Acute Phase Reactants Predict the Risk of Amputation in Diabetic

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ORIGINAL ARTICLES

Acute Phase Reactants Predict the Risk of Amputation inDiabetic Foot Infection

Baris Akinci, MD*

Serkan Yener, MD*Sena Yesil, MD*Nur Yapar, MD

Yasin Kucukyavas, MDFirat Bayraktar, MD*

Background: Prediction of amputation would aid clinicians in the management ofdiabetic foot infections. We aimed to assess the predictive value of baseline and post-treatment levels of acute phase reactants in the outcome of patients with diabetic footinfections.

Methods: We collected data prospectively during minimum follow-up of 6 months inpatients with infected diabetic foot ulcers hospitalized in Dokuz Eylul University Hospitalbetween January 1, 2003, and January 1, 2008. After excluding patients who did notattend the hospital for follow-up visits regularly (n = 36), we analyzed data from 165 footulcer episodes.

Results: Limb ischemia and osteomyelitis were much more frequent in patients whounderwent amputation. Wagner grade, which assesses ulcer depth and the presence ofosteomyelitis or gangrene, was higher in patients who needed amputation. Ulcer sizewas slightly larger in the amputation group. Baseline and post-treatment C-reactiveprotein levels, erythrocyte sedimentation rates, white blood cell counts, and plateletcounts were significantly elevated in patients who underwent amputation. Albuminlevels were significantly suppressed in the amputation group. Univariate analysisshowed that a 1-SD increase in baseline and post-treatment C-reactive protein levels,

erythrocyte sedimentation rates, and white blood cell counts and a 1-SD decrease inpost-treatment albumin levels were significantly associated with increased risk ofamputation. Post-treatment C-reactive protein level was strongly associated withamputation risk.

Conclusions: Circulating levels of acute phase reactants were associated withamputation risk in diabetic foot infections. (J Am Podiatr Med Assoc 101(1): 1-6, 2011)

Diabetic patients with long-term, inadequately

controlled blood glucose levels are at significant

risk for diabetic foot ulcers, a major reason for

lower-extremity amputations.1 Standard manage-

ment of diabetic foot ulcers includes evaluation of

vascular status, identification of infection and

osteomyelitis, antibiotic therapy, surgical debride-

ment, and metabolic control of diabetes.2, 3 Patients

whose ulcers fail to heal after standard treatment

may undergo amputation. Despite well-defined riskfactors for diabetic foot ulcer development, little is

known about which factors predict amputation in a

diabetic foot ulcer episode. Previous studies4-8 have

shown that limb ischemia, ulcer depth, and osteo-

myelitis are important predictors of amputation.

Ulcer classification by several systems was also

found to predict the risk of amputation.9-11 Addi-

tional factors that have been proposed to be

*Division of Endocrinology and Metabolism, Department ofInternal Medicine, Dokuz Eylul University Medical School,

Izmir, Turkey.

Department of Infection Diseases, Dokuz Eylul University

Medical School, Izmir, Turkey.

Department of General Internal Medicine, Dokuz Eylul

University Medical School, Izmir, Turkey.

Corresponding author: Baris Akinci, MD, Division of

Endocrinology and Metabolism, Department of Internal

Medicine, Dokuz Eylul University Medical School, Inciralti,

Izmir, Turkey 35340. (E-mail: [email protected])

Journal of the American Podiatric Medical Association Vol 101 No 1 January/February 2011 1


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associated with amputation risk include older age

and macrovascular and microvascular comorbidi-

ties.1, 8, 9, 12, 13

Levels of acute phase reactants alter in response

to infection, tissue injury, and inflammation.14 Acute

phase reactants, primarily erythrocyte sedimenta-

tion rate, C-reactive protein level, and white blood

cell count, are commonly used in routine clinical

practice when there is a suspicion of infection.14, 15

However, these measures are not specific to

infection, and the values may be elevated owing to

noninfectious conditions such as ischemia.16 These

measures should be considered markers of inflam-

mation that rise in the presence of systemic

inflammation.17 Altered levels of acute phase

reactants have been proposed to be useful in

indicating disease activity in patients with inflam-

matory disorders and may be predictive of either

functional outcome or mortality.18 The aim of the

present study was to assess the predictive value of

baseline and post-treatment levels of acute phasereactants in the outcome of patients with diabetic

foot infections.

