Granulocyte Colony Stimulating Factor as a Therapy for Pneumonia and Sepsis in the Nonneutropenic Host: Preclinical and Clinical Trials

  • Chantal Parent
  • Peter Q. Eichacker
Part of the Perspectives on Critical Care Infectious Diseases book series (CCID, volume 2)


Outcome associated with severe pneumonia, especially when it is complicated by sepsis and septic shock remains poor in the nonneutropenic host despite our best conventional therapies (30 to 50%) (1,2). New modes of therapy are needed. An alternative to blocking the intense inflammatory response of sepsis, an approach which has not shown convincing benefit in clinical trials thus far, is to administer agents to augment host defense and better control the underlying infection. One such agent is recombinant granulocyte colony stimulating factor (G-CSF), a potent stimulator of neutrophil number and function (3,4). Similar to antiinflammatory agents however, despite promising results in preclinical studies, G-CSF has not shown convincing benefit in early clinical trials in nonneutropenic patients presenting with pneumonia or sepsis (5,6). While disappointing, our evolving preclinical and clinical experience with G-CSF may provide insight into ways to increase the effectiveness of this therapeutic approach in the future.


Septic Shock Lung Injury Granulocyte Colony Stimulate Factor Severe Pneumonia Tumor Necrosis Factor Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Natanson C, Hoffman WD, Suffredini AF, Eichacker PQ, Danner RL. Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis. Ann Intern Med 1994;120(9):771–783.PubMedGoogle Scholar
  2. 2.
    Freeman B, Eichacker PQ, Natanson C. The role of inflammation in sepsis and septic shock: a meta-analysis of both clinical and preclinical trials of anti-inflammatory therapies. In: Gallin JI SR, editor. Inflammation: Basic Principles and Correlates: Lippincott-Raven; 1999. p 965–976.Google Scholar
  3. 3.
    Root R, Dale, DC. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor: comparisons and potential for use in the treatment of infections in nonneutropenic patients. J Infect Dis 1999;179((Suppl 2)):S342–352.PubMedCrossRefGoogle Scholar
  4. 4.
    Nelson S, Summer WR. Innate immunity, cytokines, and pulmonary host defense. In: Infectious Disease Clinics of North America. Volume 12; 1998. p 555–567.PubMedCrossRefGoogle Scholar
  5. 5.
    Nelson S, Belknap SM, Carlson RW, Dale D, DeBoisblanc, Farkas S, Fotheringham N, Ho H, Marrie T, Hassan M, Root R, Wilson J. A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia. J Infect Dis 1998;178:1075–1080.PubMedCrossRefGoogle Scholar
  6. 6.
    Root RK. Granulocyte colony-stimulating factor in the treatment of severe pneumonia: studies in patients with sepsis and septic shock and/or multilobar pneumonia. First International Congress on Cytokines and Chemokines in Infectious Diseases; 1999. p A134.Google Scholar
  7. 7.
    Hammond W, Csiba E, Canin A, Hockman H, Souza LM, Layton JE, Dale DC. Chronic neutropenia — a new canine model induced by human granulocyte colony-stimulating factor. J Clin Invest 1991;87(2):704–710.PubMedCrossRefGoogle Scholar
  8. 8.
    Hammond W, Price TH, Sonta LM, Dale DC. Treatment of cyclic neutropenia with granulocyte colony-stimulating factor. N Engl J Med 1989;320:1306–1311.PubMedCrossRefGoogle Scholar
  9. 9.
    Hebert J, O’Reilly M, Gamelli RL. Protective effect of recombinant human granulocyte colony-stimulating factor against pneumococcal infections in splenectomized mice. Arch Surg 1990; 125:1075–1078.PubMedCrossRefGoogle Scholar
  10. 10.
    Mooney D, Gamelli RL, O’Reilly M, Hebert JC. Recombinant human granulocyte colony-stimulating factor and Pseudomonas burn wound sepsis. Arch Surg 1988;123:1353–1357.PubMedCrossRefGoogle Scholar
  11. 11.
    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(5):679–682.PubMedCrossRefGoogle Scholar
  12. 12.
    Nelson S, Summer W, Bagby G, Nakamura C, Stewart L, Lipscomb G, Andresen J. Granulocyte colony-stimulating factor enhances pulmonary host defenses in normal and ethanol-treated rats. J Infect Dis 1991;164:901–906.PubMedCrossRefGoogle Scholar
  13. 13.
    Kanazawa M, Ishizaka A, Hasegawa N, Suzuki Y, Yokoyama T. Granulocyte colony-stimulating factor does not enhance endotoxin-induced acute lung injury in guinea pigs. Am Rev Resp Dis 1992;145:1030–1035.PubMedCrossRefGoogle Scholar
  14. 14.
