Intensive Care Medicine

, Volume 36, Issue 11, pp 1859–1866 | Cite as

Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock

  • Caroline Landelle
  • Alain Lepape
  • Nicolas Voirin
  • Eve Tognet
  • Fabienne Venet
  • Julien Bohé
  • Philippe Vanhems
  • Guillaume Monneret
Original

Abstract

Purpose

Sepsis-induced immunosuppression is postulated to contribute to a heightened risk of nosocomial infection (NI). This prospective, single-center, observational study was conducted to assess whether low monocyte human leukocyte antigen-DR expression (mHLA-DR), proposed as a global biomarker of sepsis immunosuppression, was associated with an increased incidence of NI after septic shock.

Methods

The study included 209 septic shock patients. mHLA-DR was measured by flow cytometry at days (D) 3–4 and 6–9 after the onset of shock. After septic shock, patients were screened daily for NI at four sites (microbiologically documented pulmonary, urinary tract, bloodstream, and catheter-related infections). A competing risk approach was used to evaluate the impact of low mHLA-DR on the incidence of NI.

Results

At D3–4, we obtained measurements in 153 patients. Non-survivors (n = 51) exhibited lower mHLA-DR values expressed as means of fluorescence intensities than survivors (n = 102) (33 vs. 67; p < 0.001). The patients who developed NI (n = 37) exhibited lower mHLA-DR values than those without NI (n = 116) (39 vs. 65; p = 0.008). mHLA-DR ≤54 remained independently associated with NI occurrence after adjustment for clinical parameters (gender, simplified acute physiology score II, sepsis-related organ failure assessment, intubation, and central venous catheterization) with an adjusted hazards ratio (aHR) of 2.52 (95% CI 1.20–5.30); p = 0.02. Similarly, at D6–9, low mHLA-DR (≤57) remained independently associated with NI with an aHR of 2.18 (95% CI 1.04–4.59); p = 0.04.

Conclusions

In septic shock patients, after adjustment with usual clinical confounders (including ventilation and central venous catheterization), persistent low mHLA-DR expression remained independently associated with the development of secondary NI.

Keywords

mHLA-DR Immunosuppression Nosocomial infection Sepsis Septic shock 

Notes

Acknowledgments

The authors are grateful to Professor Christian Brun-Buisson, Dr. Raphaele Girard, all the intensivists of the Centre Hospitalier Lyon Sud, CCLIN Sud Est. The study was conducted thanks to the logistic support of Centre d’Investigation Clinique (CIC 201) of INSERM and Hospices Civils de Lyon. Thanks are also due to Ovid Da Silva for editing this manuscript. The present work was supported by Hospices Civils de Lyon. In addition, C. Landelle was funded by Hospices Civils de Lyon and Centre National de la Recherche Scientifique (Contrat d’Assistant Hospitalier de Recherche HCL/CNRS). C. Landelle received the International Sepsis Forum (ISF) Sepsis Award for a part of this work during the joint ESCMID (European Society of Clinical Microbiology and Infectious Disease)/ISF Sepsis Forum on May 2009 at the 19th ECCMID (European Congress of Clinical Microbiology and Infectious Disease) in Helsinki, Finland.

Conflict of interest statement

None of the authors have any financial interests or affiliations with commercial organizations whose products or services are related to the subject matter of this manuscript (i.e., no existing conflicts of interest).

Supplementary material

134_2010_1962_MOESM1_ESM.doc (182 kb)
Supplementary material 1 (DOC 181 kb)

