Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Critical Care
Published in: Critical Care 1/2011

Open Access 01-02-2011 | Research

Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis

Authors: Lulong Bo, Fei Wang, Jiali Zhu, Jinbao Li, Xiaoming Deng

Published in: Critical Care | Issue 1/2011

Login to get access

Abstract

Introduction

To investigate the effects of G-CSF or GM-CSF therapy in non-neutropenic patients with sepsis.

Methods

A systematic literature search of Medline, Embase and Cochrane Central Register of Controlled Trials was conducted using specific search terms. A manual review of references was also performed. Eligible studies were randomized control trials (RCTs) that compared granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) therapy with placebo for the treatment of sepsis in adults. Main outcome measures were all-cause mortality at 14 days and 28 days after initiation of G-CSF or GM-CSF therapy, in-hospital mortality, reversal rate from infection, and adverse events.

Results

Twelve RCTs with 2,380 patients were identified. In regard to 14-day mortality, a total of 9 death events occurred among 71 patients (12.7%) in the treatment group compared with 13 events among 67 patients (19.4%) in the placebo groups. Meta-analysis showed there was no significant difference in 28-day mortality when G-CSF or GM-CSF were compared with placebo (relative risks (RR) = 0.93, 95% confidence interval (CI): 0.79 to 1.11, P = 0.44; P for heterogeneity = 0.31, I2 = 15%). Compared with placebo, G-CSF or GM-CSF therapy did not significantly reduce in-hospital mortality (RR = 0.97, 95% CI: 0.69 to 1.36, P = 0.86; P for heterogeneity = 0.80, I2 = 0%). However, G-CSF or GM-CSF therapy significantly increased the reversal rate from infection (RR = 1.34, 95% CI: 1.11 to 1.62, P = 0.002; P for heterogeneity = 0.47, I2 = 0%). No significant difference was observed in adverse events between groups (RR = 0.93, 95% CI: 0.70 to 1.23, P = 0.62; P for heterogeneity = 0.03, I2 = 58%). Sensitivity analysis by excluding one trial did not significantly change the results of adverse events (RR = 1.05, 95% CI: 0.84 to 1.32, P = 0.44; P for heterogeneity = 0.17, I2 = 36%).

