Diabetes Care

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Predictors of Lower-Extremity Amputation in Patients With an Infected Diabetic Foot Ulcer DOI: 10.2337/dc14-1598

OBJECTIVE

Infection commonly complicates diabetic foot ulcers and is associated with a poor outcome. In a cohort of individuals with an infected diabetic foot ulcer, we aimed to determine independent predictors of lower-extremity amputation and the predictive value for amputation of the International Working Group on the Diabetic Foot (IWGDF) classification system and to develop a risk score for predicting amputation. RESEARCH DESIGN AND METHODS

We prospectively studied 575 patients with an infected diabetic foot ulcer presenting to 1 of 14 diabetic foot clinics in 10 European countries.

Among these patients, 159 (28%) underwent an amputation. Independent risk factors for amputation were as follows: periwound edema, foul smell, (non)purulent exudate, deep ulcer, positive probing to bone test, pretibial edema, fever, and elevated C-reactive protein. Increasing IWGDF severity of infection also independently predicted amputation. We developed a risk score for any amputation and for amputations excluding the lesser toes (including the variables sex, pain on palpation, periwound edema, ulcer size, ulcer depth, and peripheral arterial disease) that predicted amputation better than the IWGDF system (area under the ROC curves 0.80, 0.78, and 0.67, respectively). CONCLUSIONS

For individuals with an infected diabetic foot ulcer, we identified independent predictors of amputation, validated the prognostic value of the IWGDF classification system, and developed a new risk score for amputation that can be readily used in daily clinical practice. Our risk score may have better prognostic accuracy than the IWGDF system, the only currently available system, but our findings need to be validated in other cohorts. Infection is a frequent complication of diabetic foot ulcers, with up to 58% of ulcers being infected at initial presentation at a diabetic foot clinic, increasing to 82% in patients hospitalized for a diabetic foot ulcer (1). These diabetic foot infections (DFIs) are associated with poor clinical outcomes for the patient and high costs for both the patient and the health care system (2). Patients with a DFI have a 50-fold increased risk of hospitalization and 150-fold increased risk of lowerextremity amputation compared with patients with diabetes and no foot infection (3). Among patients with a DFI, ;5% will undergo a major amputation and 20–30% a

1 Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands 2 Research Unit for General Practice and Section of General Practice, Department of Public Health, University of Copenhagen, Copenhagen, Denmark 3 Department of Endocrinology, University of Malm¨o, Malm¨o, Sweden 4 International Diabetes Federation, Consultative Section and International Working Group on the Diabetic Foot, Heemstede, the Netherlands 5 Diabetic Department, Kings College Hospital, London, U.K. 6 Copenhagen Wound Healing Centre, Bispebjerg Hospital, Copenhagen, Denmark 7 Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic 8 Diabetes Centre, Tameside General Hospital, Ashton-under-Lyne, U.K. 9 Department of Endocrinology and Nutrition, Hospital de Sant Pau, Autonomous University of Barcelona, Barcelona, Spain 10 Sezione Dipartimentale Piede Diabetico, Dipartimento di Area Medica, Azienda OspedalieroUniversitaria Pisana, Pisa, Italy 11 Swedish Institute for Health Economics, Lund, Sweden 12 Innere Abteilung, Mariannen Hospital, Werl, Germany 13 Mathias-Spital, Diabetic Department, Rheine, Germany 14 Policlinico Tor Vergata, Department of Internal medicine, Rome, Italy 15 Department of Endocrinology, University Medical Centre, Ljubljana, Slovenia 16 Department of Endocrinology, H Familie Ziekenhuis and Centre de Sante´ des Fagnes, Rumst and Chimay, Belgium 17 Department of Surgery, Twenteborg Ziekenhuis, Almelo, the Netherlands

Corresponding author: Kristy Pickwell, k.pickwell@ mumc.nl. Received 3 July 2014 and accepted 7 January 2015. This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/ suppl/doi:10.2337/dc14-1598/-/DC1. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Diabetes Care Publish Ahead of Print, published online February 9, 2015

PATHOPHYSIOLOGY/COMPLICATIONS

RESULTS

Kristy Pickwell,1 Volkert Siersma,2 Marleen Kars,1 Jan Apelqvist,3 Karel Bakker,4 Michael Edmonds,5 ´7 Per Holstein,6 Alexandra Jirkovska, 8 9 Edward Jude, Didac Mauricio, Alberto Piaggesi,10 Gunnel Ragnarson Tennvall,11 Heinrich Reike,12 Maximilian Spraul,13 Luigi Uccioli,14 Vilma Urbancic,15 Kristien van Acker,16 Jeff van Baal,17 and Nicolaas Schaper1