    Fink M, O’Sullivan BP, Menconi MJ, Wollert SP, Wang H, Youssef ME, Bellelsle JM. Effect of granulocyte colony-stimulating factor on systemic and pulmonary responses to endotoxin in pigs. J Trauma 1993;34(4):571–578.PubMedCrossRefGoogle Scholar
  15. 15.
    Koizumi T, Kubo K, Shinozaki S, Koyama S, Kobayashi T, Sekiguchi M. Granulocyte colony-stimulating factor does not exacerbate endotoxin-induced lung injury in sheep. Am Rev Respir Dis 1993; 148:132–137.PubMedGoogle Scholar
  16. 16.
    DeBoisblanc B, Mason CM, Andresen J, Logan E, Bear MB, Johnson S, Shellito J, Summer WR, Nelson S. Phase 1 safety trial of Filgrastim (r-metHuG-CSF) in non-neutropenic patients with severe community-acquired pneumonia. Resp Med 1997;91:387–394.CrossRefGoogle Scholar
  17. 17.
    Hustinex W, Van Kessel CPM, Heezius E, Burgers S, Lammers JW, Hoepelman IM. Effects of granulocyte colony-stimulating factor (G-CSF) treatment on granulocyte function and receptor expression in patients with ventilator-dependent pneumonia. Clin Exp Immunol 1998;112:334–340.CrossRefGoogle Scholar
  18. 18.
    Endo S, Inada K, Inoue Y, Yamada Y, Takakuwa T, Kasai T, Nakae H, Kuwata Y, Hoshi S, Yashida M. Evaluation of recombinant human granulocyte colony-stimulating factor (rhG-CSF) therapy in granulopoetic patients complicated with sepsis. Curr Med Res Opin 1994;13(4):233–239.PubMedCrossRefGoogle Scholar
  19. 19.
    Gross-Weege W, Weiss M, Schneider M, Wenning M, Harms B, Dumon K, Ohmann C, Röher H.-D. Safety of a low-dosage Filgrastim (rhG-CSF) treatment in non-neutropenic surgical intensive care patients with an inflammatory process. Intensive Care Med 1997;23:16–22.PubMedCrossRefGoogle Scholar
  20. 20.
    Ishikawa K, Tanaka H, Matsuoka T, Shimazu T, Yoshioka T, Sugimoto H. Recombinant human granulocyte colony-stimulating factor attenuates inflammatory responses in septic patients with neutropenia. J Trauma 1998;44(6):1047–1055.PubMedCrossRefGoogle Scholar
  21. 21.
    Nishida T, Hasegawa J, Nakao K, Fujita N. Granulocyte colony-stimulating factor for gastrointestinal perforation in patients with leukopenia. J Trauma 1996;40(5):727–732.PubMedCrossRefGoogle Scholar
  22. 22.
    Gough A, Clapperton M, Rolando N, Foster AVM, Philpott-Howard J, Edmonds ME. Randomised placebo-controlled trial of granulocyte-colony stimulating factor in diabetic foot infection. Lancet 1997;350:855–859.PubMedCrossRefGoogle Scholar
  23. 23.
    Wunderwink R, Leeper KV, Schein RMH, Nelson S, DeBoisblanc B, Baker F, Fotheringham N, Logann E. Clinical response to figrastim in pneumonia with severe sepsis. Am J Resp Crit Care Med; 1996;153:A123.Google Scholar
  24. 24.
    Eichacker P, Waisman Y, Natanson C, Farese A, Hoffman WD, Banks SM, MacVittie. Cardiopulmonary effects of granulocyte colony-stimulating factor in a canine model of bacterial sepsis. J Appl Physiol 1994;77(5):2366–2373.PubMedGoogle Scholar
  25. 25.
    Quezado Z, Natanson C, Hoffman WD, Karzai W, Koev C, Danner RL, Banks SM, Wilson L, Eichacker PQ. Granulocyte colony stimulating factor (G-CSF) treatment at the onset of E. coli-peritonitis-induced septic shock in canines. Am J Resp Crit Care Med 1995;151:A447.Google Scholar
  26. 26.
    Eichacker P, Hammond W, Farese A, Hoffman WD, Danner RL, Banks SM, MacVittie TJ, Natanson C. Serial serum granulocyte colony stimulating factor levels in a canine model of bacterial sepsis. Clin Res 1993;41:240.Google Scholar
  27. 27.
    Dunne J, Dunkin BJK, Nelson S, White JC. Effects of granulocyte colony stimulating factor in a nonneutropenic rodent model of Escherichia coli peritonitis. J Surg Res 1996;61:348–354.PubMedCrossRefGoogle Scholar
  28. 28.
