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Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock

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Abstract

Objective

The immediate overwhelming release of inflammatory mediators in septic shock is rapidly followed by strong anti-inflammatory responses inducing a state of immunosuppression. The patients who survive the initial hyper-inflammatory step of septic shock but subsequently die may be those who do not recover from immunosuppression. We assessed whether a low monocyte human leukocyte antigen-DR (mHLA-DR) expression, proposed as a marker of immunosuppression, is an independent predictor of mortality in patients who survived the initial 48 h of septic shock.

Design and setting

Prospective observational study performed in two adult intensive care units at a university hospital.

Patients

93 consecutive patients with septic shock.

Measurements and results

At days 1–2, mHLA-DR values (determined by flow cytometry) were not significantly different between survivors and non-survivors. A sharp difference became highly significant at days 3–4 when survivors had increased their values, while non-survivors had not (43% vs. 18%, percentage of HLA-DR positive monocyte, p < 0.001). Multivariate logistic regression analysis revealed that low mHLA-DR (< 30%) at days 3–4 remained independently associated with mortality after adjustment for usual clinical confounders, adjusted odds ratio (CI): 6.48 (95% CI: 1.62–25.93).

Conclusion

The present preliminary results show that mHLA-DR is an independent predictor of mortality in septic shock patients. Being a marker of immune failure, low mHLA-DR may provide a rationale for initiating therapy to reverse immunosuppression. After validation of the current results in multicenter studies, mHLA-DR may help to stratify patients when designing a mediator-directed therapy in a time-dependent manner.

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References

  1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated cost of care. Crit Care Med 29:1303–1310

    Article  PubMed  CAS  Google Scholar 

  2. Annane D, Bellissant E, Cavaillon JM (2005) Septic shock. Lancet 365:63–78

    Article  PubMed  CAS  Google Scholar 

  3. Reddy RC, Chen GH, Tekchandani PK, Standiford TJ (2001) Sepsis-induced immunosuppression: from bad to worse. Immunol Res 24:273–287

    Article  PubMed  CAS  Google Scholar 

  4. Hotchkiss RS, Karl EI (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150

    Article  PubMed  CAS  Google Scholar 

  5. Munford RS, Pugin J (2001) Normal response to injury prevents systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med 163:316–321

    PubMed  CAS  Google Scholar 

  6. Haveman JW, Muller Kobold AC, Tervaert JW, van den Berg AP, Tulleken JE, Kallenberg CG, The TH (1999) The central role of monocytes in the pathogenesis of sepsis: Consequences for immunomonitoring and treatment. Neth J Med 55:132–141

    Article  PubMed  CAS  Google Scholar 

  7. Hershman MJ, Cheadle WG, Wellhausen SR, Davidson PF, Polk HC Jr (1990) Monocyte HLA-DR antigen expression characterizes clinical outcome in the trauma patient. Br J Surg 77:204–207

    Article  PubMed  CAS  Google Scholar 

  8. Ditschkowski M, Kreuzfelder E, Rebmann V, Ferencik S, Majetschak M, Schmid EN, Obertacke U, Hirche H, Schade UF, Grosse-Wilde H (1999) HLA-DR expression and soluble HLA-DR levels in septic patients after trauma. Ann Surg 229:246–254

    Article  PubMed  CAS  Google Scholar 

  9. Satoh A, Miura T, Satoh K, Masamune A, Yamagiwa T, Sakai Y, Shibuya K, Takeda K, Kaku M, Shimosegawa T (2002) Human leukocyte antigen-DR expression on peripheral monocytes as a predictive marker of sepsis during acute pancreatitis. Pancreas 25:245–250

    Article  PubMed  Google Scholar 

  10. Muehlstedt SG, Lyte M, Rodriguez JL (2002) Increased IL-10 production and HLA-DR suppression in the lungs of injured patients precede the development of nosocomial pneumonia. Shock 17:443–450

    Article  PubMed  Google Scholar 

  11. Allen ML, Peters MJ, Goldman A, Elliott M, James I, Callard R, Klein NJ (2002) Early postoperative monocyte deactivation predicts systemic inflammation and prolonged stay in pediatric cardiac intensive care. Crit Care Med 30:1140–1145

