Log in | Register

Reversal of immunoparalysis by recombinant human granulocyte-macrophage colony-stimulating factor in patients with severe sepsis

Axel Nierhaus, Barbara Montag, Nicole Timmler, Daniel P. Frings, Kai Gutensohn, Roman Jung, Claus G. Schneider, Werner Pothmann, Anne K. Brassel, Jochen Schulte am Esch
Brief Report
Volume 29, Issue 4 / April , 2003

Pages 646 - 651

Abstract

Objective

To evaluate the effect of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on immunoparalysis as defined by a sustained decrease of HLA-DR expression on monocytes in patients with severe sepsis.

Design

Prospective, non-randomised observational study.

Setting

Two anaesthesiological intensive care units of a university hospital.

Intervention

Administration of a daily dose of 5 µg/kg rhGM-CSF over a period of 3 days.

Patients

Nine consecutive patients with severe sepsis and a documented HLA-DR expression on peripheral monocytes of less than 150 mean fluorescence intensity (MFI) over a period of at least 48 h prior to intervention.

Measurements and results

Mean MFI was 69.4±13.2 24 h before and 56.7±8.2 on the day of the administration of 5 µg/kg rhGM-CSF. Within 24 h a significant increase of HLA-DR expression to a mean of 327.7±78.8 MFI was observed in all patients. This increase was maintained on days 2–10. It was accompanied by a significant rise in white blood count. The ex vivo TNF-α production in whole blood after lipopolysaccharide (LPS)-stimulation increased significantly from a mean of 82±29.2 pg/ml to 793±546.8 pg/ml. Apart from febrile reactions in two patients, no side effects were recorded. No increases of pro-inflammatory markers (IL-6, C-reactive protein, LPS-binding protein, procalcitonin) were observed. SOFA values before and after rhGM-CSF did not differ significantly. The mortality rate was 33%.

Conclusion

This preliminary study demonstrates that rhGM-CSF upregulates HLA-DR expression on monocytes in septic patients with multi-organ dysfunction. Moreover, with the concomitant increase of the ex vivo whole blood TNF-α response, this upregulation of a monocytic activation marker is paralleled by a functional recovery.