References

  1. 1.
    Annane D, Aegerter P, Jars-Guincestre MC, Guidet B, Network ft C-R (2003) Current epidemiology of septic shock. The CUB-Réa Network. Am J Respir Crit Care Med 168:165–172CrossRefPubMedGoogle Scholar
  2. 2.
    Landelle C, Lepape A, Français A, Tognet E, Thizy H, Voirin N, Timsit JF, Monneret G, Vanhems P (2008) Nosocomial infection after septic shock among intensive care unit patients. Infect Control Hosp Epidemiol 29:1054–1065CrossRefPubMedGoogle Scholar
  3. 3.
    Friedman G, Silva E, Vincent JL (1998) Has the mortality of septic shock changed with time. Crit Care Med 26:2078–2086CrossRefPubMedGoogle Scholar
  4. 4.
    Annane D, Bellissant E, Cavaillon JM (2005) Septic shock. Lancet 365:63–78CrossRefPubMedGoogle Scholar
  5. 5.
    Reddy RC, Chen GH, Tekchandani PK, Standiford TJ (2001) Sepsis-induced immunosuppression: from bad to worse. Immunol Res 24:273–287CrossRefPubMedGoogle Scholar
  6. 6.
    Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150CrossRefPubMedGoogle Scholar
  7. 7.
    Munford RS, Pugin J (2001) Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med 163:316–321PubMedGoogle Scholar
  8. 8.
    Pugin J (2007) Immunostimulation is a rational therapeutic strategy in sepsis. Novartis Found Symp 280:21–27; discussion 27–36, 160–164CrossRefPubMedGoogle Scholar
  9. 9.
    Monneret G, Venet F, Pachot A, Lepape A (2008) Monitoring immune dysfunctions in the septic patient: a new skin for the old ceremony. Mol Med 14:64–78CrossRefPubMedGoogle Scholar
  10. 10.
    Schefold JC, Hasper D, Volk HD, Reinke P (2008) Sepsis: time has come to focus on the later stages. Med Hypotheses 71:203–208CrossRefPubMedGoogle Scholar
  11. 11.
    Caille V, Chiche JD, Nciri N, Berton C, Gibot S, Boval B, Payen D, Mira JP, Mebazaa A (2004) Histocompatibility leukocyte antigen-D related expression is specifically altered and predicts mortality in septic shock but not in other causes of shock. Shock 22:521–526CrossRefPubMedGoogle Scholar
  12. 12.
    Monneret G, Lepape A, Voirin N, Bohé J, Venet F, Debard AL, Thizy H, Bienvenu J, Gueyffier F, Vanhems P (2006) Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med 32:1175–1183CrossRefPubMedGoogle Scholar
  13. 13.
    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 77:204–207CrossRefPubMedGoogle Scholar
  14. 14.
    Cheadle WG, Hershman MJ, Wellhausen SR, Polk HC Jr (1991) HLA-DR antigen expression on peripheral blood monocytes correlates with surgical infection. Am J Surg 161:639–645CrossRefPubMedGoogle Scholar
  15. 15.
    Venet F, Tissot S, Debard AL, Faudot C, Crampé C, Pachot A, Ayala A, Monneret G (2007) Decreased monocyte human leukocyte antigen-DR expression after severe burn injury: correlation with severity and secondary septic shock. Crit Care Med 35:1910–1917CrossRefPubMedGoogle Scholar
  16. 16.
    Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ (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 101:1644–1655CrossRefPubMedGoogle Scholar
  17. 17.
    Vanhems P, Lepape A, Savey A, Jambou P, Fabry J (2000) Nosocomial pulmonary infection by antimicrobial-resistant bacteria of patients hospitalized in intensive care units: risk factors and survival. J Hosp Infect 45:98–106CrossRefPubMedGoogle Scholar
  18. 18.
    HELICS (2005) Surveillance of nosocomial infections in intensive care units. http://helics.univ-lyon1.fr/documents/icu_protocol.pdf. Accessed 15 June 2009
  19. 19.
    Monneret G, Elmenkouri N, Bohe J, Debard AL, Gutowski MC, Bienvenu J, Lepape A (2002) Analytical requirements for measuring monocytic human lymphocyte antigen DR by flow cytometry: application to the monitoring of patients with septic shock. Clin Chem 48:1589–1592PubMedGoogle Scholar
  20. 20.
    Gray RJ (1988) A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141–1154CrossRefGoogle Scholar
  21. 21.
