A Randomized Phase II Trial of Granulocyte-Macrophage Colony-Stimulating Factor Therapy in Severe Sepsis with Respiratory Dysfunction

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates hemopoiesis and effector functions of granulocytes and macrophages and is involved in pulmonary surfactant homeostasis. We investigated whether GM-CSF therapy improved clinically diagnosed severe sepsis and respiratory dysfunction in critically ill patients. This randomized, double-blind, placebo-controlled phase II study added low-dose (3 mcg/kg) intravenous recombinant human GM-CSF daily for 5 days to conventional therapy in 10 patients, with a further eight patients receiving placebo. GM-CSF-treated patients showed improvement in Pa(O(2))/FI(O(2)) over 5 days (p = 0.02) and increased peripheral blood neutrophils (p = 0.08), whereas alveolar neutrophils decreased (p = 0.02). GM-CSF therapy was not associated with decreased 30-day survival or with increased acute respiratory distress syndrome or extrapulmonary organ dysfunction. GM-CSF therapy was associated with increased blood granulocyte superoxide production and restoration or preservation of blood and alveolar leukocyte phagocytic function. We conclude that low-dose GM-CSF was associated with improved gas exchange without pulmonary neutrophil infiltration, despite functional activation of both circulating neutrophils and pulmonary phagocytes. In addition, GM-CSF therapy was not associated with worsened acute respiratory distress syndrome or the multiple organ dysfunction syndrome, suggesting a homeostatic role for GM-CSF in sepsis-related pulmonary dysfunction.

Local delivery of Granulocyte/Macrophage Colony Stimulating Factor protects mice from lethal pneumococcal pneumonia

“…Consistent with our experimental data, a clinical trial in preterm neonates also showed that systemic administration of GM-CSF is not able to reduce sepsis rates or improve survival (51). In contrast, intravenous infusion of GM-CSF in patients with severe sepsis and respiratory failure significantly improved oxygenation and had a positive impact on the development of ARDS, which was associated with improved function of blood and alveolar neutrophils (52). This suggests that GM-CSF is most effective when administered directly to the site of infection, which may explain why systemic delivery of GM-CSF was not protective in mice with pneumococcal pneumonia.…”

Monitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony

“…However, despite interesting results regarding secondary end points in some subgroups of patients (decreased severity in nosocomial infections, decreased mortality in infected patients), they remained inconclusive regarding overall mortality or infection rates (187,188). Presneill et al (189) presented preliminary GM-CSF data in 10 patients with sepsis-induced respiratory failure. They observed modest improvement in gas exchange, ARDS resolution, and alveolar leukocyte phagocytic functions, but it was not accompanied by enhanced survival.…”

Interleukin 5 Is Protective during Sepsis in an Eosinophil-Independent Manner

“…This has generated interest in targeting factors responsible for myeloid cell maturation and function in sepsis. Administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) while recruiting additional and potentially proinflammatory leukocytes improved pathogen control and bacterial clearance in sepsis (17)(18)(19). In addition, administration of IL-33, which stimulates production of Th2 cytokines (including IL-5 and IL-13), improved survival in septic mice by neutrophil recruitment and improved pathogen control (20).…”