Conclusions

There is no current evidence supporting the routine use of G-CSF or GM-CSF in patients with sepsis. Large prospective multicenter clinical trials investigating monocytic HLA-DR (mHLA-DR)-guided G-CSF or GM-CSF therapy in patients with sepsis-associated immunosuppression are warranted.
Appendix
Available only for authorised users
Literature
1.
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR: Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001, 29: 1303-1310. 10.1097/00003246-200107000-00002PubMedCrossRef
2.
Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001, 345: 1368-1377. 10.1056/NEJMoa010307PubMedCrossRef
3.
Martin GS, Mannino DM, Eaton S, Moss M: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003, 348: 1546-1554. 10.1056/NEJMoa022139PubMedCrossRef
4.
Annane D, Bellissant E, Cavaillon JM: Septic shock. Lancet 2005, 365: 63-78. 10.1016/S0140-6736(04)17667-8PubMedCrossRef
5.
6.
Carlet J, Cohen J, Calandra T, Opal SM, Masur H: Sepsis: time to reconsider the concept. Crit Care Med 2008, 36: 964-966. 10.1097/CCM.0B013E318165B886PubMedCrossRef
7.
Schefold JC: Measurement of monocytic HLA-DR (mHLA-DR) expression in patients with severe sepsis and septic shock: assessment of immune organ failure. Intensive Care Med 2010, 36: 1810-1812. 10.1007/s00134-010-1965-7PubMedCrossRef
8.
Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med 2003, 348: 138-150. 10.1056/NEJMra021333PubMedCrossRef
9.
Pachot A, Monneret G, Brion A, Venet F, Bohe J, Bienvenu J, Mougin B, Lepape A: Messenger RNA expression of major histocompatibility complex class II genes in whole blood from septic shock patients. Crit Care Med 2005, 33: 31-38. discussion 236-237 10.1097/01.CCM.0000150958.20209.A3PubMedCrossRef
10.
Pachot A, Lepape A, Vey S, Bienvenu J, Mougin B, Monneret G: Systemic transcriptional analysis in survivor and non-survivor septic shock patients: a preliminary study. Immunol Lett 2006, 106: 63-71. 10.1016/j.imlet.2006.04.010PubMedCrossRef
11.
Monneret G, Lepape A, Voirin N, Bohe J, Venet F, Debard AL, Thizy H, Bienvenu J, Gueyffier F, Vanhems P: Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med 2006, 32: 1175-1183. 10.1007/s00134-006-0204-8PubMedCrossRef
12.
Heidecke CD, Weighardt H, Hensler T, Bartels H, Holzmann B: [Immune paralysis of T-lymphocytes and monocytes in postoperative abdominal sepsis. Correlation of immune function with survival]. Chirurg 2000, 71: 159-165. 10.1007/s001040050028PubMedCrossRef
13.
Munford RS, Pugin J: Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med 2001, 163: 316-321.PubMedCrossRef
14.
Monneret G, Venet F, Pachot A, Lepape A: Monitoring immune dysfunctions in the septic patient: a new skin for the old ceremony. Mol Med 2008, 14: 64-78. 10.2119/2007-00102.MonneretPubMedPubMedCentralCrossRef
15.
Schefold JC, Hasper D, Volk HD, Reinke P: Sepsis: time has come to focus on the later stages. Med Hypotheses 2008, 71: 203-208. 10.1016/j.mehy.2008.03.022PubMedCrossRef
16.
Pugin J: Immunostimulation is a rational therapeutic strategy in sepsis. Novartis Found Symp 2007, 280: 21-27. discussion 27-36, 160-164 full_textPubMedCrossRef
17.
Wesche DE, Lomas-Neira JL, Perl M, Chung CS, Ayala A: Leukocyte apoptosis and its significance in sepsis and shock. J Leukoc Biol 2005, 78: 325-337. 10.1189/jlb.0105017PubMedCrossRef
18.
Monneret G, Debard AL, Venet F, Bohe J, Hequet O, Bienvenu J, Lepape A: Marked elevation of human circulating CD4+CD25+ regulatory T cells in sepsis-induced immunoparalysis. Crit Care Med 2003, 31: 2068-2071. 10.1097/01.CCM.0000069345.78884.0FPubMedCrossRef
19.
20.
Hoesel LM, Gao H, Ward PA: New insights into cellular mechanisms during sepsis. Immunol Res 2006, 34: 133-141. 10.1385/IR:34:2:133PubMedCrossRef
21.
Hotchkiss RS, Tinsley KW, Swanson PE, Schmieg RE Jr, Hui JJ, Chang KC, Osborne DF, Freeman BD, Cobb JP, Buchman TG, Karl IE: Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol 2001, 166: 6952-6963.PubMedCrossRef
22.
Volk HD, Reinke P, Falck P, Staffer G, v Backer R: Diagnostic value of an immune monitoring program for the clinical management of immunosuppressed patients with septic complications. Clin Transplant 1989, 3: 246-252.
23.
Schefold JC, Hasper D, Reinke P, Monneret G, Volk HD: Consider delayed immunosuppression into the concept of sepsis. Crit Care Med 2008, 36: 3118. 10.1097/CCM.0b013e31818bdd8fPubMedCrossRef