Keywords

References

  1. Sorg C (1991) Macrophages in acute and chronic inflammation. Chest 100:173S–175S
    • View reference on PubMed
  2. Volk HD, Reinke P, Krausch D, Zuckermann H, Asadullah K, Muller JM, Döcke WD, Kox WJ (1996) Monocyte deactivation—rationale for a new therapeutic strategy in sepsis. Intensive Care Med 22:S474–481
    • View reference on PubMed
  3. 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
    • View reference on PubMed
  4. Muller Kobold AC, Tulleken JE, Zijlstra JG, Sluiter W, Hermans J, Kallenberg CG, Cohen Tervaert JW (2000) Leukocyte activation in sepsis, correlation with disease state and mortality. Intensive Care Med 26:883–892
    • View reference on PubMed
  5. Oberhoffer M, Vogelsang H, Russwurm S, Hartung T, Reinhart K (1999) Outcome prediction by traditional and new markers of inflammation in patients with sepsis. Clin Chem Lab Med 37:363–368
    • View reference on PubMed
  6. Flohe S, Borgermann J, Dominguez FE, Majetschak M, Lim L, Kreuzfelder E, Obertacke U, Nast-Kolb D, Schade FU (1999) Influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) on whole blood endotoxin responsiveness following trauma, cardiopulmonary bypass and severe sepsis. Shock 12:17–24
    • View reference on PubMed
  7. Williams MA, Kelsey SM, Collins PW, Gutteridge CN, Newland AC (1995) Administration of rHuGM-CSF activates monocyte reactive oxygen species secretion and adhesion molecule expression in vivo in patients following high-dose chemotherapy. Br J Haematol 90:31–40
    • View reference on PubMed
  8. Williams MA, Kouroumoussis I, Syndercombe-Court D, Hendry L, Newland AC, Kelsey SM (1995) Administration of recombinant human granulocyte-macrophage colony-stimulating factor after chemotherapy regulates the expression and secretion of monocyte tumor necrosis factor (TNF) and TNF receptors p55 and p75. Blood 86:4234–4242
    • View reference on PubMed
  9. Presneill JJ, Harris T, Stewart AG, Cade JF, Wilson JW (2002).. A randomized phase II trial of granulocyte-macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction. Am J Respir Crit Care Med 166:138–143
    • View reference on publisher's website
    • View reference on PubMed
  10. Hill AD, Naama HA, Calvano SE, Daly JM (1995) The effect of granulocyte-macrophage colony-stimulating factor on myeloid cells and its clinical applications. J Leukoc Biol 58:634–642
    • View reference on PubMed
  11. Root RK, Dale DC (1999) Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor: comparisons and potential for use in the treatment of infections in nonneutropenic patients. J Infect Dis 179: S342–352
    • View reference on PubMed
  12. Ganser A, Seipelt G, Eder M, Geissler G, Ottmann OG, Hess U, Hoelzer D (1992) Treatment of myelodysplastic syndromes with cytokines and cytotoxic drugs. Semin Oncol. 19:95–101
  13. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG (1996) 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 22:707–710
  14. Nebe T (1998) Flow cytometric analysis of immunoparalysis. Clin Lab 44:441–446
  15. Frings DP, Nierhaus A, Montag B, Gutensohn K, Schulte am Esch J (2001) Quantitative assessment of HLA-DR expression on monocytes as a key prognostic marker in SIRS and sepsis (abstract). Crit Care Med 29: S206
  16. Kox WJ, Bone RC, Krausch D, Docke WD, Kox SN, Wauer H, Egerer K, Querner S, Asadullah K, von Baehr R, Volk HD (1997) Interferon gamma-1b in the treatment of compensatory anti-inflammatory response syndrome. A new approach: proof of principle. Arch Intern Med 157:389–393
  17. Bilgin K, Yaramis A, Haspolat K, Tas MA, Gunbey S, Derman O (2001) A randomized trial of granulocyte-macrophage colony-stimulating factor in neonates with sepsis and neutropenia. Pediatrics 107:36–41
    • View reference on PubMed
  18. Bone RC (1996) Sir Isaac Newton, sepsis, SIRS and CARS. Crit Care Med 24:1125–1128
  19. Livingston DH, Appel SH, Wellhausen SR, Sonnenfeld G, Polk HC Jr (1988) Depressed interferon gamma production and monocyte HLA-DR expression after severe injury. Arch Surg 123:1309–1312
    • View reference on PubMed
  20. Nierhaus A, Montag B, Frings D, Schulte am Esch J (2000) Initial decrease and sustained depression of HLA-DR expression on monocytes is predictive of outcome in SIRS and sepsis (abstract). Anesthesiology 93: A461
  21. Döcke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, Volk DH, Kox WJ (1997) Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 3:678–681
    • View reference on PubMed
  22. Hubel K, Dale DC, Liles WC (2002) Therapeutic use of cytokines to modulate phagocyte function for the treatment of infectious diseases: current status of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor and interferon-gamma. J Infect Dis 185:1490–1501
    • View reference on publisher's website
    • View reference on PubMed
  23. Mellstedt H, Fagerberg J, Frodin JE, Henriksson L, Hjelm–Skoog AL, Liljefors M, Ragnhammar P, Shetye J, Osterborg A (1999) Augmentation of the immune response with granulocyte-macrophage colony-stimulating factor and other hematopoietic growth factors. Curr Opin Hematol 6:169–175
    • View reference on PubMed
  24. Williams MA, Withington S, Newland AC, Kelsey SM (1998) Monocyte anergy in septic shock is associated with a predilection to apoptosis and is reversed by granulocyte-macrophage colony-stimulating factor ex vivo. J Infect Dis 178:1421–1433
    • View reference on PubMed
  25. Perry SE, Mostafa SM, Wenstone R, McLaughlin PJ (2002) Low plasma granulocyte-macrophage colony stimulating factor is an indicator of poor prognosis in sepsis. Intensive Care Med 28:981–984
  26. Trapnell BC (2002) Granulocyte macrophage colony-stimulating factor augmentation in sepsis. Is there a role? Am J Respir Crit Care Med 166:129–130
    • View reference on publisher's website
    • View reference on PubMed

Sign In

Connect with ICM

Top 5 Articles Supplement Letters to the Editor