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Amputation in Infected Diabetic Foot Ulcers

minor amputation, with the presence of peripheral arterial disease (PAD) greatly increasing amputation risk (4–6). Furthermore, lower-limb amputation is associated not only with significant morbidity and mortality but also with major psychosocial and financial consequences (7–9). As infection of a diabetic foot wound heralds a poor outcome, early diagnosis and treatment are important. Unfortunately, systemic signs of inflammation such as fever and leukocytosis are often absent even with a serious foot infection (10,11). As local signs and symptoms of infection are also often diminished, because of concomitant peripheral neuropathy and ischemia (12), diagnosing and defining resolution of infection can be difficult. Amputation, instead of resolution of symptoms or signs of infection, could therefore be a reliable outcome measure. The system developed by the International Working Group on the Diabetic Foot (IWGDF) and the Infectious Diseases Society of America (IDSA) provides criteria for the diagnosis of infection of ulcers and classifies it into three categories: mild, moderate, or severe. The system was validated in three relatively small cohorts of patients with a DFI (13–15), and increasing severity of infection was associated with toe amputations in one large cohort (16). While the system seems valid in predicting amputation, it does not take into account the results of diagnostic tests such as probing to bone and does not include more general patient characteristics that may have a major impact on the outcome of a DFI. The European Study Group on Diabetes and the Lower Extremity (Eurodiale) prospectively studied a large cohort of patients with a diabetic foot ulcer (17), enabling us to determine the prognostic value of the IWGDF system for clinically relevant lower-extremity amputations. A previously published study of this cohort identified determinants of minor amputation but did not specifically focus on patients with an infected diabetic foot ulcer (18). The aims of the current study were to 1) identify which signs of infection independently predict amputation within 1 year in patients from the Eurodiale cohort presenting with a DFI, 2) determine the predictive value of the IWGDF system for amputation in this cohort, and 3) develop an alternative risk

Diabetes Care

score for amputation in individuals with a DFI from characteristics of the foot (ulcer), the leg, and the patient that can readily be assessed by the clinician at presentation to guide further management. RESEARCH DESIGN AND METHODS Study Design

Between 1 September 2003 and 1 October 2004, all patients with diabetes presenting with a new foot ulcer to any of 14 diabetic foot centers in 10 European countries were included. Both in- and outpatients were included. The design and rationale of the multicenter, observational, prospective Eurodiale study have previously been described in detail (17). We excluded patients treated in the participating centers for an ulcer of the ipsilateral foot during the previous 12 months and those with a life expectancy of ,1 year. Patients were followed monthly until healing of the foot ulcer(s), major amputation, or deathdup to a maximum of 1 year. Healing was defined as complete epithelialization of the whole foot at two consecutive visits. All patients were treated according to protocols based on the International Consensus on the Diabetic Foot (19). Ulcer characteristics were described according to the PEDIS system of the IWGDF, which classifies foot ulcers according to five categories: perfusion, extent, depth, infection and sensation (19,20). Ankle-brachial index (ABI) ,0.9 was considered to represent the presence of PAD. A deep ulcer was defined as a lesion of the skin extending through the subcutis with visible muscle, tendon, or bone, whereas a superficial ulcer was limited to the skin. In patients with a deep ulcer, the probe-to-bone test was performed, yielding two categories of deep ulcers: those with a positive and negative probe-to-bone test. Infection was diagnosed according to the IWGDF system by the presence of two or more of the following signs: frank purulence, local warmth, periwound redness, lymphangitis, periwound edema, pain or tenderness on palpation, or fever (21). For the current study, only the data of patients with an infected foot ulcer diagnosed by the IWGDF/IDSA guidelines were analyzed. We defined two separate outcomes: 1) any amputation, including all minor and major amputations, and 2) amputations proximal to and including

the hallux, excluding amputations of digits 2–5. We performed analyses for both of these outcomes, as amputations of digits 2–5 could be considered functionally less important for mobility and quality of life and as part of treatment rather than a measure of poor outcome. Statistical Analyses

