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Immunostimulation using granulocyte- and granulocyte-macrophage colony stimulating factor in patients with severe sepsis and septic shock


Sepsis is associated with failure of multiple organs, including failure of the immune system. The resulting 'sepsis-associated immunosuppression' resembles a state of immunological anergy that is characterized by repeated 'infectious hits', prolonged multiple-organ failure, and death. As a consequence, adjunctive treatment approaches using measures of immunostimulation with colony-stimulating factors (CSFs) were tested in animal experiments and clinical trials. Herein, data from randomized clinical trials will be discussed in the context of a recently published meta-analysis investigating the effects of granulocyte- and granulocyte-macrophage colony-stimulating factor therapy in patients with severe sepsis and septic shock.

Sepsis is a serious medical problem and constitutes an enormous burden for health care systems. A recent meta-analysis published in Critical Care[1] evaluated clinical effects of colony-stimulating factors in patients with severe sepsis/septic shock. Here, the results will be discussed in the context of the available data.

A large body of evidence indicates that the early 'hyper-inflammatory' phase in sepsis is often followed by a persistent 'hypo-inflammation' with severe alterations in both innate and cellular immunity [25]. Findings during this state of 'sepsis-associated immunosuppression' include diminished phagocytotic activity, cytokine expression profile changes towards an anti-inflammatory phenotype, increased expression of negative (co-)stimulatory molecules, reduced monocytic antigen presentation via the major histocompatibility (MHC) class II complex (mHLA-DR), dysfunction and apoptosis of lymphocytes, and upregulation of regulatory T cells [27]. Mounting data show that patients with persistent 'sepsis-associated immunosuppression' are at increased risk for nosocomial infections [8], prolonged ICU stay, and death [4, 9]. Typically, these patients will be resuscitated successfully in the early shock phase, will then develop an 'anergic' immunological state, and will finally succumb to repeated infections from rather avirulent secondary pathogens.

Keeping this in mind, immunostimulation in sepsis seems tempting but only few trials have investigated the immunological and clinical effects of immune reconstructive therapies [46, 10]. Such approaches include immunostimulation with interferon-γ [11], selective extra-corporeal reduction of immunodepressants [12], and medication with granulocyte-colony stimulating factor (G-CSF)/granulocyte-macrophage colony stimulating factor (GM-CSF) (summarized in [1]). However, when analysing the available data on CSF therapy in sepsis, it seems important that G-CSF and GM-CSF have distinct properties. Both are potent immunostimulators, induce leukocytosis, augment the activity of granulocytes and have anti-infectious (mostly anti-bacterial) capabilities. GM-CSF additionally stimulates monocytes/macrophages, induces monocytic cytokine expression (for example, tumor necrosis factor-α, interferon-γ) and induces antigen presentation (mHLA-DR) [13].

As demonstrated in the recent meta-analysis [1], a total of 12 placebo-controlled randomized controlled trials (RCTs; n = 2,380 patients) investigated the clinical effects of G-CSF (n = 8 RCTs) and GM-CSF (n = 4 RCTs) in patients with severe sepsis/septic shock. The main outcome measure of this sytematic review was all-cause short-term (14-day; data from n = 138 patients available) and 28-day mortality. No significant difference in 28-day mortality (relative risk (RR) 0.93, 95% confidence interval (CI) 0.79 to 1.11, P = 0.44) and in-hospital mortality (RR 0.97, 95% CI 0.69 to 1.36, P = 0.86) was observed when patients receiving G-CSF or GM-CSF were compared to placebo-treated controls. Analysis of G-CSF (n = 2,044, 6 RCTs) or GM-CSF (n = 89, 3 RCTs) treatment subgroups revealed no 28-day mortality benefit. In line with previous findings from non-randomized trials, CSF therapy appeard safe. Nevertheless, although an effect on mortality was not observed, the meta-analysis identified that patients receiving G-CSF or GM-CSF therapy have a significantly increased rate of reversal from infection (RR 1.34, 95% CI 1.11 to 1.62, P = 0.002). Although this finding is mainly based on available G-CSF data, it supports earlier findings from animal models that CSF therapy may indeed induce a faster reversal from infection. This seems especially the case in pneumogenic sepsis [14]. In line with data from animal models and G-CSF trials, we recently demonstrated in the first biomarker-guided immunostimulatory placebo-controlled RCT in sepsis that GM-CSF therapy significantly shortens the time of mechanical ventilation [15].

However, a number of limitations of the meta-analysis need to be discussed. First, a combined G-CSF/GM-CSF analysis might be challenged due to the distinct biology and underlying treatment concepts of each. Whereas G-CSF is typically given to increase antimicrobial defense via numerical induction of granulocytes, GM-CSF therapy aims to re-stimulate antigen-presenting cell function/adaptive immunity. Moreover, as G-CSF is often applied in induction-chemotherapy-induced neutropenia, the role of neutropenia-related sepsis in the included trials remains unclear. Second, the heterogeneity of the trials under investigation is noteworthy as the trials differed greatly in regard to applied CSF doses, routes of administration, pharmacological CSF subtypes and patient characteristics (for example, disease severity). This certainly constrains data comparability. Third, most trials did not stratify study patients according to their immunological state and the efficacy of the immunological intervention was not tested or reported. We believe that this remains a prerequisite for future immunomodulatory trials in sepsis. Although assessment of the underlying complex immunological condition using a single biomarker may be regarded as challenging, standardized quantitative tests (for example, flow-cytometric mHLA-DR assessment) were recently developed that may both serve as global biomarkers for cellular immunity and help to guide future immunotherapies [7, 10, 16].

