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

  1. Mario Cruciani1,*,
  2. Benjamin A Lipsky2,
  3. Carlo Mengoli3,
  4. Fausto de Lalla4

Editorial Group: Cochrane Wounds Group

Published Online: 17 AUG 2013

Assessed as up-to-date: 14 MAR 2013

DOI: 10.1002/14651858.CD006810.pub3


How to Cite

Cruciani M, Lipsky BA, Mengoli C, de Lalla F. Granulocyte-colony stimulating factors as adjunctive therapy for diabetic foot infections. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD006810. DOI: 10.1002/14651858.CD006810.pub3.

Author Information

  1. 1

    ULSS 20 Verona, Center of Community Medicine and Infectious Diseases Service, Verona, Italy

  2. 2

    University of Washington, Medicine, Seattle, Washington, USA

  3. 3

    Università di Padova, Department of Histology, Microbiology and Medical Biotechnology, PADOVA, Italy

  4. 4

    Ospedale san Bortolo, Department of Infectious Diseases, Vicenza, Italy

*Mario Cruciani, Center of Community Medicine and Infectious Diseases Service, ULSS 20 Verona, Via Germania, 20, Verona, 37135, Italy. crucianimario@virgilio.it.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 17 AUG 2013

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Characteristics of included studies [ordered by study ID]
de Lalla 2001

MethodsRCT; single centre


Participants40 inpatients with Wagner grade 3 or 4 ulcer (defined as limb-threatening infection)
Mean age (SD), 56.6 (8.6) in G-CSF group, 59.8 (9.6) in controls
No. males/no. females: 16/4 in G-CSF group, 14/6 in controls
Groups appear balanced at baseline


InterventionsAll received treatment as usual (local treatment and oral/intravenous ciprofloxacin combined to clindamycin)
Group 1: 20 patients randomised to G-CSF (lenograstim, 263 µg s.c. daily for 21 days). G-CSF reduced or stopped if the neutrophil count was > 35,000 or > 50,000 cells/mmc, respectively.
Group 2: 20 patients randomised to control group


OutcomesNumber of patients in whom infection resolved:

  • at week 3, G-CSF and controls = 0
  • at week 9, G-CSF 7 (35%), controls 7 (35%)


Number of patients with improvement of the infection:

  • at week 3, G-CSF 12 (60%), controls 9 (45%)
  • at week 8, G-CSF 7 (40%), controls 4 (20%)


Number who required amputation:

  • at week 9: G-CSF 3, controls 6, P = 0.038


Number of patients with ESR > 70 mm/h: G-CSF 11/20, controls 13/20

Microbiological assessment of ulcers; median (range) and mean (± SD) duration of systemic antibiotic therapy: G-CSF 62.5 (30 to 163) and 68.9 ± 22.9 days, controls 60 (30 to 119) and 58.7 ± 23.7 days

At 6 months follow up 13 out of 16 G-CSF patients and 15 out of 20 controls were cured or showed stable conditions


NotesOsteomyelitis present in all patients recruited; 2 patients in the control group had life-threatening infections. Microbiological assessment at enrolment and 3 weeks; clinical assessment at weeks 3 and 9, and further evaluation 6 months after enrolment.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients were randomized (1:1) to receive..."
Comments: but the method of sequence generation was not explicit

Allocation concealment (selection bias)Unclear riskNo details provided

Blinding (performance bias and detection bias)
Investigators
Low riskFoot lesions were clinically monitored and evaluated by the same investigators, who were not informed about the study randomisation

Blinding (performance bias and detection bias)
Participants
High riskNo

Blinding (performance bias and detection bias)
Outcome assessors
High riskNo

Blinding (performance bias and detection bias)
Data analyst
Unclear riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
Low risk40 patients were recruited and all of them were evaluated

ITT analysisLow risk40 patients were recruited and all of them were evaluated

Completeness of follow upUnclear riskFour patients (all in G-CSF group) were lost at the 6-month follow up

Gough 1997

MethodsRCT; single centre


Participants40 inpatients with extensive cellulitis
Median (range) of age: 65 (30 to 86) in G-CSF group, 66 (55 to 81) in controls
Male/female: 14/6 in G-CSF group, 15/5 in controls
Median duration of foot ulcer before study entry higher in placebo group compared to study group (39.5 versus 21.0 days)


InterventionsAll received treatment as usual (mostly a combination of 4 intravenous antibiotics: ceftazidime, amoxycillin, flucloxacillin and metronidazole)
Group 1: 20 patients randomised to G-CSF
Group 2: 20 patients randomised to placebo
G-CSF (filgrastim, 5 µg/kg daily) was given subcutaneously for 7 days. G-CSF dose was reduced or stopped if the neutrophil count was > 25,000 or > 50,000 cells/mmc, respectively.