    Villa P, Shaklee CL, Meazza C, Agnello D, Ghezzi P, Senaldi G. Granulocyte colony-stimulating factor and antibiotics in the prophylaxis of a murine model of polymicrobial peritonitis and sepsis. J Infect Dis 1998; 178(471-477).Google Scholar
  29. 29.
    Lorenz W, Reimund KP, Weitzel F, Celik I, Kurnatowski M, Schneider C, Mannheim W, Heiske A, Neumann K, Sitter H, Rothmund M. Granulocyte colony-stimulating factor prophylaxis before operation protects against lethal consequences of postoperative peritonitis. Surg 1997;116(5):925–934.Google Scholar
  30. 30.
    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 Immunop 1993;69(3):278–284.CrossRefGoogle Scholar
  31. 31.
    Smith W, Sumnicht GE, Sharpe RW, Samuelson D, Millard FE. Granulocyte colony-stimulating factor versus placebo in addition to penicillin G in a randomized blinded study of gram negative pneumonia sepsis: analysis of survival and multisystem organ failure. Blood 1995;86(4):1301–1309.PubMedGoogle Scholar
  32. 32.
    Frank U, Chambers HF. Treatment of staphylococcus aureus catheter-related infection and infective endocarditis with granulocyte colony-stimulating factor in the experimental rabbit model. Antimicrob Agents Ch 1996;40(5):1308–1310.Google Scholar
  33. 33.
    Silver G, Gamelli RL, O’Reilly M. The beneficial effect of granulocyte colony-stimulating factor (G-CSF) in combination with gentamicin on survival after Pseudomonas burn wound infection. Surg 1989;106:452–456.Google Scholar
  34. 34.
    Weiss M, Gross-Weege W, Schneider M, Neidhardt H, Liebert S, Mirow N, Wernet P. Enhancement of neutrophil function by in vivo filgrastim treatment for prophylaxis of sepsis in surgical intensive care patients. J Crit Care 1995;10(1):21–26.PubMedCrossRefGoogle Scholar
  35. 35.
    Heard SO, Fink MP, Gamelli RL, Solomkin JS, Joshi M, Trask AL, Fabian TC, Hudson LD, Gerold KB, Logan ED. Effect of prophylactic administration of recombinant human granulocyte colony-stimulating factor (filgrastim) on the frequency of nosocomial infections in patients with acute traumatic brain injury or cerebral hemorrhage. Critical Care Medicine 1998;26(4):748–754.PubMedCrossRefGoogle Scholar
  36. 36.
    Freeman BD, Quezado Z, Zeni F, Natanson C, Danner RL, Banks S, Quezado M, Fitz Y, Bacher J, Eichacker PQ. rG-CSF reduces endotoxemia and improves survival during E-coli pneumonia. Journal of Applied Physiology 1997;83(5):1467–1475.PubMedGoogle Scholar
  37. 37.
    Freeman BD, Correa R, Karzai W, Natanson C, Patterson M, Banks S, Fitz Y, Danner RL, Wilson L, Eichacker PQ. Controlled trials of rG-CSF and CD lib-directed MAb during hyperoxia and E-coli pneumonia in rats. J Appl Physiol 1996;80(6):2066–2076.PubMedGoogle Scholar
  38. 38.
    Karzai W, von Specht BU, Parent C, Haberstroh J, Wollersen K, Natanson C, Banks SM, Eichacker PQ. G-CSF during Escherichia coli versus Staphylococcus aureus pneumonia in rats has fundamentally different and opposite effects. Am J Resp Crit Care Med 1999;159(5):1377–1382.PubMedGoogle Scholar
  39. 39.
    Eichacker P, Quezado M, Zeni F, Correa R, Rontana J, Banks S, Fitz Y, Danner RL, Natanson C. G-CSF increases or decreases the relative risk of death dependent on site and severity of infection in rats. Am J Resp Crit Care Med 1996;153:A252.Google Scholar
  40. 40.
    Karzai W, Eichacker PQ, Mehlorn B, Bloos F, Reinhart K. The role of neutrophils in ventilation induced lung injury. Anesthesiology 1999;91:A1394.Google Scholar
  41. 41.
    Eichacker P. Prophylactic granulocyte colony-stimulating factor in critically ill patients: not time yet. Crit Care Med 1998;26(4):636–637.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Chantal Parent
    • 1
  • Peter Q. Eichacker
    • 1
  1. 1.Critical Care Medicine DepartmentClinical Center National Institutes of HealthBethesdaUSA

Personalised recommendations