Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial.

Meisel C; Schefold JC; Pschowski R; Baumann T; Hetzger K; Gregor J; Weber-Carstens S; Hasper D; Keh D; Zuckermann H; Reinke P; Volk HD

doi:10.1164/rccm.200903-0363oc

Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial.

Keh D ,

Affiliations

1. Department of Medical Immunology, Charité Campus Mitte, Berlin, Germany.
Authors
Meisel C¹
(1 author)

ORCIDs linked to this article

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American Journal of Respiratory and Critical Care Medicine, 09 Jul 2009, 180(7):640-648
https://doi.org/10.1164/rccm.200903-0363oc PMID: 19590022

A comment on this article appears in "Do corticosteroids influence the granulocyte macrophage colony-stimulating factor-mediated effects on monocyte function?" Am J Respir Crit Care Med. 2010 Mar 1;181(5):522; author reply 523. A comment on this article appears in "A novel biomarker-guided immunomodulatory approach for the therapy of sepsis." Am J Respir Crit Care Med. 2009 Oct 1;180(7):585-6.

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 microg/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).