24.
Stephens DP, Fisher DA, Currie BJ: An audit of the use of granulocyte colony-stimulating factor in septic shock. Intern Med J 2002, 32: 143-148. 10.1046/j.1445-5994.2002.00195.xPubMedCrossRef
25.
Flohe S, Borgermann J, Dominguez FE, Majetschak M, Lim L, Kreuzfelder E, Obertacke U, Nast-Kolb D, Schade FU: Influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) on whole blood endotoxin responsiveness following trauma, cardiopulmonary bypass, and severe sepsis. Shock 1999, 12: 17-24. 10.1097/00024382-199907000-00003PubMedCrossRef
26.
Flohe S, Lendemans S, Selbach C, Waydhas C, Ackermann M, Schade FU, Kreuzfelder E: Effect of granulocyte-macrophage colony-stimulating factor on the immune response of circulating monocytes after severe trauma. Crit Care Med 2003, 31: 2462-2469. 10.1097/01.CCM.0000089640.17523.57PubMedCrossRef
27.
Haberstroh J, Breuer H, Lucke I, Massarrat K, Fruh R, Mand U, Hagedorn P, Brunnberg L, von Specht BU: Effect of recombinant human granulocyte colony-stimulating factor on hemodynamic and cytokine response in a porcine model of Pseudomonas sepsis. Shock 1995, 4: 216-224. 10.1097/00024382-199509000-00011PubMedCrossRef
28.
O'Reilly M, Silver GM, Greenhalgh DG, Gamelli RL, Davis JH, Hebert JC: Treatment of intra-abdominal infection with granulocyte colony-stimulating factor. J Trauma 1992, 33: 679-682.PubMedCrossRef
29.
Goya T, Torisu M, Doi F, Yoshida T: Effects of granulocyte colony stimulating factor and monobactam antibiotics (Aztreonam) on neutrophil functions in sepsis. Clin Immunol Immunopathol 1993, 69: 278-284. 10.1006/clin.1993.1181PubMedCrossRef
30.
Eichacker PQ, Waisman Y, Natanson C, Farese A, Hoffman WD, Banks SM, MacVittie TJ: Cardiopulmonary effects of granulocyte colony-stimulating factor in a canine model of bacterial sepsis. J Appl Physiol 1994, 77: 2366-2373.PubMed
31.
Carr R, Modi N, Doré C: G-CSF and GM-CSF for treating or preventing neonatal infections. Cochrane Database Syst Rev 2003, (3):CD003066.
32.
Moher D, Liberati A, Tetzlaff J, Altman DG: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009, 151: 264-269. W264PubMedCrossRef
33.
Robinson KA, Dickersin K: Development of a highly sensitive search strategy for the retrieval of reports of controlled trials using PubMed. Int J Epidemiol 2002, 31: 150-153. 10.1093/ije/31.1.150PubMedCrossRef
34.
Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008, 36: 296-327. 10.1097/01.CCM.0000298158.12101.41PubMedCrossRef
35.
Landis JR, Koch GG: The measurement of observer agreement for categorical data. Biometrics 1977, 33: 159-174. 10.2307/2529310PubMedCrossRef
36.
37.
Nelson Steve, Belknap SM: A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia. The Journal of Infectious Diseases 1998, 178: 1075-1080. 10.1086/515694PubMedCrossRef
38.
Nelson S, Heyder AM, Stone J, Bergeron MG, Daugherty S, Peterson G, Fotheringham N, Welch W, Milwee S, Root R: A randomized controlled trial of filgrastim for the treatment of hospitalized patients with multilobar pneumonia. Journal of Infectious Diseases 2000, 182: 970-973. 10.1086/315775PubMedCrossRef
39.
Tanaka H, Nishino M, Nakamori Y, Ogura H, Ishikawa K, Shimazu T, Sugimoto H: Granulocyte colony-stimulating factor (G-CSF) stiffens leukocytes but attenuates inflammatory response without lung injury in septic patients. J Trauma 2001, 51: 1110-1116. 10.1097/00005373-200112000-00016PubMedCrossRef
40.
Wunderink RG, Leeper KV Jr, Schein R, Nelson S, DeBoisblanc BP, Fotheringham N, Logan E: Filgrastim in patients with pneumonia and severe sepsis or septic shock. Chest 2001, 119: 523-529. 10.1378/chest.119.2.523PubMedCrossRef
41.
Presneill JJ, Harris T, Stewart AG, Cade JF, Wilson JW: A randomized phase II trial of granulocyte-macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction. Am J Respir Crit Care Med 2002, 166: 138-143. 10.1164/rccm.2009005PubMedCrossRef
42.
Root RK, Lodato RF, Patrick W, Cade JF, Fotheringham N, Milwee S, Vincent JL, Torres A, Rello J, Nelson S, Pneumonia Sepsis Study G: Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis. Critical Care Medicine 2003, 31: 367-373. 10.1097/01.CCM.0000048629.32625.5DPubMedCrossRef
43.
Hartmann P, Lammertink J, Mansmann G, Hübel K, Salzberger B, Stützer H, Engert A, Fätkenheuer G: A randomized, placebo-controlled study of the use of filgrastim in non neutropenic patients with nosocomial pneumonia. European Journal of Medical Research 2005, 10: 29-35.PubMed
