 Traen S, Bochanen N, Ieven M et al. Is acyclovir effective among critically ill patients with herpes simplex in the respiratory tract? J. Clin. Virol. 60(3), 215–221 (2014).
    • 184 Kalil AC, Syed A, Rupp ME et al. Is bacteremic sepsis associated with higher mortality in transplant recipients than in nontransplant patients? A matched case-control propensity-adjusted study. Clin. Infect. Dis. 60(2), 216–222 (2015).
    • 185 Goldenberg NM, Leligdowicz A, Slutsky AS, Friedrich JO, Lee WL. Is nosocomial infection really the major cause of death in sepsis? Crit. Care 18(5), 540 (2014).
    • 186 Muszynski JA, Nofziger R, Greathouse K et al. Innate immune function predicts the development of nosocomial infection in critically injured children. Shock 42(4), 313–321 (2014).
    • 187 Hashiba M, Huq A, Tomino A et al. Neutrophil extracellular traps in patients with sepsis. J. Surg. Res. 194(1), 248–254 (2015).
    • 188 O'callaghan DJ, O'dea KP, Scott AJ, Takata M, Gordon AC. Monocyte tumor necrosis factor-alpha-converting enzyme catalytic activity and substrate shedding in sepsis and noninfectious systemic inflammation. Crit. Care Med. 43(7), 1375–1385 (2015).
    • 189 Cavaillon JM, Adrie C, Fitting C, Adib-Conquy M. Reprogramming of circulatory cells in sepsis and SIRS. J. Endotoxin Res. 11(5), 311–320 (2005).
    • 190 Muret J, Marie C, Fitting C, Payen D, Cavaillon JM. Ex vivo T-lymphocyte derived cytokine production in SIRS patients is influenced by experimental procedures. Shock 13(3), 169–174 (2000).
    • 191 Adib-Conquy M, Moine P, Asehnoune K et al. Toll-like receptor-mediated tumor necrosis factor and interleukin-10 production differ during systemic inflammation. Am. J. Respir. Crit. Care Med. 168(2), 158–164 (2003).
    • 192 Adib-Conquy M, Adrie C, Fitting C, Gattolliat O, Beyaert R, Cavaillon JM. Up-regulation of MyD88s and SIGIRR, molecules inhibiting Toll-like receptor signaling, in monocytes from septic patients. Crit. Care Med. 34(9), 2377–2385 (2006).
    • 193 Roquilly A, Braudeau C, Cinotti R et al. Impaired blood dendritic cell numbers and functions after aneurysmal subarachnoid hemorrhage. PLoS ONE 8(8), e71639 (2013).
    • 194 Suzuki A, Mitsuyama K, Koga H et al. Bifidogenic growth stimulator for the treatment of active ulcerative colitis: a pilot study. Nutrition 22(1), 76–81 (2006).
    • 195 Cavaillon JM, Adib-Conquy M, Cloez-Tayarani I, Fitting C. Immunodepression in sepsis and SIRS assessed by ex vivo cytokine production is not a generalized phenomenon: a review. J. Endotoxin Res. 7(2), 85–93 (2001).
    • 196 Gomez HG, Gonzalez SM, Londono JM et al. Immunological characterization of compensatory anti-inflammatory response syndrome in patients with severe sepsis: a longitudinal study. Crit. Care Med. 42(4), 771–780 (2014).
    • 197 Munoz C, Carlet J, Fitting C, Misset B, Bleriot JP, Cavaillon JM. Dysregulation of in vitro cytokine production by monocytes during sepsis. J. Clin. Invest. 88(5), 1747–1754 (1991).
    • 198 Kritselis I, Tzanetakou V, Adamis G et al. The level of endotoxemia in sepsis varies in relation to the underlying infection: impact on final outcome. Immunol. Lett. 152(2), 167–172 (2013).
    • 199 Pena OM, Hancock DG, Lyle NH et al. An endotoxin tolerance signature predicts sepsis and organ dysfunction at initial clinical presentation. EBioMedicine 1(1), 64–71 (2014).
    • 200 Wheeler DS, Lahni PM, Denenberg AG et al. Induction of endotoxin tolerance enhances bacterial clearance and survival in murine polymicrobial sepsis. Shock 30(3), 267–273 (2008).