Unadjusted associations between the 1-year amputation incidence and patient, leg, ulcer, and infection characteristics were tested with x2 tests (categorical characteristics) and t tests (continuous characteristics). The characteristics studied included sex, age, immobility, serum creatinine, HbA1c, presence of PAD and polyneuropathy, ulcer size, depth, duration and location, periwound redness, (periwound) edema, pain, foul smell, exudate/pus, increased local skin temperature, lymphadenitis/lymphangitis, fever, and CRP levels. The relation of the different characteristics with amputation was analyzed in multivariable Cox proportional hazard regression models. In these analyses, a hazard ratio (HR) .1 indicates a higher amputation rate for the corresponding category of a certain characteristic compared with a baseline category. For instance, an HR of 2 means that at any time point during follow-up, the patients in the corresponding category are twice as likely to undergo an amputation as the patients in the baseline category. The patient demographics and foot, ulcer, and infection characteristics were used to construct risk scores for any amputation and for amputations excluding lesser toes in patients with an infected ulcer. Firstly, a score corresponding to a full model was defined as the linear term of a logistic regression model on the 1-year amputation incidence that included all demographics, foot and ulcer characteristics, and infection characteristics. Thereafter, this full model was reduced by iterative (backward) elimination of the least significant predictor until all predictors were significant (P , 0.05); the final risk scores are a version of the reduced models where the parameters are rounded to increase usability. The full models and the risk scores were evaluated, together with the IWGDF/IDSA classification, with receiver operating characteristic (ROC) curves. RESULTS

Five hundred and ninety-one (57%) of 1,033 patients who completed the

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Pickwell and Associates

Eurodiale study had an infected ulcer, and data were complete for 575 (97.3%) of them. One hundred and ninety-nine patients had a grade 2 (mild) infection, 338 a grade 3 (moderate), and 38 a grade 4 (severe). Amputations were performed on 159 (28%) patients (126 minor and 33 major) within the year of follow-up; 103 patients (18%) underwent amputations proximal to and including the hallux. Variables Associated With Amputation

Several general patient and ulcer characteristics were univariately associated with any amputation as depicted in Table 1. The incidence of amputation increased with increasing redness, periwound or pretibial edema, the presence of pus, lymphadenitis/lymphangitis, fever (all P , 0.01), and elevated C-reactive protein (CRP) levels (P = 0.01). The same

variables were associated with amputations excluding the lesser toes, with the exception of pus and lymphadenitis/ lymphangitis. Incidence of amputation was also directly related to increasing severity of infection according to the IWGDF system (P , 0.01), with 50% of patients with systemic inflammatory signs (IWGDF grade 4 infection) undergoing any amputation and 40% undergoing amputations excluding the lesser toes. Immobility, serum creatinine, HbA 1c , presence of polyneuropathy, and ulcer duration and location were not associated with amputation. Signs of Infection Independently Predicting Amputation

Table 2 shows the results of Cox regression analysis corrected for all of the variables as listed in RESEARCH DESIGN AND METHODS as well as for center (unadjusted analyses in Supplementary Table 1). The

Table 1—Association between patient, leg, ulcer, and infection characteristics and lower-extremity amputation Any amputation No

Yes

Total patients

74.1 25.9

Patient characteristics Female sex Age, years (mean)

40.6 29.5 65.4 66.2

Leg characteristics PAD PAD with ABI ,0.5

37.4 55.8 6.8 13.6

P*

0.02 0.49

Amputation excluding lesser toes No

Yes

82.1

17.9

40.5 65.4

25.2 66.4

38.4 7.0

59.4 15.8

52.7 13.6

59.2 26.2

22.2 29.1

30.4 53.9

47.9 41.1 54.8 49.8 61.2 32.3 10.2

35.3 57.8 71.8 60.2 63.1 35.0 14.6

5.7 12.1

14.6 15.5

39.2 55.9 4.9

13.6 71.8 14.6

,0.01

Ulcer characteristics Ulcer size (cm2) 1–5 .5 Deep ulcer Without probing to bone With probing to bone

22.7 26.5 24.1 60.5

Infection characteristics Periwound redness (cm) 0.5–2 .2 Periwound edema Pain or tenderness to palpation Local skin temperature increased Pus Lymphangitis/lymphadenitis Body temperature Fever (.38.08C) Not recorded IDSA severity 2 (mild)† 3 (moderate)† 4 (severe)†