Materials and Methods

The study population was composed of patients

with infected diabetic foot ulcers hospitalized in

Dokuz Eylul University Hospital between January 1,

2003, and January 1, 2008. Data were collected

prospectively during minimum follow-up of 6

months. After patients who did not attend the

hospital for follow-up visits regularly (n=

36) wereexcluded, data from 165 foot ulcer episodes were

analyzed. The procedures were approved by the

institutional review board of Dokuz Eylul University.

Characteristics of patients, including diabetic

complications, smoking habits, and physical exam-

ination findings, were recorded. At baseline, the

ulcer was photographed. The site and the largest

diameter of the ulcer were noted. The depth of the

ulcer was determined by inspection, with additional

use of a sterile probe if indicated. Foot lesions were

classified according to the Wagner classification as

follows: grade 0, risk of foot ulcer; grade 1,

ulcerated skin and subcutaneous tissue; grade 2,deeper lesions may penetrate to tendon, bone, or

joint capsule, without abscess or osteomyelitis;

grade 3, deep tissues are involved, and abscess,

osteitis, or osteomyelitis is present; grade 4, local

gangrene; and grade 5, diffuse gangrene.

Standard radiographs were taken. Magnetic res-

onance imaging of the extremity was performed

according to consensus in weekly diabetic foot

team meetings. Baseline hemoglobin A1c level was

recorded. Arterial circulation was evaluated by

palpation of the peripheral pulses and ankle

brachial index with a handheld Doppler. Patients

with absent or reduced pedal pulses or an ankle

brachial index less than 0.9 underwent conventional

Doppler examination. Patients with vascular insuf-

ficiency were evaluated by the vascular surgeon,

and a revascularization procedure was performed ifindicated. Conventional or magnetic resonance

angiography was performed in selected patients.

Symptoms of neuropathy were questioned. All of

the patients were tested for neuropathy using the

10-g monofilament test. Loss of vibration perception

was evaluated with a biothesiometer on the pulp of

the hallux. Further neurologic assessments were

performed when required.

Standard treatment included wound care, bed

rest, proper off-loading, parenteral antibiotics, and

debridement. Wound debridement was performed

routinely to remove extensive callus and necrotictissue. Infected diabetic foot ulcer was defined

according to the Infectious Diseases Society of

America guidelines as the presence of purulent

wound drainage or at least three designated

systemic or local inflammatory findings. Samples

were obtained for culture by deep-needle aspiration,

bone biopsy, or curettage of the ulcer. In patients

with infected diabetic foot ulcers, antibiotics were

given according to the decision of the infectious

diseases specialist. After obtaining culture speci-

mens, empirical parenteral treatment was started;

change in the antimicrobial regimen was guided by

culture results and clinical follow-up. Parenteral

treatment was followed by prolonged oral therapy.

Levels of acute phase reactants were obtained

first at admission and then 1 week after standard

treatment. Erythrocyte sedimentation rate was

analyzed with the Sedimatic 100 method. White

blood cell count and platelet count were measured

with an automatic analyzer (LH 780; Beckman

Coulter, Krefeld, Germany). Serum albumin level

was measured spectrophotometrically with the

Abbott Architect c16000 system (Abbott Diagnos-

tics, Wiesbaden-Delkenheim, Germany). Serum

highly sensitive C-reactive protein level was mea-sured by an autoanalyzer, using a particle-enhanced

turbidimetric assay (Cobas Integra 400; Roche

Diagnostics, Indianapolis, Indiana). The sensitivity

of C-reactive protein was 0.11 mg/L. The intra-assay

and interassay coefficients of variation were 1.34

and 5.70, respectively.

Logistic regression was used to estimate the

independent effect of each selected variable on the

2 January/February 2011 Vol 101 No 1 Journal of the American Podiatric Medical Association


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outcome. The association between prognostic var-

iables and amputation rate was evaluated by

calculating the odds ratios and their corresponding

95% confidence intervals. The t test for independent

samples, after correction for equality of variance,

was used to compare patient variables. Differences

in proportions were compared with the v2 test.