    Article  PubMed  Google Scholar 

  12. Bone RC, Balk RA, Cerra FB (1992) 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

    Article  PubMed  CAS  Google Scholar 

  13. McCabe WR, Jackson GC (1962) Gram-negative bacteremia. Arch Intern Med 110:847–864

    Google Scholar 

  14. Le Gall JR, Lemeshow S, Saulnier F (1993) A new Simplified Acute Physiology Score [SAPS II] based on a European/North American multicenter study. JAMA 270:2957–2963

    Article  PubMed  Google Scholar 

  15. Vincent JL, de Mendonca A, Cantraine F, Moreno R, Takala J, Suter PM, Sprung CL, Colardyn F, Blecher S (1998) Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Crit Care Med 26:1793–1800

    PubMed  CAS  Google Scholar 

  16. Harbarth S, Garbino J, Pugin J, Romand JA, Lew D, Pittet D (2003) Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med 115:529–535

    Article  PubMed  Google Scholar 

  17. Monneret G, Elmenkouri N, Bohe J, Debard AL, Gutowski MC, Bienvenu J, Lepape A (2002) Analytical requirements for measuring monocytic HLA-DR by flow cytometry: Application to the monitoring of patients with septic shock. Clin Chem 48:1589–1592

    PubMed  CAS  Google Scholar 

  18. Docke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, Volk HD, Kox W (1997) Monocyte deactivation in septic patients: Restoration by IFN-gamma treatment. Nat Med 3:678–681

    Article  PubMed  CAS  Google Scholar 

  19. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M, Early goal-directed therapy collaborative group (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368–1377

    Article  PubMed  CAS  Google Scholar 

  20. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P, Bellissant E (2002) Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288:862–871

    Article  PubMed  CAS  Google Scholar 

  21. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr, Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group (2001) Efficacy and safety of recombinant activated protein C for severe sepsis. N Engl J Med 344:699–709

    Article  PubMed  CAS  Google Scholar 

  22. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM, Surviving Sepsis Campaign Management Guidelines Committee (2004) Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 32:858–873

    Article  PubMed  Google Scholar 

  23. Koppelman B, Neefjes JJ, de Vries JE, de Waal Malefyt R (1997) Interleukin-10 down-regulates MHC class II alphabeta peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling. Immunity 7:861–871

    Article  PubMed  CAS  Google Scholar 

  24. Krakauer T, Oppenheim JJ (1993) IL-1 and tumor necrosis factor-alpha each up-regulate both the expression of IFN-gamma receptors and enhance IFN-gamma-induced HLA-DR expression on human monocytes and a human monocytic cell line (THP-1). J Immunol 150:1205–1211

    PubMed  CAS  Google Scholar 

  25. Schwiebert LM, Schleimer RP, Radka SF, Ono SJ (1995) Modulation of MHC class II expression in human cells by dexamethasone. Cell Immunol 165:12–19

    Article  PubMed  CAS  Google Scholar 

  26. Basta PV, Moore TL, Yokota S, Ting JP (1989) A beta-adrenergic agonist modulates DR alpha gene transcription via enhanced cAMP levels in a glioblastoma multiforme line. J Immunol 142:2895–2901

    PubMed  CAS  Google Scholar 

  27. Astiz M, Saha D, Lustbader D, Lin R, Rackow E (1996) Monocyte response to bacterial toxins, expression of cell surface receptors, and release of anti-inflammatory cytokines during sepsis. J Lab Clin Med 128:594–600

    Article  PubMed  CAS  Google Scholar 

  28. Manjuck J, Saha DC, Astiz M, Eales LJ, Rackow EC (2000) Decreased response to recall antigens is associated with depressed co-stimulatory receptor expression in septic critically ill patients. J Lab Clin Med 135:153–160

    Article  PubMed  CAS  Google Scholar 

  29. Wolk K, Docke WD, von Baehr V, Volk HD, Sabat R (2000) Impaired antigen presentation by human monocytes during endotoxin tolerance. Blood 96:218–223

