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Meta-Analysis
. 2013 Aug 17;2013(8):CD006810.
doi: 10.1002/14651858.CD006810.pub3.

Granulocyte-colony stimulating factors as adjunctive therapy for diabetic foot infections

Mario Cruciani  1 , Benjamin A Lipsky, Carlo Mengoli, Fausto de Lalla
Affiliations
Meta-Analysis

Granulocyte-colony stimulating factors as adjunctive therapy for diabetic foot infections

Mario Cruciani et al. Cochrane Database Syst Rev. .

Abstract

Background: Granulocyte-colony stimulating factor (G-CSF) increases the release of neutrophil endothelial progenitor cells from the bone marrow and improves neutrophil functions, which are often impaired in people with diabetes.

Objectives: To examine the effects of adjunctive G-CSF compared with placebo or no growth factor added to usual care on rates of infection, cure and wound healing in people with diabetes who have a foot infection.

Search methods: In March 2013, for this second update, we searched the Cochrane Wounds Group Specialised Register (searched 14 March 2013); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 2); Ovid MEDLINE (1948 to March Week 1 2013); Ovid EMBASE (1974 to 2013 March 13); Ovid MEDLINE (In-Process march 13,2013); and EBSCO CINAHL (1982 to 28 February 2013).

Selection criteria: Randomised controlled trials (RCTs) that evaluated the effect of adding G-CSF to usual care in people with a diabetic foot infection.

Data collection and analysis: Three review authors independently assessed trial eligibility, methodological quality and extracted data. We reported risk ratio (RR) or, for continuous outcomes, mean differences (MD), with 95% confidence intervals (CI). In the case of low or no heterogeneity we pooled studies using a fixed-effect model.

Main results: We identified and included five eligible trials with a total of 167 patients. The investigators administered various G-CSF preparations, at different doses and for different durations of time. Adding G-CSF did not significantly affect the likelihood of resolution of infection or wound healing, but it was associated with a significantly reduced likelihood of lower extremity surgical interventions (RR 0.38; 95 % CI 0.21 to 0.70), including amputation (RR 0.41; 95 % CI 0.18 to 0.95). Moreover, providing G-CSF reduced the duration of hospital stay (MD -1.40 days; 95% CI -2.27 to -0.53 days), but did not significantly affect the duration of systemic antibiotic therapy (MD -0.27 days; 95% CI -1.30 to 0.77 days).

Authors' conclusions: The available evidence is limited, but suggests that adjunctive G-CSF treatment in people with a diabetic foot infection, including infected ulcers, does not appear to increase the likelihood of resolution of infection or healing of the foot ulcer. However, it does appear to reduce the need for surgical interventions, especially amputations, and the duration of hospitalisation. Clinicians might consider adding G-CSF to the usual treatment of diabetic foot infections, especially in patients with a limb-threatening infection, but it is not clear which patients might benefit.

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Conflict of interest statement

Mario Cruciani, Carlo Mengoli and Fausto de Lalla: none declared. Benjamin A. Lipsky: has remuneration or grant support from several biopharmaceutical companies (Pfizer, Merck, Wyeth‐Ayerst, Cubist, Ortho‐McNeil, Novartis, and Innocoll) but none of these constitute a competing interest for this submitted work.

Figures

1
1
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
3
3
Forest plot of comparison: 3 Need for surgery, outcome: 3.1 Overall surgical intervention.
4
4
Forest plot of comparison: 3 Need for surgery, outcome: 3.2 Amputation.
1.1
1.1. Analysis
Comparison 1 Infection status, Outcome 1 Resolution of infection.
1.2
1.2. Analysis
Comparison 1 Infection status, Outcome 2 Improvement.
2.1
2.1. Analysis
Comparison 2 Healing of wounds, Outcome 1 Healing of wounds.
3.1
3.1. Analysis
Comparison 3 Need for surgery, Outcome 1 Overall surgical intervention.
3.2
3.2. Analysis
Comparison 3 Need for surgery, Outcome 2 Amputation.
4.1
4.1. Analysis
Comparison 4 Adverse events, Outcome 1 Occurrence of side effects.
5.1
5.1. Analysis
Comparison 5 Duration of antibiotic therapy provided, Outcome 1 Days with systemic antibiotics.
6.1
6.1. Analysis
Comparison 6 Duration of hospitalisation needed, Outcome 1 Days of hospital stay.
7.1
7.1. Analysis
Comparison 7 Total leucocyte count, Outcome 1 White blood cell count.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