,0.01 35.8 57.4 72.5 ,0.01 54.4 0.44 65.8 0.21 41.6 ,0.01 18.8 ,0.01 ,0.01 5.2 13.4 12.3 14.1 ,0.01 41.1 16.1 54.7 70.5 4.2 13.4

,0.01

,0.01

49.1 39.4 52.7 50.7 60.0 29.7 8.2

,0.01 0.50 ,0.01

,0.01 51.8 59.7 13.7 22.2

P*

,0.01

0.01

,0.01 0.06 0.71 0.60 0.20 ,0.01 ,0.01

Data are percent unless otherwise indicated. *Pearson x2 test (categorical variables) or Student t test (continuous variables). †Mild, infection of the skin/subcutaneous tissue; moderate, mild with erythema .2 cm or infection of structures deeper than the subcutaneous tissue; severe, infection with systemic signs of inflammation.

independent predictors of any amputation were as follows: periwound edema, HR 2.01 (95% CI 1.33–3.03); foul smell, HR 1.74 (1.17–2.57); purulent and nonpurulent exudate, HR 1.67 (1.17–2.37) and 1.49 (1.02–2.18), respectively; deep ulcer, HR 3.49 (1.84–6.60); positive probing-to-bone test, HR 6.78 (3.79–12.15); pretibial edema, HR 1.53 (1.02–2.31); fever, HR 2.00 (1.15–3.48); elevated CRP levels but less than three times the upper limit of normal, HR 2.74 (1.40–5.34); and elevated CRP levels more than three times above the upper limit, HR 3.84 (2.07–7.12). The independent predictors of amputations proximal to and including the hallux were as follows: the presence of either periwound or pretibial edema, HR 1.84 (95% CI 1.14–2.98) and 1.89 (1.17– 3.05), respectively; a deep ulcer, HR 4.12 (2.01–8.47); positive probing-to-bone test, HR 3.98 (2.05–7.71); and CRPlevels more than three times the upper limit, HR 2.71 (1.31–5.61). In summary, the same variables predicted any amputation and amputations excluding the lesser toes, with the exception of foul smell, nonpurulent and purulent exudate, and fever, which predicted any amputation only. In comparison with mild infection, the presence of a moderate infection increased the hazard for any amputation by a factor of 2.15 (95% CI 1.25–3.71) and 3.01 (1.51–6.01) for amputations excluding the lesser toes. For severe infection, the hazard for any amputation increased by a factor of 4.12 (1.99–8.51) and for amputations excluding the lesser toes by a factor of 5.40 (2.20– 13.26). Larger ulcer size and presence of PAD were also independent predictors of both any amputation and amputations excluding the lesser toes, with HRs between 1.81 and 3 (and 95% CIs between 1.05 and 6.6). Eurodiale Risk Scores Versus IWGDF System for Predicting Amputation

The risk score for any amputation that included all the studied variables as reported in RESEARCH DESIGN AND METHODS had an area under the ROC curve of 0.84; the risk score for amputations excluding lesser toes had an area under the ROC curve of 0.85. To increase the applicability of the scores, we reduced them as described above to the ones presented in Table 3, which include the variables

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Diabetes Care

Table 2—HRs for amputation for individual infection characteristics Any amputation HR (95% CI)

P value

Amputation excluding lesser toes P value

HR (95% CI)

P value

1.05 (0.45–2.44) 1.49 (0.65–3.38)

0.91† 0.34†

0.11‡

P value

Periwound redness (cm) 0.5–2 (vs. ,0.5) .2 (vs. ,0.5)

1.13 (0.54–2.36) 1.68 (0.82–3.45)

Periwound edema

2.01 (1.33–3.03)

,0.01

1.84 (1.14–2.98)

0.01

Pretibial edema

1.53 (1.02–2.31)

0.04

1.89 (1.17–3.05)

,0.01

Pain or tenderness to palpation

1.04 (0.70–1.54)

0.84

1.36 (0.84–2.18)

0.21

Local skin temperature increased

1.15 (0.79–1.68)

0.47

1.00 (0.64–1.58)

1.0

Increased exudate

1.49 (1.02–2.18)

0.04

0.97 (0.62–1.53)

0.91

Pus Lymphangitis/lymphadenitis

1.67 (1.17–2.37) 1.41 (0.84–2.37)

,0.01 0.19

1.10 (0.70–1.72) 0.85 (0.43–1.68)

