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 metaanalysis published in Critical Care [1] evaluated clinical eff ects 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 'hyperinfl ammatory' phase in sepsis is often followed by a persistent 'hypo-infl ammation' with severe alterations in both innate and cellular immunity [2][3][4][5]. Findings during this state of 'sepsis-associated immunosuppression' include diminished phagocytotic activity, cytokine expression profi le changes towards an anti-infl ammatory phenotype, increased expression of negative (co-)stimu latory molecules, reduced monocytic antigen presenta tion via the major histocompatibility (MHC) class II complex (mHLA-DR), dysfunction and apoptosis of lymphocytes, and upregulation of regulatory T cells [2][3][4][5][6][7]. 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 success fully in the early shock phase, will then develop an 'anergic' immunological state, and will fi nally succumb to repeated infections from rather avirulent secondary pathogens.
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 eff ects of G-CSF (n = 8 RCTs) and GM-CSF (n = 4 RCTs) in patients with severe sepsis/septic shock. Th e 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 signifi cant diff erence in 28-day mortality (relative risk (RR) 0.93, 95% confi dence 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

Abstract
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 metaanalysis investigating the eff ects of granulocyte-and granulocyte-macrophage colony-stimulating factor therapy in patients with severe sepsis and septic shock. 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 benefi t. In line with previous fi ndings from non-randomized trials, CSF therapy appeard safe. Nevertheless, although an eff ect on mortality was not observed, the meta-analysis identifi ed that patients receiving G-CSF or GM-CSF therapy have a signifi cantly increased rate of reversal from infection (RR 1.34, 95% CI 1.11 to 1.62, P = 0.002). Although this fi nding is mainly based on available G-CSF data, it supports earlier fi ndings from animal models that CSF therapy may indeed induce a faster reversal from infection. Th is seems especially the case in pneumogenic sepsis [14]. In line with data from animal models and G-CSF trials, we recently demonstrated in the fi rst biomarker-guided immunostimulatory placebo-controlled RCT in sepsis that GM-CSF therapy signifi cantly 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 diff ered greatly in regard to applied CSF doses, routes of adminis tration, pharmacological CSF subtypes and patient characteristics (for example, disease severity). Th is certainly constrains data comparability. Th ird, most trials did not stratify study patients according to their immuno logical state and the effi cacy of the immunological inter vention was not tested or reported. We believe that this remains a prerequisite for future immuno modulatory trials in sepsis. Although assessment of the underlying complex immunological condition using a single bio marker may be regarded as challenging, standardized quantitative tests (for example, fl ow-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 stratifi ed 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 benefi t 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.