    Fine J, Gray RJ (1999) A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94:496–509CrossRefGoogle Scholar
  22. 22.
    R Development Core Team (2009) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0. http://www.R-project.org
  23. 23.
    Vincent JL (2003) Nosocomial infections in adult intensive-care units. Lancet 361:2068–2077CrossRefPubMedGoogle Scholar
  24. 24.
    Brawley RL, Weber DJ, Samsa GP, Rutala WA (1989) Multiple nosocomial infections. An incidence study. Am J Epidemiol 130:769–780PubMedGoogle Scholar
  25. 25.
    Alberti C, Brun-Buisson C, Burchardi H, Martin C, Goodman S, Artigas A, Sicignano A, Palazzo M, Moreno R, Boulmé R, Lepage E, Le Gall R (2002) Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med 28:108–121CrossRefPubMedGoogle Scholar
  26. 26.
    Wolk K, Docke WD, von Baehr V, Volk HD, Sabat R (2000) Impaired antigen presentation by human monocytes during endotoxin tolerance. Blood 96:218–223PubMedGoogle Scholar
  27. 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 128:594–600CrossRefPubMedGoogle Scholar
  28. 28.
    Manjuck J, Saha DC, Astiz M, Eales LJ, Rackow EC (2000) Decreased response to recall antigens is associated with depressed costimulatory receptor expression in septic critically ill patients. J Lab Clin Med 135:153–160CrossRefPubMedGoogle Scholar
  29. 29.
    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 30:3140–3146CrossRefPubMedGoogle Scholar
  30. 30.
    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 25:245–250CrossRefPubMedGoogle Scholar
  31. 31.
    Le Tulzo Y, Pangault C, Amiot L, Guilloux V, Tribut O, Arvieux C, Camus C, Fauchet R, Thomas R, Drénou B (2004) Monocyte human leukocyte antigen-DR transcriptional downregulation by cortisol during septic shock. Am J Respir Crit Care Med 169:1144–1151CrossRefPubMedGoogle Scholar
  32. 32.
    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 30:1140–1145CrossRefPubMedGoogle Scholar
  33. 33.
    Lukaszewicz AC, Grienay M, Resche-Rigon M, Pirracchio R, Faivre V, Boval B, Payen D (2009) Monocytic HLA-DR expression in intensive care patients: interest for prognosis and secondary infection prediction. Crit Care Med 37:2746–2752CrossRefPubMedGoogle Scholar
  34. 34.
    Döcke 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 3:678–681CrossRefPubMedGoogle Scholar
  35. 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 30:1488–1494CrossRefPubMedGoogle Scholar
  36. 36.
    Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, Weber-Carstens S, Hasper D, Keh D, Zuckermann H, Reinke P, Volk HD (2009) Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind randomized placebo-controlled multicenter trial. Am J Respir Crit Care Med 180:640–648CrossRefPubMedGoogle Scholar
  37. 37.
    Döcke WD, Höflich C, Davis KA, Röttgers 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 51:2341–2347CrossRefPubMedGoogle Scholar

Copyright information

© Copyright jointly held by Springer and ESICM 2010

Authors and Affiliations

  • Caroline Landelle
    • 1
    • 2
  • Alain Lepape
    • 3
  • Nicolas Voirin
    • 1
    • 2
  • Eve Tognet
    • 4
  • Fabienne Venet
    • 5
  • Julien Bohé
    • 4
  • Philippe Vanhems
    • 1
    • 2
  • Guillaume Monneret
    • 5
  1. 1.Laboratoire de Biométrie et Biologie Evolutive, Epidémiologie et Santé PubliqueCNRS, UMR 5558, Université Lyon 1; Université de LyonLyonFrance
  2. 2.Hospices Civils de Lyon, Hôpital Edouard HerriotService d’Hygiène, Epidémiologie et PréventionLyonFrance
  3. 3.Hospices Civils de Lyon, Centre Hospitalier de Lyon SudService de Réanimation ChirurgicaleLyonFrance
  4. 4.Hospices Civils de Lyon, Centre Hospitalier de Lyon SudService de Réanimation MédicaleLyonFrance
  5. 5.Laboratoire d’ImmunologieHôpital E. Herriot, Hospices Civils de LyonLyon Cedex 03France

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