de Lalla 2001 {published data only}
    1. Lalla F, Pellizzer G, Strazzabosco M, Martini Z, Du Jardin G, Lora L, et al. Randomized prospective controlled trial of recombinant granulocyte colony‐stimulating factor as adjunctive therapy for limb‐threatening diabetic foot infection. Antimicrobial Agents and Chemotherapy 2001;45(4):1094‐8. - PMC - PubMed
Gough 1997 {published data only}
    1. 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(9081):855‐9. - PubMed
    1. Gough A, Clapperton M, Rolando N, Foster AVM, Philpott‐Howard J. Early report: randomised placebo‐controlled trial of granulocyte‐colony stimulating factor in diabetic foot infection. British Journal of Podiatry 1998;1(2):53‐8. - PubMed
    1. Gough A, Clapperton M, Rolando N, Wadman MH. Granulocyte‐colony stimulating factor hastened healing of severe foot infections in patients with diabetes mellitus. Enfermedades Infeciosas y Microbiologia 1999;19(2):104‐5.
Kastenbauer 2003 {published and unpublished data}
    1. Kastenbauer T, Horlein B, Sokol G, Irsigler K. Evaluation of granulocyte‐colony stimulating factor (Filgastrim) in infected diabetic foot ulcers. Diabetologia 2003;46(1):27‐30. - PubMed
Viswanathan 2003 {published and unpublished data}
    1. Viswanathan V, Mahesh U, Jayaraman M, Shina K, Ramachandram A. Beneficial role of granulocyte colony stimulating factor in foot infection in diabetic patients. Journal of the Association of Physicians India 2003;51:90‐1. - PubMed
Yonem 2001 {published data only}
    1. Yonem A, Cakir B, Guler S, Azal OO, Corakci A. Effects of granulocyte‐colony stimulating factor in the treatment of diabetic foot infection. Diabetes, Obesity and Metabolism 2001;3(3):332‐7. - PubMed

References to studies excluded from this review

Amery 2005 {published data only}
    1. Amery CM. Growth factors and the management of the diabetic foot. Diabetic Medicine 2005;22(Suppl 1):12‐4. - PubMed
Chatelau 1998 {published data only}
    1. Chantelau E, Kimmerle R. Granulocyte‐colony‐stimulating factor in diabetic foot infection. Lancet 1998;351(9099):370. - PubMed
Dubsky 2011 {published data only}
    1. Dubsky M, Jirkovska A, Bem R, Pagacova L, Fejfarova V, Varga M, et al. [Treatment of critical limb ischemia and diabetic foot disease by the use of autologous stem cells].. Vnitrni lekarstvi 2011;57:451‐5. - PubMed
Enoch 2006 {published data only}
    1. Enoch S, Grey JE, Harding KG. ABC of wound healing: recent advances and emerging treatments. BMJ 2006;332(7547):962‐5. - PMC - PubMed
Fadini 2006 {published data only}
    1. Fadini GP, Avogaro A. Autologous transplantation of granulocyte colony‐stimulating factor‐mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care 2006;29(2):478‐9. - PubMed
Huang 2005 {published data only}
    1. Huang P, Li S, Han M, Xiao Z, Yang R, Han ZC. Autologous transplantation of granulocyte colony‐stimulating factor‐mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care 2005;28(9):2155‐60. - PubMed
Ishida 2005 {published data only}
    1. Ishida A, Ohya Y, Sakuda H, Ohshiro K, Higashiuesato Y, Nakaema M, et al. Autologous peripheral blood mononuclear cell implantation for patients with peripheral arterial disease improves limb ischemia. Circulation Journal 2005;69(10):1260‐5. - PubMed
Kawamura 2005 {published data only}
    1. Kawamura A, Horie T, Tsuda I, Ikeda A, Egawa H, Imamura E, et al. Prevention of limb amputation in patients with limbs ulcers by autologous peripheral blood mononuclear cell implantation. Therapeutic Apheresis and Dialysis 2005;9(1):59. - PubMed
Lazareth 2002a {published data only}
    1. Lazareth I. X. Local care and medical treatment of ischemic trophic disorders in the diabetic patients. Journal des Maladies Vasculaires 2002;27(5):287‐8. - PubMed
Lazareth 2002b {published data only}
    1. Lazareth I. Local care and medical treatment for ischemic diabetic ulcers. Journal des Maladies Vasculaires 2002;27(3):157‐63. - PubMed
Tanaka 2012 {published data only}
    1. Tanaka R, Masuda H, Kato S, Imagawa K, Kanabuichi K, Nakashioya C, Yoshiba F, Fukui T, Ito R, Kobori M, Wada M, Asahara T, Miyasaka M. Autologous G‐CSF mobilized peripheral blood CD34(+) cell therapy for diabetic patients with chronic non‐healing ulcer. Cell Transplant 2012;Oct 25:[Epub ahead of print]. [doi: 10.3727/096368912X658007. [Epub ahead of print]] - PubMed

