Use of G-CSF in Patients With Severe Sepsis or Septic Shock
Use of G-CSF in Patients With Severe Sepsis or Septic Shock
Purpose. The efficacy and safety of granulocyte colony-stimulating factor (G-CSF) in critically ill patients with severe sepsis or septic shock were evaluated.
Summary. The medical literature was reviewed to identify published trials, case reports, and case series on the use of G-CSF in critically ill patients for treatment of severe sepsis or septic shock. G-CSF has been evaluated as an adjunct to standard care for critically ill patients. Initial studies involving critically ill patients with severe sepsis or septic shock found mortality benefits with G-CSF therapy; however, these findings are limited by factors such as small sample sizes, selection bias, and lack of an appropriate control group. Prospective, randomized, multicenter, double-blind studies failed to confirm the benefits in mortality for patients receiving G-CSF for the treatment of severe sepsis and septic shock. Due to the limitations in the design of the studies that report a mortality benefit and prospective, randomized, multicenter, double-blind studies that report the lack of a mortality benefit, a recommendation to add G-CSF as an adjunctive therapy in critically ill patients with severe sepsis and septic shock cannot be made at this time.
Conclusion. The available data, especially those from large, prospective, randomized, double-blind studies, do not support the use of G-CSF as an adjunct therapy to standard care for critically ill patients with severe sepsis or septic shock. Data from prospective, large, randomized, controlled, well-designed studies are needed to define the optimal G-CSF dosing regimen, the safety of this therapy, and the effects of G-CSF on patient morbidity and survival.
The rate of hospitalization due to severe sepsis and septic shock has increased over the years. Hospitalization rates for severe sepsis nearly doubled from 1993 to 2003, and in 1995 the mortality rate of severe sepsis was estimated to be almost 30%. Since sepsis is considered to stimulate production of endogenous granulocyte colony-stimulating factor (G-CSF) and since patients with sepsis are generally immunosuppressed, G-CSF administration could improve patients' ability to restore neutrophil count and function, potentially improving morbidity and mortality rates. G-CSF, a growth factor produced by fibroblasts, monocytes, and endothelial cells, stimulates the production of neutrophils and modulates the function and activity of developing and mature neutrophils. Increases in neutrophil motility and phagocytic activity against viable bacteria have been demonstrated with G-CSF administration. G-CSF may also block the hyperinflammatory cytokine cascade mediated by inflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin 1, before severe tissue damage occurs. The timing of G-CSF administration may also affect patient outcomes. Unresolved infections may precipitate and drive the systemic inflammatory response, potentially resulting in multiple organ failure (MOF) and septic shock. Early G-CSF administration before the systemic inflammatory response could enhance the host defense process and successfully resolve the inciting event. Several preclinical and clinical studies support early G-CSF administration in patients with infections or at high risk of developing infections.
Two formulations of recombinant G-CSF are available in the United States: filgrastim and pegfilgrastim. Filgrastim is approved by the Food and Drug Administration (FDA) for the prevention of febrile neutropenia in patients with nonmyeloid and acute myeloid leukemia, malignancies after chemotherapy, and progenitor cell transplantation; harvesting of bone marrow stem cells; and treatment of severe, chronic, and symptomatic neutropenic disorders. Pegfilgrastim is approved for the prevention of febrile neutropenia in patients with nonmyeloid malignancies. Lenograstim, another formulation of recombinant G-CSF, is available in Asia and Europe. Filgrastim is G-CSF derived from Escherichia coli, has an extra methionine group at the N-terminal end of the peptide chain when compared with lenograstim, and is nonglycosylated. Pegfilgrastim is the pegylated formulation of filgrastim; however, pegfilgrastim has not been studied in patients with severe sepsis or septic shock. Lenograstim is G-CSF derived from a Chinese hamster ovary and differs from the native G-CSF in that it contains 174 amino acids with 4% carbohydrate. In vitro studies have demonstrated that lenograstim is more stable and potent than filgrastim (weight-for-weight comparison); however, prospective clinical studies have not conclusively demonstrated a difference in efficacy between the two drugs. The difference between G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF) should also be noted. GM-CSF exhibits broader effects and induces proliferation and differentiation of neutrophils, monocytes, macrophages, and myeloid-derived dendritic cells. G-CSF may play a role in downregulating inflammatory immune response while GM-CSF may promote the release of inflammatory cytokines, such as interleukin 1, TNF and interleukin 6. This article focuses only on the use of G-CSF in critically ill patients.
The use of G-CSF in several animal models with various infections (e.g., pneumonia, sepsis, intra-abdominal infection) resulted in enhanced neutrophil production and function, increased clearance of bacteria from the lungs, and improved survival compared with placebo. G-CSF was also shown to be beneficial for nonneutropenic sepsis in animal models. In these preclinical studies, a decrease in cytokine concentrations and an increase in elimination of endotoxin and bacteria led to reduced mortality rates in the G-CSF group. These results prompted clinical studies to evaluate the efficacy and safety of G-CSF as adjunct therapy to antibiotics for bacterial and fungal infections in nonimmunocompromised patients. However, the results of these clinical studies were conflicting. In 1998, Nelson et al. found a reduction in serious complications due to rapid radiological lung improvement in response to G-CSF (filgrastim) treatment in a subgroup of patients with severe pneumonia. However, in 2007, a meta-analysis evaluating the use of G-CSF in non-neutropenic patients as an adjunct therapy to antibiotics for the treatment of pneumonia showed no significant reduction in mortality with G-CSF use.