44.
Rosenbloom AJ, Linden PK, Dorrance A, Penkosky N, Cohen-Melamed MH, Pinsky MR: Effect of granulocyte-monocyte colony-stimulating factor therapy on leukocyte function and clearance of serious infection in nonneutropenic patients. Chest 2005, 127: 2139-2150. 10.1378/chest.127.6.2139PubMedCrossRef
45.
Orozco H, Arch J, Medina-Franco H, Pantoja JP, González QH, Vilatoba M, Hinojosa C, Vargas-Vorackova F, Sifuentes-Osornio J: Molgramostim (GM-CSF) associated with antibiotic treatment in nontraumatic abdominal sepsis: a randomized, double-blind, placebo-controlled clinical trial. Archives of Surgery 2006, 141: 150-153. discussion 154 10.1001/archsurg.141.2.150PubMedCrossRef
46.
Cheng AC, Limmathurotsakul D, Chierakul W, Getchalarat N, Wuthiekanun V, Stephens DP, Day NP, White NJ, Chaowagul W, Currie BJ, Peacock SJ: A randomized controlled trial of granulocyte colony-stimulating factor for the treatment of severe sepsis due to melioidosis in Thailand. Clinical Infectious Diseases 2007, 45: 308-314. 10.1086/519261PubMedCrossRef
47.
Stephens DP, Thomas JH, Higgins A, Bailey M, Anstey NM, Currie BJ, Cheng AC: Randomized, double-blind, placebo-controlled trial of granulocyte colony-stimulating factor in patients with septic shock. Crit Care Med 2008, 36: 448-454. 10.1097/01.CCM.0B013E318161E480PubMedCrossRef
48.
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: Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med 2009, 180: 640-648. 10.1164/rccm.200903-0363OCPubMedCrossRef
49.
Cheng AC, Stephens DP, Currie BJ: Granulocyte-Colony Stimulating Factor (G-CSF) as an adjunct to antibiotics in the treatment of pneumonia in adults. Cochrane Database Syst Rev 2007, (2):CD004400.
50.
Fumeaux T, Pugin J: Is the measurement of monocytes HLA-DR expression useful in patients with sepsis? Intensive Care Med 2006, 32: 1106-1108. 10.1007/s00134-006-0205-7PubMedCrossRef
51.
Tschoeke SK, Moldawer LL: Human leukocyte antigen expression in sepsis: what have we learned? Crit Care Med 2005, 33: 236-237. 10.1097/01.CCM.0000150835.66819.CAPubMedCrossRef
52.
Engelhard M, Brittinger G: Clinical relevance of granulocyte-macrophage colony-stimulating factor. Semin Oncol 1994, 21: 1-4.PubMed
53.
Lin E, Calvano SE, Lowry SF: Inflammatory cytokines and cell response in surgery. Surgery 2000, 127: 117-126. 10.1067/msy.2000.101584PubMedCrossRef
54.
Gough A, Clapperton M, Rolando N, Foster AV, Philpott-Howard J, Edmonds ME: Randomised placebo-controlled trial of granulocyte-colony stimulating factor in diabetic foot infection. Lancet 1997, 350: 855-859. 10.1016/S0140-6736(97)04495-4PubMedCrossRef
55.
Nierhaus A, Montag B, Timmler N, Frings DP, Gutensohn K, Jung R, Schneider CG, Pothmann W, Brassel AK, Schulte Am Esch J: Reversal of immunoparalysis by recombinant human granulocyte-macrophage colony-stimulating factor in patients with severe sepsis. Intensive Care Med 2003, 29: 646-651.PubMed
56.
Schneider C, von Aulock S, Zedler S, Schinkel C, Hartung T, Faist E: Perioperative recombinant human granulocyte colony-stimulating factor (Filgrastim) treatment prevents immunoinflammatory dysfunction associated with major surgery. Ann Surg 2004, 239: 75-81. 10.1097/01.sla.0000103062.21049.82PubMedPubMedCentralCrossRef
Metadata
Title
Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis
Authors
Lulong Bo
Fei Wang
Jiali Zhu
Jinbao Li
Xiaoming Deng
Publication date
01-02-2011
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2011
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/cc10031

Other articles of this Issue 1/2011

Critical Care 1/2011 Go to the issue

Commentary

In-hospital brain natriuretic peptide and N-terminal prohormone brain natriuretic peptide variations are predictors of short-term and long-term outcome in acute decompensated heart failure

Research

Effect of norepinephrine dosage and calibration frequency on accuracy of pulse contour-derived cardiac output

Commentary

Platelets, endothelium and shear join forces to mislead neutrophils in sepsis

Research

An updated study-level meta-analysis of randomised controlled trials on proning in ARDS and acute lung injury

Research

Hormonal responses upon return of spontaneous circulation after cardiac arrest: a retrospective cohort study

Review

Clinical review: Blood purification for sepsis