Additional references

Ashry 1998
    1. Ashry HR, Lavery LA, Armstrong DG, Lavery DC, Houtum WH. Cost of diabetes‐related amputations in minorities. Journal of Foot and Ankle Surgery 1998;37(3):186‐90. - PubMed
Azoulay 2004
    1. Azoulay E, Delclaux C. Is there a place for granulocyte colony‐stimulating factor in non‐neutropenic critically ill patients?. Intensive Care Medicine 2004;30(1):10‐17. - PMC - PubMed
Baddour 2002
    1. Baddour LM. Randomized prospective controlled trial of recombinant granulocyte colony‐stimulating factor as adjunctive therapy for limb‐threatening diabetic foot infection. Current Infectious Diseases Reports 2002;4(4):413‐4. - PubMed
Begg 1994
    1. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50(4):1088‐101. - PubMed
Cruciani 2005
    1. Cruciani M, Lipsky BA, Mengoli C, Lalla F. Are granulocyte colony‐stimulating factors beneficial in treating diabetic foot infections? A meta‐analysis. Diabetes Care 2005;28(2):454‐60. - PubMed
Dale 1995
    1. Dale DC, Liles WC, Summer WR, Nelson S. Review: granulocyte colony‐stimulating factor ‐ role and relationships in infectious diseases. Journal of Infectious Diseases 1995;172(4):1061‐75. - PubMed
de Lalla 2000
    1. Lalla F, Nicolin R, Lazzarini L. Safety and efficacy of recombinant granulocyte colony‐stimulating factor as an adjunctive therapy for Streptococcus pneumoniae meningitis in non‐neutropenic adult patients: a pilot study. Journal of Antimicrobial Chemotherapy 2000;46(5):843‐6. - PubMed
Delamaire 1997
    1. Delamaire M, Maugendre D, Moreno M, Goff MC, Allannic H, Genetet B. Impaired leucocyte functions in diabetic patients. Diabetic Medicine 1997;14(1):29‐34. - PubMed
Edmonds 1999
    1. Edmonds M, Gough A, Solovera J, Standaert B. Filgrastim in the treatment of infected diabetic foot ulcers: retrospective cost analysis of a phase II randomised clinical trial. Clinical Drug Investigation 1999;17(4):275‐86.
Edmonds 2000
    1. Edmonds M, Bates M, Doxford M, Gough A, Foster A. New treatments in ulcer healing and wound infection. Diabetes/Metabolism Research Reviews 2000;16(Suppl 1):S51‐4. - PubMed
Egger 1997
    1. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta‐analysis detected by a simple, graphical test. BMJ 1997;315(7109):629‐34. - PMC - PubMed
Geerlings 1999
    1. Geerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes mellitus (DM). FEMS Immunology and Medical Microbiology 1999;26(3‐4):259‐65. - PubMed
Gupta 2007
    1. Gupta S, Koirala J, Khardori R, Khardori N. Infections in diabetes mellitus and hyperglicemia. Infectious Diseases Clinics of North America 2007;21(3):617‐38. - PubMed
Hartung 1999
    1. Hartung T. Granulocyte colony‐stimulating factor: its potential role in infectious disease. AIDS 1999;13(Suppl 2):S3‐9. - PubMed
Higgins 2003
    1. Higgins J, Thompson S, Deeks J, Altman D. Measuring inconsistency in meta‐analyses. BMJ 2003;327(7414):557‐60. - PMC - PubMed
Higgins 2009
    1. Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]. The Cochrane Collaboration, 2009. Available from www.cochrane‐handbook.org.
Hirsch 2012