Receiver operating characteristic curves were gen-

erated to determine the predictability of levels ofacute phase reactants for amputations. Sensitivity,

specificity, and positive and negative predictive

values for different cutoff levels of C-reactive

protein were calculated. Analyses were conducted

with statistical software (SPSS version 11.0; SPSS

Inc, Chicago, Illinois). Values are given as mean 6

SD. Tests of significance were 2-tailed. A P, .05

was considered statistically significant.

Results

Seventy patients underwent amputation (20 toeamputations, 21 ray amputations, ten transmetatar-

sal amputations, one Symes amputation, 17 below-

the-knee amputations, and one above-the-knee

amputation). Patients who underwent amputation

were older. There was no significant difference

between patients who underwent amputation and

those who did not in terms of sex, type of diabetes,

diabetes duration, previous insulin use, smoking,

body mass index, and microvascular complications

of diabetes. Baseline hemoglobin A1c levels were

similar. More people had ischemia and osteomyeli-

tis in the amputation group. Patients who under-went amputation had a slightly increased ulcer size;

however, it was not statistically significant. Site of

ulcers and Wagner scores are given in Table 1.

Baseline and post-treatment C-reactive protein

levels, erythrocyte sedimentation rates, white blood

cell counts, and platelet counts were significantly

elevated in patients who underwent amputation.

Albumin levels were significantly suppressed in the

amputation group (Table 1).

Clinical and laboratory predictors of amputation

were evaluated with univariate analysis (Table 2).

Limb ischemia; osteomyelitis; presence of gangrene;

ulcer depth; a 1-SD increase in baseline and post-treatment C-reactive protein levels, erythrocyte

sedimentation rates, and white blood cell counts;

and a 1-SD decrease in levels of post-treatment

albumin were found to be significantly associated

with increased risk of amputations.

Receiver operating characteristic curves were

generated to evaluate the relationship between

levels of acute phase reactants and amputations.

Table 1. Comparison of Baseline Characteristics of

Patients Who Underwent Amputation and Those Who Did

Not Require Amputationa

Amputation(n = 70)

No Amputation(n = 95)

Age (y)b 62.76 6 9.98 58.32 6 11.51

Male sex (No. [%]) 46 (65.7) 63 (66.3)

Type 2 diabetes (No. [%]) 68 (97.1) 90 (94.7)Diabetes duration (y) 15.446 9.34 14.67 6 8.65

Previous insulin use (No. [%]) 48 (68.6) 67 (70.5)

Smoking (No. [%]) 24 (34.3) 32 (33.7)

BMI 25.84 6 3.65 26.78 6 4.42

Retinopathy (No. [%]) 41 (58.6) 62 (65.3)

Nephropathy (No. [%]) 34 (48.6) 50 (52.6)

Neuropathy (No. [%]) 53 (75.7) 83 (87.4)

Limb ischemia (No. [%])b 54 (77.1) 36 (37.9)

Osteomyelitis (No. [%])b 51 (72.9) 38 (40.0)

Ulcer size (cm) 5.81 6 4.03 5.26 6 3.88

Site of ulcer (No. [%])b

Toe 38 (54.3) 36 (37.9)

Forefoot 24 (34.3) 20 (21.1)

Midfoot 3 (4.3) 15 (15.8)

Hindfoot 5 (7.1) 15 (15.8)

Leg 0 9 (9.5)

Wagner score (No. [%])b

Grade 1 0 6 (6.3)

Grade 2 3 (4.3) 43 (45.3)

Grade 3 29 (41.4) 39 (41.1)

Grade 4 34 (48.6) 6 (6.3)

Grade 5 4 (5.7) 1 (1.1)

Hemoglobin A1c (%) 9.68 6 2.78 9.36 6 2.44

Baseline CRP (mg/dL)b 127.996 86.92 58.26 6 75.87

Post-treatment CRP

(mg/dL)b95.8 6 83.61 28.95 6 42.64

Baseline ESR (mm/h)b 71.06 6 27.04 56.56 6 28.21

Post-treatment ESR

(mm/h)b70.68 6 29.12 55.34 6 29.39

Baseline WBC (cells/lL)b 13.55 6 4.91 10.38 6 3.66

Post-treatment WBC

(cells/lL)b11.89 6 4.18 8.97 6 2.61

Baseline PLT (cells/lL)b 369.64 6 107.22 316.36 127.01

Post-treatment PLT

(cells/lL)b392.11 6 138.99 326.746 143.9

Baseline albumin (g/dL)b 3.54 6 0.57 3.88 6 0.64

Post-treatment albumin

(g/dL)b3.29 6 0.6 3.76 6 0.55

Abbreviations: BMI, body mass index (calculated as weightin kilograms divided by the square of the height in meters); CRP,C-reactive protein; ESR, erythrocyte sedimentation rate; PLT,platelet count; WBC, white blood cell count.

