Journal Article

Granulocyte-Macrophage Colony-stimulating Factor to Reverse Sepsis-associated Immunosuppression: A Double-Blind, Randomized, Placebo-controlled Multicenter Trial

Pschowski, Rene, Baumann, Tycho, Gregor, Jan, Hetzger, Katrin, Reinke, Petra, Weber-Carstens, Steffen, Meisel, Christian, Keh, Didier, Schefold, Joerg C, Zuckermann, Heidrun, Hasper, Dietrich, Volk, Hans-Dieter

2009

Overview

Abstract Rationale Sustained sepsis-associated immunosuppression is associated with uncontrolled infection, multiple organ dysfunction, and death. Objectives In the first controlled biomarker-guided immunostimulatory trial in sepsis, we tested whether granulocyte–macrophage colony-stimulating factor (GM-CSF) reverses monocyte deactivation, a hallmark of sepsis-associated immunosuppression (primary endpoint), and improves the immunological and clinical course of patients with sepsis. Methods In a prospective, randomized, double-blind, placebo-controlled, multicenter trial, 38 patients (19/group) with severe sepsis or septic shock and sepsis-associated immunosuppression (monocytic HLA-DR [mHLA-DR] <8,000 monoclonal antibodies (mAb) per cell for 2 d) were treated with GM-CSF (4 μg/kg/d) or placebo for 8 days. The patients' clinical and immunological course was followed up for 28 days. Measurements and Main Results Both groups showed comparable baseline mHLA-DR levels (5,609 ± 3,628 vs. 5,659 ± 3,332 mAb per cell), which significantly increased within 24 hours in the GM-CSF group. After GM-CSF treatment, mHLA-DR was normalized in 19/19 treated patients, whereas this occurred in 3/19 control subjects only (P < 0.001). GM-CSF also restored ex-vivo Toll-like receptor 2/4–induced proinflammatory monocytic cytokine production. In patients receiving GM-CSF, a shorter time of mechanical ventilation (148 ± 103 vs. 207 ± 58 h, P = 0.04), an improved Acute Physiology and Chronic Health Evaluation-II score (P = 0.02), and a shorter length of both intrahospital and intensive care unit stay was observed (59 ± 33 vs. 69 ± 46 and 41 ± 26 vs. 52 ± 39 d, respectively, both not significant). Side effects related to the intervention were not noted. Conclusions Biomarker-guided GM-CSF therapy in sepsis is safe and effective for restoring monocytic immunocompetence. Use of GM-CSF may shorten the time of mechanical ventilation and hospital/intensive care unit stay. A multicenter trial powered for the improvement of clinical parameters and mortality as primary endpoints seems indicated. Clinical trial registered with www.clinicaltrials.gov (NCT00252915).

• Publisher: Am Thoracic Soc,Oxford University Press,American Thoracic Society
• Subject: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / Biological and medical sciences / Biomarkers / Biomarkers - blood / Cytokines / Double-Blind Method / Emergency and intensive care: infection, septic shock / Female / Flow Cytometry / Follow-Up Studies / Granulocyte-Macrophage Colony-Stimulating Factor - blood / Granulocyte-Macrophage Colony-Stimulating Factor - immunology / Granulocyte-Macrophage Colony-Stimulating Factor - therapeutic use / Granulocytes / HLA-DR Antigens - blood / HLA-DR Antigens - drug effects / HLA-DR Antigens - immunology / Hospitals / Humans / Immune Tolerance - drug effects / Immune Tolerance - immunology / Immunology / Immunosuppressive agents / Intensive care / Intensive care medicine / Length of Stay - statistics & numerical data / Male / Medical research / Medical sciences / Middle Aged / Monoclonal antibodies / Mortality / Neutrophils / Patients / Prospective Studies / Respiration, Artificial - statistics & numerical data / Sepsis / Sepsis - blood / Sepsis - complications / Sepsis - immunology / Severity of Illness Index / Shock, Septic - blood / Shock, Septic - complications / Shock, Septic - immunology / Treatment Outcome / Ventilators