OutcomesMedian (range) time (days) to resolution of infection: G-CSF 7 (5 to 20), controls 12 (5 to 93), P = 0.03
Median (range) time to negative swab culture: G-CSF 4 (5 to 10), controls 8 (2 to 79), P = 0.02
Median (range) time to hospital discharge: G-CSF 10 (7 to 31), controls 17.5 (9 to 100), P = 0.02
Median (range) time on intravenous antibiotics: G-CSF 8.5 (5 to 30), controls 14.5 (8 to 63), P = 0.02 
Number of patients in whom infection resolved at day 7: G-CSF 11 (55%), controls 4 (20%), P= 0.05
Number of patients in whom ulcer healed at day 7: G-CSF 4 (21%), controls 0,  P = 0.09
Number of patients who required amputation (G-CSF 0, controls 2), or other surgical interventions (extensive debridement under anaesthesia, G-CSF 0, controls 2; angioplasty or vascular surgery, G-CSF  3, controls 6)


NotesOsteomyelitis present in 24 patients (12 G-CSF, 12 placebo). Median duration of foot ulcer before study entry higher in placebo group compared to study group (39.5 versus 21.0). Neutrophil function (assays of superoxide production) reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe pharmacist generated and held the randomisation list
Comment: we have judged this to be acceptable random sequence generation

Allocation concealment (selection bias)Low riskThe pharmacist dispensed all study drugs, and was responsible for changing the dose of G-CSF in response to the dose of G-CSF daily cell counts

Blinding (performance bias and detection bias)
Investigators
Low riskInvestigators had no access to randomisation codes or to modification of G-CSF doses, and were unaware of cell counts when making clinical decisions

Blinding (performance bias and detection bias)
Participants
Unclear riskNot stated

Blinding (performance bias and detection bias)
Outcome assessors
Low riskOutcome assessors had no access to randomisation codes or to modification of G-CSF doses, and were unaware of cell counts when making clinical decisions

Blinding (performance bias and detection bias)
Data analyst
Unclear riskNot stated

Incomplete outcome data (attrition bias)
All outcomes
Low risk40 patients were randomised and 40 were analysed

ITT analysisLow risk40 patients were randomised and 40 were analysed

Completeness of follow upLow risk40 patients were randomised and 40 were analysed

Kastenbauer 2003

MethodsRCT; single centre


Participants37 inpatients with Wagner grade 2 or 3 ulcers
Mean age (SD), 60.8 (11.1) in G-CSF group, 58.2 (8.1) in controls
Male/female: 14/6 in G-CSF, 13/4 in controls
At baseline, the degree of infection was reported as the same in both groups


InterventionsAll received treatment as usual (intravenous and then oral ciprofloxacin plus clindamycin)
20 patients randomised to G-CSF and 17 to placebo
G-CSF (filgrastim, 5 µg/kg daily) was given subcutaneously for 10 days. G-CSF dose was intermitted if the neutrophil count was > 50,000 cells/mmc.


OutcomesResolution of cellulitis: patients who received G-CSF did not have an earlier resolution of cellulitis than controls; at day 10, local, forefoot and local erythema were absent in more than 80% of patients receiving G-CSF or placebo
No subjects had lymphangitis or persistent putrid wounds at the end of the study. Ulcer volume at days 10, G-CSF 83 ± 140, controls 358 ± 395 (P < 0.01); ulcer volume decreased by 59% in G-CSF group, and by 35% in controls (P = 0.0005)
Variation in Wagner grade ulcer after treatment not statistically significant
Number of patients requiring amputation or other surgical interventions: the G-CSF group had 1 peripheral angioplasty, and 1 peripheral angioplasty + minor amputation; controls had 2 angiographies and 1 amputation
Mean CRP (mg dl-1) at day 2 to 10: G-CSF 2.14 ± 2.27, controls 1.04 ± 0.63 (P = 0.06)

Other information provided by authors after correspondence: time of resolution of cellulitis: G-CSF 6.25 ± 3.4 days, controls 6.18 ± 3.0 days; number of patients treated with IV antibiotics: all 37 patients were treated with IV antibiotics at study entry until cellulitis had visually improved; the mean antibiotic duration was 5.6 ± 2.5 days in G-CSF and 5.8 ± 2.3 days in controls; afterwards, 6 G-CSF and 8 placebo patients had antibiotics orally to study end at day 10; number of patients with ulcers healed at day 7: no ulcer was completely healed during the study; neither at day 7 nor at day 10.