aData are given as mean 6 SD except where indicatedotherwise.

bAmputation versus no amputation, P, .05.



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Post-treatment levels of acute phase reactants were

more closely associated with amputations accord-

ing to area under the curve values, which were

obtained from receiver operating characteristic

curves (Table 3). There was a strong relationship

between post-treatment C-reactive protein level and

amputation (area under the curve, 0.809; 95%

confidence interval, 0.7440.874). Multivariate anal-

ysis showed that post-treatment C-reactive protein

level was an independent predictor of amputation

when the data were controlled for age, sex,

presence of ischemia, and osteomyelitis (a 1-SDincrease in post-treatment C-reactive protein level;

model r2, 0.269; odds ratio, 4.445; 95% confidence

interval, 1.53212.9; P = .006). Potential cutoff

values of post-treatment C-reactive protein were

determined for prediction of amputations (Fig. 1).

Sensitivity, specificity, and positive and negative

predictive values for different cutoff levels of post-

treatment C-reactive protein are given in Table 4.

Discussion

These results suggest that levels of acute phase

reactants, which were obtained first at admission

and then 1 week after management of the diabetic

foot infection, were associated with amputation

risk. According to receiver operating characteristic

Table 2. Clinical and Laboratory Factors Predicting

Amputation

OR (95% CI)a P Value

Age 2.318 (0.9725.528) .058

Smoking 1.027 (0.5351.971) .936

Limb ischemia 5.531 (2.76011.083) ,.001

Osteomyelitis 4.026 (2.0657.851) ,.001

Ulcer diameter 1.833 (0.7104.732) .210

Gangrene (Wagner

grades 4 and 5)

14.924 (6.05636.778) ,.001

Ulcer depth (Wagner

grade 3 versus

grades 1 and 2)

12.137 (3.44142.812) ,.001

Baseline CRP 3.428 (1.4857.916) .004

Post-treatment CRP 5.933 (2.23615.744) ,.001

Baseline ESR 2.760 (1.2686.008) .011

Post-treatment ESR 2.300 (1.0994.815) .027

Baseline WBC 4.676 (2.00110.926) ,.001

Post-treatment WBC 8.599 (2.78126.581) ,.001

Baseline PLT 1.424 (0.5793.500) .441

Post-treatment PLT 1.333 (0.5223.407) .548

Baseline albumin 1.924 (0.8354.419)b .124

Post-treatment albumin 4.343 (1.68311.203)b .002

Abbreviations: CI, confidence interval; CRP, C-reactive

protein; ESR, erythrocyte sedimentation rate; OR, odds ratio;

PLT, platelet count; WBC, white blood cell count.aFor continuous parameters, the ORs were standardized to

express the risk associated with a 1-SD increase.bThe OR for serum albumin level was standardized to

express the risk associated with a 1-SD decrease.

Table 3. Baseline and Post-treatment Levels of Acute

Phase Reactants in the Prediction of Amputationa

Area 95% CI

AUCBaseline CRP 0.754 0.6780.830

AUCPost-treatment CRP 0.809 0.7440.874

AUCBaseline ESR 0.641 0.5570.726

AUCPost-treatment ESR 0.649 0.5630.735

AUCBaseline WBC 0.690 0.6050.774

AUCPost-treatment WBC 0.713 0.6320.794

AUCBaseline PLT 0.646 0.5620.729

AUCPost-treatment PLT 0.662 0.5770.746

AUCBaseline albuminb 0.661 0.5770.745

AUCPost-treatment albuminb 0.724 0.6410.807

Abbreviations: AUC, area under the curve; CI, confidence

interval; CRP, C-reactive protein; ESR, erythrocyte sedimen-

tation rate; PLT, platelet count; WBC, white blood cell count.aData are expressed as AUC of the corresponding receiver

operating characteristic curve.bThe receiver operating characteristic curve is generated

regarding suppressed albumin levels.