    PubMed  CAS  Google Scholar 

  30. Piani A, Hossle JP, Birchler T, Siegrist CA, Heumann D, Davies G, Loeliger S, Seger R, Lauener RP (2000) Expression of MHC class II molecules contributes to lipopolysaccharide responsiveness. Eur J Immunol 30:3140–3146

    Article  PubMed  CAS  Google Scholar 

  31. Fumeaux T, Pugin J (2002) Role of interleukin-10 in the intracellular sequestration of human leukocyte antigen-DR in monocytes during septic shock. Am J Respir Crit Care Med 166:1475–1482

    Article  PubMed  Google Scholar 

  32. Perry SE, Mostafa SM, Wenstone R, Shenkin A, McLaughlin PJ (2003) Is low monocyte HLA-DR expression helpful to predict outcome in severe sepsis? Intensive Care Med 29:1245–1252

    Article  PubMed  Google Scholar 

  33. Hynninen M, Pettila V, Takkunen O, Orko R, Jansson SE, Kuusela P, Renkonen R, Valtonen M (2003) 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

    Article  PubMed  CAS  Google Scholar 

  34. Lekkou A, Karakantza M, Mouzaki A, Kalfarentzos F, Gogos CA (2004) Cytokine production and monocyte HLA-DR expression as predictors of outcome for patients with community-acquired severe infections. Clin Diagn Lab Immunol 11:161–167

    Article  PubMed  CAS  Google Scholar 

  35. Nakos G, Malamou-Mitsi VD, Lachana A, Karassavoglou A, Kitsiouli E, Agnandi N, Lekka ME (2002) Immunoparalysis in patients with severe trauma and the effect of inhaled interferon-gamma. Crit Care Med 30:1488–1494

    Article  PubMed  CAS  Google Scholar 

  36. Nierhaus A, Montag B, Timmler N, Frings DP, Gutensohn K, Jung R, Schneider CG, Pothmann W, Brassel AK, Schulte Am Esch J (2003) Reversal of immunoparalysis by recombinant human granulocyte-macrophage colony-stimulating factor in patients with severe sepsis. Intensive Care Med 29:646–651

    PubMed  Google Scholar 

  37. Docke WD, Hoflich C, Davis KA, Rottgers K, Meisel C, Kiefer P, Weber SU, Hedwig-Geissing M, Kreuzfelder E, Tschentscher P, Nebe T, Engel A, Monneret G, Spittler A, Schmolke K, Reinke P, Volk HD, Kunz D (2005) Monitoring temporary immunodepression by flow cytometric measurement of monocytic HLA-DR expression: a multicenter standardized study. Clin Chem 51:2341–2347

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank J. Kingsley for greatly assisting in the preparation of this manuscript and the technical staff of the Flow Cytometry Unit (J. Baudot, C. Fernandez, M.A. Guinand, M.C. Gutowski) of the Lyon Sud University Hospital.

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Authors and Affiliations

  1. Immunology Laboratory, Hôpital Neurologique, Lyon, France

    Guillaume Monneret & Fabienne Venet

  2. Immunology Laboratory, Lyon-Sud University Hospital, Lyon, France

    Anne-Lise Debard & Jacques Bienvenu

  3. Intensive Care Units, Lyon-Sud University Hospital, Lyon, France

    Alain Lepape & Julien Bohé

  4. Laboratory of Epidemiology and Public Health, INSERM U271, Claude Bernard University, Lyon, France

    Nicolas Voirin & Philippe Vanhems

  5. Centre d'Investigation Clinique (Clinical Research Center), INSERM and Hospices Civils de Lyon, Lyon, France

    Hélène Thizy & François Gueyffier

  6. Flow Cytometry Unit, Immunology laboratory, Hôpital Neurologique, 69677, Bron, France

    Guillaume Monneret

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  1. Guillaume Monneret
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Correspondence to Guillaume Monneret.

Additional information

This article is discussed in the editorial available at: http://dx.doi.org/10.1007/s00134-006-0205-7

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Monneret, G., Lepape, A., Voirin, N. et al. Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med 32, 1175–1183 (2006). https://doi.org/10.1007/s00134-006-0204-8

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  • DOI: https://doi.org/10.1007/s00134-006-0204-8

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