    • 201 Adib-Conquy M, Adrie C, Moine P et al. NF-kappaB expression in mononuclear cells of patients with sepsis resembles that observed in lipopolysaccharide tolerance. Am. J. Respir. Crit. Care Med. 162(5), 1877–1883 (2000).
    • 202 Kobayashi K, Hernandez LD, Galan JE, Janeway CA Jr, Medzhitov R, Flavell RA. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110(2), 191–202 (2002).
    • 203 Escoll P, Del Fresno C, Garcia L et al. Rapid up-regulation of IRAK-M expression following a second endotoxin challenge in human monocytes and in monocytes isolated from septic patients. Biochem. Biophys. Res. Commun. 311(2), 465–472 (2003).
    • 204 Palazon A, Goldrath AW, Nizet V, Johnson RS. HIF transcription factors, inflammation, and immunity. Immunity 41(4), 518–528 (2014).
    • 205 Fink MP. Bench-to-bedside review: cytopathic hypoxia. Crit. Care 6(6), 491–499 (2002).
    • 206 Thiel M, Caldwell CC, Kreth S et al. Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. PLoS ONE 2(9), e853 (2007).
    • 207 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 18(1), R3 (2014).
    • 208 Demaret J, Dupont G, Venet F et al. STAT5 phosphorylation in T cell subsets from septic patients in response to recombinant human interleukin-7: a pilot study. J. Leukoc. Biol. 97(4), 791–796 (2015).
    • 209 Shindo Y, Unsinger J, Burnham CA, Green JM, Hotchkiss RS. Interleukin-7 and anti-programmed cell death 1 antibody have differing effects to reverse sepsis-induced immunosuppression. Shock 43(4), 334–343 (2015).
    • 210 Annane D, Sharshar T. Cognitive decline after sepsis. Lancet. Respir. Med. 3(1), 61–69 (2015).
    • 211 Michels M, Vieira AS, Vuolo F et al. The role of microglia activation in the development of sepsis-induced long-term cognitive impairment. Brain. Behav. Immun. 43, 54–59 (2015).
    • 212 Michels M, Danieslki LG, Vieira A et al. CD40-CD40 ligand pathway is a major component of acute neuroinflammation and contributes to long-term cognitive dysfunction after sepsis. Mol. Med 21, 219–226 (2015).
    • 213 Mina F, Comim CM, Dominguini D et al. IL1-beta involvement in cognitive impairment after sepsis. Mol. Neurobiol. 49(2), 1069–1076 (2014).
    • 214 Calsavara AC, Soriani FM, Vieira LQ, Costa PA, Rachid MA, Teixiera AL. TNFR1 absence protects against memory deficit induced by sepsis possibly through over-expression of hippocampal BDNF. Metab. Brain Dis. 30(3), 669–678 (2015).
    • 215 Friedrich O, Reid MB, Van Den Berghe G et al. The sick and the weak: neuropathies/myopathies in the critically ill. Physiol. Rev. 95(3), 1025–1109 (2015). • A review addressing a key issue on postsepsis consequences.
    • 216 Reid CL, Campbell IT, Little RA. Muscle wasting and energy balance in critical illness. Clin. Nutr. 23(2), 273–280 (2004).
    • 217 Schweickert WD, Pohlman MC, Pohlman AS et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 373(9678), 1874–1882 (2009).
    • 218 Kayambu G, Boots R, Paratz J. Physical therapy for the critically ill in the ICU: a systematic review and meta-analysis. Crit. Care Med. 41(6), 1543–1554 (2013).
    • 219 Rocheteau P, Chatre L, Briand D et al. Sepsis induces long-term metabolicand mitochondrial muscle stem cell dysfunction amenable by mesenchymal stemcell therapy. Nat. Commun. 6, 10145 (2015).
    • 220 Zolfaghari PS, Carre JE, Parker N, Curtin NA, Duchen MR, Singer M. Skeletal muscle dysfunction is associated with derangements in mitochondrial bioenergetics (but not UCP3) in a rodent model of sepsis. Am. J. Physiol. Endocrinol. Metab. 308(9), e713–e725 (2015).