Figure 1. Receiver operating characteristic curvesshowing serum levels of post-treatment C-reactive

protein in the prediction of amputations.



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curves, post-treatment levels of acute phase reac-

tants were more closely associated with outcome.

Post-treatment C-reactive protein levels were

strongly related to amputation risk.

Circulating levels of acute phase reactants are

affected by the presence of infection, tissue injury,

and inflammation.17 Levels of acute phase reactants

in diabetic foot ulcers mostly alter in response to

superficial and deep tissue infections, osteomyelitis,

and limb ischemia.14, 16 Several studies have report-

ed that baseline levels of acute phase reactants are

associated with the outcome of the diabetic foot

ulcer. In one study,19 elevated C-reactive protein

levels were found to be strongly predictive of major

amputation in long-standing diabetic patients with

ischemic foot lesions. A prospective trial conducted

by Lipsky et al20 showed that baseline white blood

cell counts, C-reactive protein levels, erythrocyte

sedimentation rates, and albumin levels were

related to clinical treatment failure in diabetic foot

infections treated with broad spectrum antibiotics.

Low serum albumin level was also reported to be

associated with increased amputation risk.6 In-

creased baseline white blood cell counts were

reported to be associated with worse clinical

outcomes in diabetic foot ulcers.20, 21 A baseline

white blood cell count greater than 12.0 cells/lL has

been proposed to be associated with increased risk

of amputation.22 Pittet et al23 showed that neutro-

phil count was an independent predictor of treat-

ment failure.

On the other hand, Armstrong et al24 found that

elevated white blood cell count was a poor indicator

of acute osteomyelitis, although there was a

significant relationship between osteomyelitis and

elevated erythrocyte sedimentation rate. Elevated

erythrocyte sedimentation rate has been proposedto be useful in the diagnosis of osteomyelitis when

combined with clinical data. An elevated erythro-

cyte sedimentation rate of more than 70 mm/h has

been reported to increase the probability of

osteomyelitis 11 times.25 It has been found that an

elevated erythrocyte sedimentation rate of more

than 70 mm/h predicted the presence of osteomy-

elitis with a sensitivity of 89.5% and a specificity of

100%.26 However, increased C-reactive protein

levels were reported in hematogenous osteomyelitis

in children, and these levels decreased faster than

erythrocyte sedimentation rates after appropriate

treatment, reflecting the effectiveness of the therapy

more sensitively than erythrocyte sedimentation

rate.27 The present results also suggest that C-

reactive protein levels obtained early after starting

standard treatment for the infected diabetic foot

ulcer are strongly correlated with the outcome.

Although univariate analysis revealed a more

elevated odds ratio of a 1-SD increase in post-

treatment white blood cell count for predicting

amputation risk, receiver operating characteristic

curve analysis suggested that post-treatment C-

reactive protein level was a better indicator of

amputation risk. On the other hand, erythrocyte

sedimentation rates obtained early after treatment

were similar to those taken at admission, probably

owing to its relatively long halftime.

In conclusion, we showed that circulating levels

of acute phase reactants were associated with

amputation risk in diabetic foot infections. Promi-

nent acute phase response after treatment seemed

more likely to be associated with amputation thandid baseline levels of acute phase reactants. Post-

treatment C-reactive protein level was a strong

predictor of treatment failure and amputation risk in

patients with infected diabetic foot ulcers. We

suggest that increased circulating levels of acute

phase reactants reflect the presence of inflammation

that occurs in response to tissue injury, superficial

and deep tissue infections, osteomyelitis, limb

ischemia, and gangrene, and they should be

considered a marker for the underlying abnormality

causing amputation.

Financial Disclosure: None reported.

Conflict of Interest: None reported.

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Table 4. Analysis of Different Cutoff Values of Post-treatment CRP in the Prediction of Amputation

Sensitivity (%) Specificity (%) PPV (%) NPV (%)

Post-treatment CRP !30 mg/dL 68.57 72.63 64.86 75.82



Abbreviations: CRP, C-reactive protein; NPV, negative predictive value; PPV, positive predictive value.



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