    1. Hirsch BR, Lyman GH. Economics of the recombinant Human Granulocyte Colony‐Stimulating Factors. In: Molineaux G, Foote MA, Arvedson T editor(s). In: Twenty Years of G‐CSF, Milestone in Drug Therapy. Basel: Springer Basel AG, 2012:409‐20. [DOI: 10.1007/978-3-0348-0218-5_22] - DOI
Hubel 2003
    1. Hubel K, Engert A. Granulocyte transfusion therapy for treatment of infections after cytotoxic chemotherapy. Onkologie 2003;26(1):73‐9. - PubMed
IDSA 2004
    1. Lipsky BA, Berendt AR, Deery HG, Embil JM, Joseph WS, Karchmer AW, et al. Diagnosis and treatment of diabetic foot infections. Clinical Infectious Diseases 2004;39(1):885‐910. - PubMed
IDSA 2012
    1. Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJ, Armstrong DG, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clinical Infectious Diseases 2012;54(12):e132‐73. - PubMed
IWGDF 2003
    1. International Working Group on the Diabetic Foot. International Consensus on the Diabetic Foot. International Diabetes Federation, CD‐ROM 2003.
Kerr 2012
    1. Kerr M. Foot Care for People with Diabetes:The Economic Case for Change. available at: http://www.diabetes.nhs.uk/news_and_events/new_foot_care_report_shows_po....
Korda 2005
    1. Korda J, Mezo R, Balint GP. Treatment of musculoskeletal infections of the foot in patients with diabetes. Therapy 2005;2(2):287‐30.
Lefebvre 2009
    1. Lefebvre C, Manheimer E, Glanville J, on behalf of the Cochrane Information Retrieval Methods Group. Chapter 6. Searching for studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]. The Cochrane Collaboration, 2009. Available from www.cochrane‐handbook.org.
Lipsky 2000
    1. Lipsky BA, Berendt AR. Principles and practice of antibiotic therapy of diabetic foot infections. Diabetes Metabolism Research and Reviews 2000;16(Suppl 1):S42‐6. - PubMed
Lipsky 2004
    1. Lipsky BA. Medical treatment of diabetic foot infections. Clinical Infectious Diseases 2004;39(Suppl 2):S104‐S114. - PubMed
Mason 1999
    1. Mason J, O'Keeffe C, Hutchinson A, McIntosh A, Young R, Booth A. A systematic review of foot ulcer in patients with Type 2 diabetes mellitus. II: treatment. Diabetic Medicine 1999;16(11):889‐909. - PubMed
Moulik 2003
    1. Moulik PK, Mtonga R, Gill GV. Amputation and mortality in new‐onset diabetic foot ulcers stratified by etiology. Diabetes Care 2003;26(2):491‐4. - PubMed
Murata 2003
    1. Murata A. Granulocyte colony‐stimulating factor as the expecting sword for the treatment of severe sepsis. Current Pharmaceutical Design 2003;9(14):1115‐20. - PubMed
Nelson 1994
    1. Nelson S. Role of granulocyte colony‐stimulating factor in the immune response to acute bacterial infection in the nonneutropenic host: an overview. Clinical Infectious Diseases 1994;18(Suppl 2):S197‐204. - PubMed
Nelson 2000
    1. Nelson S, Heyder AM, Stone J, Bergeron MG, Daugherty S, Peterson G, et al. A randomized controlled trial of filgrastim for the treatment of hospitalized patients with multilobar pneumonia. Journal of Infectious Diseases 2000;182(3):970‐3. - PubMed
Nelson 2006a
    1. Nelson EA, O'Meara S, Craig D, Iglesias C, Golder S, Dalton J, et al. A series of systematic reviews to inform a decision analysis for sampling and treating infected diabetic foot ulcers. Health Technology Assessment 2006;10(12):1‐86. - PubMed
Nelson 2006b
