Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial.
BACKGROUND
Sustained sepsis-associated immunosuppression is associated with uncontrolled infection, multiple organ dysfunction, and death.


OBJECTIVE
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.


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).
Meisel
Christian
C
Department of Medical Immunology, Charité Campus Mitte, Berlin, Germany.
Schefold
Joerg C
JC
Pschowski
Rene
R
Baumann
Tycho
T
Hetzger
Katrin
K
Gregor
Jan
J
Weber-Carstens
Steffen
S
Hasper
Dietrich
D
Keh
Didier
D
Zuckermann
Heidrun
H
Reinke
Petra
P
Volk
Hans-Dieter
HD
D015415:Biomarkers / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood* / Q000276:immunology / Q000627:therapeutic use*; D006684:HLA-DR Antigens / Q000097:blood / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D007902:Length of Stay / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012121:Respiration, Artificial / Q000706:statistics & numerical data; D018805:Sepsis / Q000097:blood* / Q000150:complications / Q000276:immunology*; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000097:blood / Q000150:complications / Q000276:immunology; D016896:Treatment Outcome
D015415:Biomarkers; D006684:HLA-DR Antigens; D016178:Granulocyte-Macrophage Colony-Stimulating Factor