Abstract and Introduction
Abstract
Purpose. The efficacy and safety of granulocyte colony-stimulating factor (G-CSF) in critically ill patients with severe sepsis or septic shock were evaluated.
Summary. The medical literature was reviewed to identify published trials, case reports, and case series on the use of G-CSF in critically ill patients for treatment of severe sepsis or septic shock. G-CSF has been evaluated as an adjunct to standard care for critically ill patients. Initial studies involving critically ill patients with severe sepsis or septic shock found mortality benefits with G-CSF therapy; however, these findings are limited by factors such as small sample sizes, selection bias, and lack of an appropriate control group. Prospective, randomized, multicenter, double-blind studies failed to confirm the benefits in mortality for patients receiving G-CSF for the treatment of severe sepsis and septic shock. Due to the limitations in the design of the studies that report a mortality benefit and prospective, randomized, multicenter, double-blind studies that report the lack of a mortality benefit, a recommendation to add G-CSF as an adjunctive therapy in critically ill patients with severe sepsis and septic shock cannot be made at this time.
Conclusion. The available data, especially those from large, prospective, randomized, double-blind studies, do not support the use of G-CSF as an adjunct therapy to standard care for critically ill patients with severe sepsis or septic shock. Data from prospective, large, randomized, controlled, well-designed studies are needed to define the optimal G-CSF dosing regimen, the safety of this therapy, and the effects of G-CSF on patient morbidity and survival.
Introduction
The rate of hospitalization due to severe sepsis and septic shock has increased over the years. Hospitalization rates for severe sepsis nearly doubled from 1993 to 2003, and in 1995 the mortality rate of severe sepsis was estimated to be almost 30%. Since sepsis is considered to stimulate production of endogenous granulocyte colony-stimulating factor (G-CSF) and since patients with sepsis are generally immunosuppressed, G-CSF administration could improve patients' ability to restore neutrophil count and function, potentially improving morbidity and mortality rates. G-CSF, a growth factor produced by fibroblasts, monocytes, and endothelial cells, stimulates the production of neutrophils and modulates the function and activity of developing and mature neutrophils. Increases in neutrophil motility and phagocytic activity against viable bacteria have been demonstrated with G-CSF administration. G-CSF may also block the hyperinflammatory cytokine cascade mediated by inflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin 1, before severe tissue damage occurs. The timing of G-CSF administration may also affect patient outcomes. Unresolved infections may precipitate and drive the systemic inflammatory response, potentially resulting in multiple organ failure (MOF) and septic shock. Early G-CSF administration before the systemic inflammatory response could enhance the host defense process and successfully resolve the inciting event. Several preclinical and clinical studies support early G-CSF administration in patients with infections or at high risk of developing infections.
Two formulations of recombinant G-CSF are available in the United States: filgrastim and pegfilgrastim. Filgrastim is approved by the Food and Drug Administration (FDA) for the prevention of febrile neutropenia in patients with nonmyeloid and acute myeloid leukemia, malignancies after chemotherapy, and progenitor cell transplantation; harvesting of bone marrow stem cells; and treatment of severe, chronic, and symptomatic neutropenic disorders. Pegfilgrastim is approved for the prevention of febrile neutropenia in patients with nonmyeloid malignancies. Lenograstim, another formulation of recombinant G-CSF, is available in Asia and Europe. Filgrastim is G-CSF derived from Escherichia coli, has an extra methionine group at the N-terminal end of the peptide chain when compared with lenograstim, and is nonglycosylated. Pegfilgrastim is the pegylated formulation of filgrastim; however, pegfilgrastim has not been studied in patients with severe sepsis or septic shock. Lenograstim is G-CSF derived from a Chinese hamster ovary and differs from the native G-CSF in that it contains 174 amino acids with 4% carbohydrate. In vitro studies have demonstrated that lenograstim is more stable and potent than filgrastim (weight-for-weight comparison); however, prospective clinical studies have not conclusively demonstrated a difference in efficacy between the two drugs. The difference between G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF) should also be noted. GM-CSF exhibits broader effects and induces proliferation and differentiation of neutrophils, monocytes, macrophages, and myeloid-derived dendritic cells. G-CSF may play a role in downregulating inflammatory immune response while GM-CSF may promote the release of inflammatory cytokines, such as interleukin 1, TNF and interleukin 6. This article focuses only on the use of G-CSF in critically ill patients.
The use of G-CSF in several animal models with various infections (e.g., pneumonia, sepsis, intra-abdominal infection) resulted in enhanced neutrophil production and function, increased clearance of bacteria from the lungs, and improved survival compared with placebo. G-CSF was also shown to be beneficial for nonneutropenic sepsis in animal models. In these preclinical studies, a decrease in cytokine concentrations and an increase in elimination of endotoxin and bacteria led to reduced mortality rates in the G-CSF group. These results prompted clinical studies to evaluate the efficacy and safety of G-CSF as adjunct therapy to antibiotics for bacterial and fungal infections in nonimmunocompromised patients. However, the results of these clinical studies were conflicting. In 1998, Nelson et al. found a reduction in serious complications due to rapid radiological lung improvement in response to G-CSF (filgrastim) treatment in a subgroup of patients with severe pneumonia. However, in 2007, a meta-analysis evaluating the use of G-CSF in non-neutropenic patients as an adjunct therapy to antibiotics for the treatment of pneumonia showed no significant reduction in mortality with G-CSF use.
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