    1. Nelson EA, O'Meara S, Golder S, Dalton J, Craig D, Iglesias C. Systematic review of antimicrobial treatments for diabetic foot ulcers. Diabetic Medicine 2006;23(4):348‐59. - PubMed
NICE 2011
    1. National Institute for Health and Clinical Excellence. Diabetic foot problems Inpatient management of diabetic foot problems. available at http://www.nice.org.uk/nicemedia/live/13416/53556/53556.pdf March 2011. - PubMed
O'Meara 2000
    1. O'Meara S, Cullum N, Majid M, Sheldon T. Systematic reviews of wound care management: (3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration. Health Technology Assessment 2000;4:1‐237. - PubMed
Oyibo 2001
    1. Oyibo SO, Jude EB, Tarawneh I, Nguyen HC, Harkless LB, Boulton AJ. A comparison of two diabetic foot ulcer classification systems: the Wagner and the University of Texas wound classification systems. Diabetes Care 2001;24(1):84‐8. - PubMed
Papanas 2007
    1. Papanas N, Maltezos E. Growth factors in the treatment of diabetic foot ulcers: new technologies, any promises?. International Journal of Lower Extremity Wounds 2007;6(1):37‐53. - PubMed
Peck 2001
    1. Peck KR, Son DW, Song JH, Kim S, Oh MD, Choe KW. Enhanced neutrophil functions by recombinant human granulocyte colony‐stimulating factor in diabetic patients with foot infections in vitro. Journal of Korean Medical Science 2001;16(1):39‐44. - PMC - PubMed
Reed 2004
    1. Reed KS, Pai MP. Adjunctive granulocyte colony‐stimulating factor therapy for diabetic foot infections. Annals of Pharmacotherapy 2004;38(12):2150‐3. - PubMed
Reiber 1988
    1. Reiber GE, Lipsky BA, Gibbons GW. The burden of diabetic foot ulcers. American Journal of Surgery 1998;176(Suppl 2A):5S‐10S. - PubMed
RevMan 2011 [Computer program]
    1. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.
Richard 2002
    1. Richard JL, Parer Richard C. Growth factors and treatment of diabetic foot ulcers. Sang Thrombose Vaisseaux 2002;14(3):158‐71.
Root 1999
    1. Root RK, 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. Journal of Infectious Diseases 1999;179(Suppl 2):S342‐52. - PubMed
Sato 1993
    1. Sato N, Shimizu H. Granulocyte‐colony stimulating factor improves an impaired bactericidal function in neutrophils from STZ‐induced diabetic rats. Diabetes 1993;42(3):470‐3. - PubMed
Sato 1997
    1. Sato N, Kashima K, Tanaka Y, Shimizu H, Mori M. Effect of granulocyte‐colony stimulating factor on generation of oxygen‐derived free radicals and myeloperoxidase activity in neutrophils from poorly controlled NIDDM patients. Diabetes 1997;46(1):133‐7. - PubMed
SIGN 2009
    1. Scottish Intercollegiate Guidelines Network (SIGN). Search filters. Available from http://www.sign.ac.uk/methodology/filters.html#random (accessed February 2009).
Temple 2000
    1. Temple ME, Nahata MC. Pharmacotherapy of lower limb diabetic ulcers. Journal of the American Geriatric Society 2000;48(7):822‐8. - PubMed
Tenvall 2000
    1. Tennvall GR, Apelqvist J, Eneroth M. Costs of deep foot infections in patients with diabetes mellitus. Pharmacoeconomics 2000;18(3):225‐38. - PubMed
Wagner 1981
    1. Wagner F. The disvascular foot: a system for diagnosis and treatment. Foot and Ankle 1981;2(2):64‐123. - PubMed

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