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
Pages 646 - 651
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.
Prospective, non-randomised observational study.
Two anaesthesiological intensive care units of a university hospital.
Administration of a daily dose of 5 µg/kg rhGM-CSF over a period of 3 days.
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%.
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.
- Sorg C (1991) Macrophages in acute and chronic inflammation. Chest 100:173S–175S
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Nebe T (1998) Flow cytometric analysis of immunoparalysis. Clin Lab 44:441–446
- 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
- 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
- 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
- Bone RC (1996) Sir Isaac Newton, sepsis, SIRS and CARS. Crit Care Med 24:1125–1128
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Trapnell BC (2002) Granulocyte macrophage colony-stimulating factor augmentation in sepsis. Is there a role? Am J Respir Crit Care Med 166:129–130