0.67 0.64

Body temperature Fever (.38.08C) Not recorded

2.00 (1.15–3.48) 1.21 (0.58–2.51)

0.01† 0.61†

IDSA severity 3 (vs. severity 2)§ 4 (vs. severity 2)§

2.15 (1.25–3.71) 4.12 (1.99–8.51)

,0.01† ,0.01†

0.75† 0.15†

0.34‡

0.05‡

0.16‡ 1.80 (0.94–3.47) 0.82 (0.37–1.83)

0.08† 0.62†

3.01 (1.51–6.01) 5.40 (2.20–13.26)

,0.01† ,0.01†

,0.01‡

,0.01‡

Analysis adjusted for the following variables: sex; age; immobility; serum creatinine; HbA1c; presence of PAD and polyneuropathy; ulcer size, depth, and location; periwound redness; (periwound) edema; pain; foul smell; presence of exudate/pus; increased local skin temperature; lymphadenitis/ lymphangitis; fever; CRP levels; and center. †P value of test of subcategory of variable vs. baseline. ‡P value of test of all categories of variable combined. §Severity 2 (mild), infection of the skin/subcutaneous tissue; severity 3 (moderate), mild with erythema .2 cm or infection of structures deeper than the subcutaneous tissue; severity 4 (severe), infection with systemic signs of inflammation.

sex, PAD, pain or tenderness on palpation, ulcer size and ulcer depth, and periwound edema yielding area under the ROC curves of 0.8 and 0.78 for any amputation and amputations excluding the lesser toes respectively. By way of comparison, the area under the ROC curve for the IWGDF system was 0.67

in our population. Six percent of patients in the lowest tertile underwent any amputation; this increased to 50% of patients in the highest tertile. The respective percentages for amputations excluding the lesser toes were 1 for the lowest tertile and 39 for the highest tertile (Fig. 1).

Table 3—Risk scores for amputation in patients with an infected diabetic foot ulcer

Sex Female Male PAD No PAD PAD with ABI ,0.5

Any amputation (points)

Amputation excluding lesser toes (points)

0 0.5

0 1

0 1 1.5

0 1 2

Pain or tenderness on palpation No Yes

0 0.5

Ulcer size (cm2) ,1 1–5 .5

0 0.5 1

Ulcer depth Superficial Deep without probing to bone Deep with probing to bone

0 1.5 2

Periwound edema No Yes

0 0.5

0 1 2

CONCLUSIONS Independent Risk Factors for Amputation

Previously published studies that have aimed to identify independent risk factors for lower-extremity amputation in patients with a DFI have noted an association with older age (5,22), the presence of fever (5), elevated acute-phase reactants (5,22,23), higher HbA1c levels (24), and renal insufficiency (5,22). In the current study, we identified the following independent risk factors for lower-extremity amputation in patients with an infected diabetic foot ulcer (in decreasing order of HR): positive probeto-bone test, deep ulcer, elevated CRP levels, and the presence of periwound or pretibial edema. The presence of increased (non)purulent exudate, foul smell, and fever independently predicted any amputation but not amputations excluding the lesser toes. Thus, we confirmed some of the previously noted risk factors but could not confirm others. This may be explained in part by several differences between our study and those previously published. Lipsky et al. (5) retrospectively studied amputation risk in 3,018 patients hospitalized for a skin or soft tissue infection, but only 16% of these patients had an infected diabetic foot ulcer. Among three other studies that focused on

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Pickwell and Associates

Figure 1—ROC curves of risk scores for any amputation (A) and for amputations excluding the lesser toes (B) in patients with an infected diabetic foot ulcer. (A high-quality color representation of this figure is available in the online issue.)

amputation risk in patients with an infected diabetic foot ulcer, one analyzed only patients with large (.3 3 3 cm) and deep ulcers (23), while we included all ulcers, and the numbers of patients included in the other two studies (22,24) were relatively small (n = 100 and 165) compared with our cohort (n = 575). There were few patients with significant renal insufficiency in our cohort, which may explain why we did not find an association between renal insufficiency and amputation. Periwound and pretibial edema as well as the presence of increased exudate have not previously been found to be associated with amputation. Periwound edema may be related to more severe infection, and pretibial edema may be associated with worse overall health status, leading to a greater risk of amputation. The presence of increased exudate and foul smell predicted any amputation, but not amputations excluding the lesser toes. It is possible that clinicians would consider an amputation of one of the digits 2–5 in the presence of these signs but would not consider it such a poor prognostic sign as to consider a larger amputation. Eurodiale Risk Score Versus IWGDF System for Predicting Amputation

