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Granulocyte–Macrophage Colony-stimulating Factor to Reverse Sepsis-associated Immunosuppression

A Double-Blind, Randomized, Placebo-controlled Multicenter Trial

¹ Department of Medical Immunology, and ³ Department of Surgery, Charité Campus Mitte; ² Department of Nephrology and Intensive Care Medicine, and ⁴ Department of Anaesthesiology, Charité Campus Virchow; and ⁵ Berlin-Brandenburg Center for Regenerative Therapies, Charité Campus Virchow, Charité University Medicine, Berlin, Germany

Correspondence and requests for reprints should be addressed to Joerg C. Schefold, M.D., Department of Nephrology and Intensive Care Medicine, Charité University Medicine Berlin, Berlin 13353, Germany. E-mail: schefold{at}charite.de

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).

Key Words: immune system • immunoparalysis • HLA-DR • sepsis • shock

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Many nonsurvivors from sepsis die in the later course of sepsis in a state of functional failure of cellular immunity. What This Study Adds to the Field This study demonstrates that immunostimulation with granulocyte–macrophage colony-stimulating factor effectively restores markers of monocytic immunocompetence. A beneficial impact on the clinical course of patients with severe sepsis and septic shock was also observed.

 

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A Novel Biomarker-guided Immunomodulatory Approach for the Therapy of Sepsis

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