NotesDaily clinical observations supplemented by the calculation of an Infection Summary Score. Ulcer volume at enrolment was higher in placebo group (358 vs 203 μl), but this difference was not reported to be statistically significant.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients were randomised to..."
Comments: but the method of sequence generation was not explicit

Allocation concealment (selection bias)Unclear riskUnclear

Blinding (performance bias and detection bias)
Investigators
High riskBecause of increase in leukocyte count, a real blinding of investigators was not possible

Blinding (performance bias and detection bias)
Participants
Low riskThe study was defined as patient-blinded

Blinding (performance bias and detection bias)
Outcome assessors
Low riskAn experienced investigator who had not been involved in the clinical decisions evaluated the clinical outcome

Blinding (performance bias and detection bias)
Data analyst
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low risk37 patients randomised; 3 patients dropped out and included in the analysis

ITT analysisLow riskOnly the intention-to-treat analysis is presented

Completeness of follow upLow riskData provided for the 10 days of hospital stay but all patients included in the analysis

Viswanathan 2003

MethodsRCT; single centre


Participants20 inpatients with extensive cellulitis, Wagner grades 2 to 3


InterventionsAll received treatment as usual (intravenous ofloxacin plus metronidazole)
10 patients randomised to G-CSF and 10 to placebo
G-CSF (filgrastim, 5 µg/kg daily) was given subcutaneously for 7 days


OutcomesImprovement of cellulitis (disappearance of soft tissue erythema): 9 out of 10 patients in G-CSF group, and 3 out of 10 controls
Time to hospital discharge: G-CSF 7.4 ± 0.8 days, controls  8.8 ± 1.6 days (P = 0.023)

Other information provided by the study authors after correspondence: amputation and angiography were not performed in any patient in both the groups. G-CSF treated patients did not need any surgery, while 2 patients in the placebo group underwent debridement and 1 patient had slough removed.  


NotesMost patients had peripheral vascular disease. Patients with Wagner grade 4 or 5 not included.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAfter correspondence with the study authors, we obtained additional information on the randomisation process. Patients were randomised to receive G-CSF or placebo based on a computer-generated randomisation list, conducted by the study pharmacy.

Allocation concealment (selection bias)Low riskPatients were randomised to receive G-CSF or placebo based on a computer-generated randomisation list, conducted by the study pharmacy.

Blinding (performance bias and detection bias)
Investigators
Low riskBlinding of investigators

Blinding (performance bias and detection bias)
Participants
Low riskBlinding of participants

Blinding (performance bias and detection bias)
Outcome assessors
High riskCorrespondence with the author revealed that at the end of the trial the blinded codes were broken and the treatment groups were identified

Blinding (performance bias and detection bias)
Data analyst
Unclear riskBlinding of data analyst not stated

Incomplete outcome data (attrition bias)
All outcomes
Low risk20 patients were randomised and 20 were analysed

ITT analysisLow risk20 patients were randomised and 20 were analysed

Completeness of follow upLow risk20 patients were randomised and 20 were analysed

Yonem 2001

MethodsRCT; single centre


Participants30 inpatients with pedal cellulitis or Wagner grade 1 or 2
Mean age (SD), 60.3 (1.3) in G-CSF group, 61.0 (1.4) in controls
Male/female: 7/8 in G-CSF, 6/9 in controls
At study entry, the 2 groups were similar with regard to age, duration of diabetes, fasting plasma glucose, basal WBC, phagocytosis test and respiratory burst test


InterventionsAll received treatment as usual (local wound care and parenteral ciprofloxacin in combination with metronidazole)
15 patients randomised to G-CSF (filgrastim, 5 µg/kg daily s.c. for 3 or more days. G-CSF dose was reduced or stopped if the neutrophil count was > 30,000 or > 45,000 cells/mmc, respectively


OutcomesMean ± SD time (days) to resolution of infection: G-CSF 23.6 ± 2.0, controls 22.3 ± 1.7, P < 0.05
Mean ± SD time (days) to hospital discharge: G-CSF 26.9 ± 2.0, controls 28.3, P < 0.05
Mean ± SD time (days) of parenteral antibiotic therapy: G-CSF 22.9 ± 2.0, controls 23.3 ± 1.9, P < 0.05
Number of patients who required amputation: G-CSF 2 (13.3%), controls 3 (20%)
Effect of  G-CSF on neutrophil functions (phagocytosis and respiratory burst tests) as secondary objectives


NotesDiabetic patients with pedal cellulitis or Wagner's grade ≤ 2. Total days of G-CSF treatment not specified.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskPatients were randomised into 2 groups - no further details provided

Allocation concealment (selection bias)Unclear riskNo details provided

Blinding (performance bias and detection bias)
Investigators
Unclear riskNo details provided

Blinding (performance bias and detection bias)
Participants
Unclear riskNo details provided

Blinding (performance bias and detection bias)
Outcome assessors
Unclear riskNo details provided. Patients were examined independently each day by 2 clinicians but it is not clear if they were blind to treatment allocation.