    • 221 Rocheteau P, Chatre L, Briand D et al. Sepsis induces long-term metabolic and mitochondrialmuscle stem cell dysfunctionamenable by mesenchymal stem cell therapy. Nat. Commun. 6, 10145 (2015).
    • 222 Cui L, Gao Y, Xie Y et al. An ADAM10 promoter polymorphism is a functional variant in severe sepsis patients and confers susceptibility to the development of sepsis. Crit. Care 19, 73 (2015).
    • 223 Wang C, Gui Q, Zhang K. Functional polymorphisms in CD86 gene are associated with susceptibility to pneumonia-induced sepsis. APMIS 123(5), 433–438 (2015).
    • 224 Mansur A, Liese B, Steinau M et al. The CD14 rs2569190 TT genotype is associated with an improved 30-day survival in patients with sepsis: a prospective observational cohort study. PLoS ONE 10(5), e0127761 (2015).
    • 225 Rautanen A, Mills TC, Gordon AC et al. Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. Lancet. Respir. Med. 3(1), 53–60 (2015). •• Describes important genetic predispositions to sepsis.
    • 226 Gao JW, Zhang AQ, Pan W et al. Association between IL-6–174G/C polymorphism and the risk of sepsis and mortality: a systematic review and meta-analysis. PLoS ONE 10(3), e0118843 (2015).
    • 227 Pan W, Zhang AQ, Yue CL et al. Association between interleukin-10 polymorphisms and sepsis: a meta-analysis. Epidemiol. Infect. 143(2), 366–375 (2015).
    • 228 Fang F, Pan J, Li Y et al. Association between interleukin 1 receptor antagonist gene 86-bp VNTR polymorphism and sepsis: a meta-analysis. Hum. Immunol. 76(1), 1–5 (2015).
    • 229 Mora-Rillo M, Fernandez-Romero N, Francisco CN et al. Impact of virulence genes on sepsis severity and survival in Escherichia coli bacteremia. Virulence 6(1), 93–100 (2015). • A paper reminding that part of the heterogeneity of the patients population is due to the different bacterial virulence.
    • 230 Peres AG, Stegen C, Li J et al. Uncoupling of pro- and anti-inflammatory properties of Staphylococcus aureus. Infect. Immun. 83(4), 1587–1597 (2015).
    • 231 De Kraker ME, Wolkewitz M, Davey PG et al. Clinical impact of antimicrobial resistance in European hospitals: excess mortality and length of hospital stay related to methicillin-resistant Staphylococcus aureus bloodstream infections. Antimicrob. Agents Chemother. 55(4), 1598–1605 (2011).
    • 232 Nair R, Ammann E, Rysavy M, Schweizer ML. Mortality among patients with methicillin-resistant Staphylococcus aureus USA300 versus non-USA300 invasive infections: a meta-analysis. Infect. Control Hosp. Epidemiol. 35(1), 31–41 (2014).
    • 233 Mclaughlin MM, Advincula MR, Malczynski M, Barajas G, Qi C, Scheetz MH. Quantifying the clinical virulence of Klebsiella pneumoniae producing carbapenemase Klebsiella pneumoniae with a Galleria mellonella model and a pilot study to translate to patient outcomes. BMC Infect. Dis. 14, 31 (2014).
    • 234 Investigators P, Yealy DM, Kellum JA et al. A randomized trial of protocol-based care for early septic shock. N. Engl. J. Med. 370(18), 1683–1693 (2014).
    • 235 Mouncey PR, Osborn TM, Power GS et al. Trial of early, goal-directed resuscitation for septic shock. N. Engl. J. Med. 372(14), 1301–1311 (2015).
    • 236 Dufour N, Debarbieux L, Fromentin M, Ricard JD. Treatment of highly virulent extraintestinal pathogenic Escherichia coli pneumonia with bacteriophages. Crit. Care Med. 43(6), e190–e198 (2015).
    • 237 Liu A, Wang W, Fang H et al. Baicalein protects against polymicrobial sepsis-induced liver injury via inhibition of inflammation and apoptosis in mice. Eur. J. Pharmacol. 748, 45–53 (2015).
    • 238 Spite M, Norling LV, Summers L et al. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature 461(7268), 1287–1291 (2009).