Previous studies have shown that with increasing grades of IWGDF infection severity, the risk of amputation increases (13–16,20,21). Also, in our cohort the number of amputations increased with increasing IWGDF risk score. The new

risk scores we developed for any amputation, and amputations excluding the lesser toes had higher prognostic capability, based on the area under the ROC curve (0.80 and 0.78, respectively), than the IWGDF system (0.67). However, it should be noted that these Eurodiale scores were developed based on the available data of our cohort, and they will need to be validated in other populations before any firm conclusions can be drawn. The advantage of these newly developed scores is that they are easier for clinicians to perform, as they do not require additional laboratory tests, as does the IWGDF system. There are relatively few signs and symptoms of infection in the Eurodiale compared with the IWGDF risk scores, and several items of the new scores are known risk factors for poor outcome (25–27). Theoretically, these new scores might predict the amputation risk of any ulcer, infected or not. In line with Louis Pasteur (“the terrain is everything, the bacteria is nothing”), the characteristics of the individual in whom an infection develops might be more important than the infection itself. Sex, PAD, and ulcer depth are included in the risk scores for both any amputation and amputations excluding the lesser toes. Ulcer size was not a risk factor for any amputation in our cohort, probably because ulcers on digits 2–5 are per definition small ulcers, diluting the effect of ulcer size on amputation risk when all amputations were analyzed. It is

unclear why periwound edema is a risk factor for any amputation but not for amputations excluding the lesser toes and why pain on palpation is a risk factor for amputations excluding the lesser toes but not for any amputation. Some experts prefer an early toe amputation to avoid long-term antibiotic treatment, and we therefore expected a large variation between centers in the selection of patients for toe amputations. However, when we added center to the risk score for any amputation, the area under the ROC curve only marginally improved, from 0.80 to 0.84, contradicting our assumption. Limitations of the Current Study

Our study has several limitations. In 37% of cases, patients had been treated by a medical specialist for their ulcer before they were enrolled. As these patients likely suffered from severe or complex diabetic foot disease, our results may not be applicable to patients with milder disease. While all patients included in the Eurodiale cohort were treated according to IWGDF protocols, it is possible that treatment differed in the various centers. Thus, we corrected all the analyses for center. As mentioned previously, the risk score we created needs to be validated in other cohorts of patients with DFI. Our data were obtained in 2003–2004, and the incidence of lower-extremity amputation in patients with DFU has decreased since then in several countries (28). However, studies have

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observed that the relative risk of amputation for these patients has not changed (29,30), which is why we believe our results are still valid and applicable. In summary, of the several clinical signs that we studied, deep ulcers, the presence of increased exudate, foul smell, periwound and pretibial edema, and fever and elevated CRP levels were identified as independent risk factors for amputation in patients with infected diabetic foot ulcers. We confirmed the prognostic value of the IWGDF system for predicting amputation and we developed two new risk scores, one for any amputation and one for amputations excluding the lesser toes, with better prognostic accuracy than this system, which is currently the only one in use for infected diabetic foot ulcers. These newly developed risk scores can be readily used in daily clinical practice without the necessity of obtaining additional laboratory testing. Future studies should be aimed at validating our findings in other cohorts of patients with an infected diabetic foot ulcer. Acknowledgments. The authors thank Prof. B. Lipsky, emeritus professor of medicine, University of Washington; visiting professor, Infectious Diseases, University of Geneva; and teaching associate, Green Templeton College, University of Oxford, for critically reviewing the manuscript. Funding. The Eurodiale study was supported by the Fifth Framework Programme of the European Commission. Duality of Interest. No potential conflicts of interest relevant to this paper were reported. Author Contributions. K.P. and V.S. researched data and wrote the manuscript. M.K. reviewed and edited the manuscript and contributed to the discussion. J.A., K.B., M.E., P.H., A.J., E.J., D.M., A.P., G.R.T., H.R., M.S., L.U., V.U., K.v.A., and J.v.B. planned the study, collected data, and reviewed and edited the manuscript. N.S. planned the study, collected data, and wrote the manuscript. K.P., V.S., and N.S. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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Diabetes Care

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