Future trials on CSF therapy should be performed in immunologically stratified patients and concomitant immune monitoring seems mandatory. As CSF therapy seems to contribute to a faster reversal of infection and may shorten the time of mechanical ventilation, there is an urgent need for larger RCTs adequately powered for 28-day mortality, respective surrogates, or reduction of nosocomial infection rates. Currently, on the basis of the limited heterogenous data available, a mortality benefit for CSF therapy cannot be demonstrated. At this point in time, CSF therapy should thus be applied in the context of clinical trials only, with the exception being individual off-label rescue approaches.



confidence interval


colony-stimulating factor


granulocyte-colony stimulating factor


granulocyte-macrophage colony stimulating factor


monocytic human leukocyte antigen-DR


randomized controlled trial


relative risk.


  1. Bo L, Wang F, Zhu J, Li J, Deng X: Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis. Crit Care 2011, 15: R58. 10.1186/cc10031

    Article  PubMed Central  PubMed  Google Scholar 

  2. Cohen J: The immunopathogenesis of sepsis. Nature 2002, 420: 885-891. 10.1038/nature01326

    Article  CAS  PubMed  Google Scholar 

  3. Annane D, Bellissant E, Cavaillon JM: Septic shock. Lancet 2005, 365: 63-78. 10.1016/S0140-6736(04)17667-8

    Article  CAS  PubMed  Google Scholar 

  4. Monneret G, Venet F, Pachot A, Lepape A: Monitoring immune dysfunctions in the septic patient: a new skin for the old ceremony. Mol Med 2008, 14: 64-78. 10.2119/2007-00102.Monneret

    Article  PubMed Central  PubMed  Google Scholar 

  5. Schefold JC, Hasper D, Volk HD, Reinke P: Sepsis: time has come to focus on the later stages. Med Hypotheses 2008, 71: 203-208. 10.1016/j.mehy.2008.03.022

    Article  PubMed  Google Scholar 

  6. Hotchkiss RS, Opal S: Immunotherapy for sepsis - a new approach against an ancient foe. N Engl J Med 2010, 363: 87-89. 10.1056/NEJMcibr1004371

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Schefold JC: Measurement of monocytic HLA-DR (mHLA-DR) expression in patients with severe sepsis and septic shock: assessment of immune organ failure. Intensive Care Med 2010, 36: 1810-1812. 10.1007/s00134-010-1965-7

    Article  PubMed  Google Scholar 

  8. Landelle C, Lepape A, Voirin N, Tognet E, Venet F, Bohe J, Vanhems P, Monneret G: Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med 2010, 36: 1859-1866. 10.1007/s00134-010-1962-x

    Article  CAS  PubMed  Google Scholar 

  9. Monneret G, Lepape A, Voirin N, Bohe J, Venet F, Debard AL, Thizy H, Bienvenu J, Gueyffier F, Vanhems P: Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med 2006, 32: 1175-1183. 10.1007/s00134-006-0204-8

    Article  PubMed  Google Scholar 

  10. Schefold JC, Hasper D, Reinke P, Monneret G, Volk HD: Consider delayed immunosuppression into the concept of sepsis. Crit Care Med 2008, 36: 3118. 10.1097/CCM.0b013e31818bdd8f

    Article  PubMed  Google Scholar 

  11. Docke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, Volk HD, Kox W: Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 1997, 3: 678-681. 10.1038/nm0697-678

    Article  CAS  PubMed  Google Scholar 

  12. Schefold JC, von Haehling S, Corsepius M, Pohle C, Kruschke P, Zuckermann H, Volk HD, Reinke P: A novel selective extracorporeal intervention in sepsis: immunoadsorption of endotoxin, interleukin 6, and complement-activating product 5a. Shock 2007, 28: 418-425. 10.1097/shk.0b013e31804f5921

    Article  CAS  PubMed  Google Scholar 

  13. Hamilton JA: Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 2008, 8: 533-544. 10.1038/nri2356

    Article  CAS  PubMed  Google Scholar 

  14. Ballinger MN, Paine R, Serezani CH, Aronoff DM, Choi ES, Standiford TJ, Toews GB, Moore BB: Role of granulocyte macrophage colony-stimulating factor during gram-negative lung infection with Pseudomonas aeruginosa . Am J Respir Cell Mol Biol 2006, 34: 766-774. 10.1165/rcmb.2005-0246OC

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. 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: Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med 2009, 180: 640-648. 10.1164/rccm.200903-0363OC

    Article  CAS  PubMed  Google Scholar 

  16. Monneret G, Venet F, Meisel C, Schefold JC: Assessment of monocytic HLA-DR expression in ICU patients: analytical issues for multicentric flow cytometry studies. Crit Care 2010, 14: 432. 10.1186/cc9184

    Article  PubMed Central  PubMed  Google Scholar 

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Correspondence to Joerg C Schefold.

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Schefold, J.C. Immunostimulation using granulocyte- and granulocyte-macrophage colony stimulating factor in patients with severe sepsis and septic shock. Crit Care 15, 136 (2011).

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