    • 239 Mirakaj V, Dalli J, Granja T, Rosenberger P, Serhan CN. Vagus nerve controls resolution and pro-resolving mediators of inflammation. J. Exp. Med. 211(6), 1037–1048 (2014). •• Describes a link between proresolving mediators and the control of inflammation by the peripheral and CNS.
    • 240 Andersson U, Tracey KJ. Neural reflexes in inflammation and immunity. J. Exp. Med. 209(6), 1057–1068 (2012). •• Reviews the key role of acetylcholine in controlling inflammation.
    • 241 Yang CH, Kao MC, Shih PC, Li KY, Tsai PS, Huang CJ. Simvastatin attenuates sepsis-induced blood-brain barrier integrity loss. J. Surg. Res. 194(2), 591–598 (2015).
    • 242 Derive M, Bouazza Y, Alauzet C, Gibot S. Myeloid-derived suppressor cells control microbial sepsis. Intensive Care Med. 38(6), 1040–1049 (2012).
    • 243 Lombardo E, Van Der Poll T, Delarosa O, Dalemans W. Mesenchymal stem cells as a therapeutic tool to treat sepsis. World J. Stem Cells 7(2), 368–379 (2015).
    • 244 Fan H, Goodwin AJ, Chang E et al. Endothelial progenitor cells and a stromal cell-derived factor-1alpha analogue synergistically improve survival in sepsis. Am. J. Respir. Crit. Care Med. 189(12), 1509–1519 (2014).
    • 245 Heuer JG, Zhang T, Zhao J et al. Adoptive transfer of in vitro-stimulated CD4+CD25+ regulatory T cells increases bacterial clearance and improves survival in polymicrobial sepsis. J. Immunol. 174(11), 7141–7146 (2005).
    • 246 Hiraki S, Ono S, Tsujimoto H et al. Neutralization of interleukin-10 or transforming growth factor-beta decreases the percentages of CD4+ CD25+ Foxp3+ regulatory T cells in septic mice, thereby leading to an improved survival. Surgery 151(2), 313–322 (2012).
    • 247 Boomer JS, Green JM, Hotchkiss RS. The changing immune system in sepsis: is individualized immuno-modulatory therapy the answer? Virulence 5(1), 45–56 (2014).
    • 248 Vincent JL. Emerging therapies for the treatment of sepsis. Curr. Opin. Anaesthesiol. 28(4), 411–416 (2015).
    • 249 Creasey AA, Chang AC, Feigen L, Wun TC, Taylor FB, Jr., Hinshaw LB. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J. Clin. Invest. 91(6), 2850–2860 (1993).
    • 250 Dominioni L, Dionigi R, Zanello M et al. Effects of high-dose IgG on survival of surgical patients with sepsis scores of 20 or greater. Arch. Surg. 126(2), 236–240 (1991).
    • 251 Sprung CL, Annane D, Keh D et al. Hydrocortisone therapy for patients with septic shock. N. Engl. J. Med. 358(2), 111–124 (2008).
    • 252 Cruz DN, Antonelli M, Fumagalli R et al. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA 301(23), 2445–2452 (2009).
    • 253 Oishi K, Mimura-Kimura Y, Miyasho T et al. Association between cytokine removal by polymyxin B hemoperfusion and improved pulmonary oxygenation in patients with acute exacerbation of idiopathic pulmonary fibrosis. Cytokine 61(1), 84–89 (2013).
    • 254 Yano K, Liaw PC, Mullington JM et al. Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality. J. Exp. Med. 203(6), 1447–1458 (2006).
    • 255 Marshall JC. Why have clinical trials in sepsis failed? Trends Mol. Med. 20(4), 195–203 (2014).
    • 256 Opal SM, Dellinger RP, Vincent JL, Masur H, Angus DC. The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C? Crit. Care Med. 42(7), 1714–1721 (2014).
    • 257 Cohen J, Vincent JL, Adhikari NK et al. Sepsis: a roadmap for future research. Lancet Infect. Dis. 15(5), 581–614 (2015).
    • 258 Gentile LF, Cuenca AG, Efron PA et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J. Trauma Acute Care Surg. 72(6), 1491–1501 (2012).