Blinding (performance bias and detection bias)
Data analyst
Unclear riskNo details provided

Incomplete outcome data (attrition bias)
All outcomes
Low risk30 patients were randomised and 30 analysed

ITT analysisLow risk30 patients were randomised and 30 analysed

Completeness of follow upLow risk30 patients were randomised and 30 analysed

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Amery 2005A review article

Chatelau 1998A case report on therapy with G-CSF in diabetic foot

Dubsky 2011An open label study aimed to assess safety and effectiveness of therapy of critical limb ischaemia by autologous stem cells. Methods: Fourteen patients were included into the study . Eight patients were treated by bone marrow stromal cells, 6 patients by peripheral blood progenitor cells after stimulation by filgrastim. The suspension of stem cells was then applied into the muscles of ischemic limbs

Enoch 2006A review article

Fadini 2006A letter related to another trial

Huang 2005In patients randomised to G-CSF (600 µg s.c. daily for 5 days), peripheral blood mononuclear cells were collected and transplanted by intramuscular injections into ischaemic limbs

Ishida 2005Not a randomised clinical trial; in this trial G-CSF was administered to 6 patients with peripheral arterial disease

Kawamura 2005G-CSF administered to diabetic and chronic renal failure patients with limb ulcers; not a RCT

Lazareth 2002aA review article

Lazareth 2002bA review article

Tanaka 2012A prospective, open label phase I/II clinical trial of autologous granulocyte colony-stimulating factor (GCS-F) mobilized endothelial progenitor cells (EPC) on diabetic patients with chronic wounds. Mobilized peripheral EPCs were harvested by apheresis and injected within the chronic wound.

 
Comparison 1. Infection status

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Resolution of infection2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 2 Improvement4140Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.99, 1.67]

 
Comparison 2. Healing of wounds

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Healing of wounds276Risk Ratio (M-H, Fixed, 95% CI)9.45 [0.54, 164.49]

 
Comparison 3. Need for surgery

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall surgical intervention5167Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.21, 0.70]

 2 Amputation5167Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.18, 0.95]

 
Comparison 4. Adverse events

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Occurrence of side effects3117Risk Ratio (M-H, Fixed, 95% CI)5.59 [0.71, 44.05]

 
Comparison 5. Duration of antibiotic therapy provided

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Days with systemic antibiotics3107Mean Difference (IV, Fixed, 95% CI)-0.27 [-1.30, 0.77]

 
Comparison 6. Duration of hospitalisation needed

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Days of hospital stay250Mean Difference (IV, Fixed, 95% CI)-1.40 [-2.27, -0.53]

 
Comparison 7. Total leucocyte count

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 White blood cell count4Mean Difference (IV, Random, 95% CI)Subtotals only

 
Summary of findings for the main comparison. G-CSF + standard treatment compared to usual treatment for diabetic foot infection

G-CSF + standard treatment compared to usual treatment for diabetic foot infection

Patient or population: patients with diabetic foot infection
Settings: inpatient
Intervention: G-CSF + standard treatment
Comparison: usual treatment

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Usual treatmentG-CSF + standard treatment

improvement of infection
clinical and microbiological assessment
Study populationRR 1.40
(1.06 to 1.85)
140
(4 studies)
⊕⊕⊝⊝
low1,2
resolution of infection was reported in 2 studies only, and one cannot be computed because zero frequencies

500 per 1000700 per 1000
(530 to 925)

Moderate


Need for surgery: Overall Surgical InterventionsStudy populationRR 0.37
(0.2 to 0.68)
167
(5 studies)
⊕⊕⊝⊝
low1,2

354 per 1000131 per 1000
(71 to 240)

Moderate


Need for surgery: AmputationStudy populationRR 0.41
(0.18 to 0.95)
167
(5 studies)
⊕⊕⊝⊝
low1,2

183 per 100075 per 1000
(33 to 174)

Moderate


*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 studies have limitations (random sequence generation, allocation concealment, blinding) that may result in a biased assessment
2 low number of patients and events