Evidence of greater severity of diabetic foot ulcers during COVID‐19 pandemic: A real‐life single‐centre cohort study

In the Sars‐Cov‐2 pandemic era, patients with diabetes mellitus (DM) manifested more severe forms of Sars‐Cov‐2 with greater mortality than non‐diabetic patients. Several studies documented more aggressive forms of diabetic foot ulcers (DFU) during the pandemic period even though the results were not unanimously confirmed. The aim of this study was to evaluate the clinical‐demographic differences between a cohort of Sicilian diabetic patients hospitalised for DFU in the pre‐pandemic 3 years and a cohort of patients hospitalised in the pandemic 2 years.


| INTRODUCTION
Since the beginning of the Sars-Cov-2 pandemic era, it has been documented that patients with diabetes mellitus (DM) manifest more severe forms of SARS-COV2 infection with greater mortality than non-diabetic patients. [1][2][3] These data were confirmed by a recent meta-analysis that considered a total of 78,874 patients hospitalised for SARS COV2 infection from 83 observational studies, which documented a prevalence of pre-existing DM in 14.3% of patients and a significantly higher prevalence of the more severe forms of SARS COV2 pneumonia and a higher risk of hospital mortality in diabetic than non-diabetic patients. 4 The prevalence of DM in patients who died of COVID-19 was shown to be higher than in the general population. 1,5 These data have led clinicians to consider diabetic patients as having greater susceptibility to hospitalisation and mortality in case of SARS-COV2 infection, consequently leading to a more incisive vaccination campaign and more rigorous isolation rules. 6 In the diabetic area, distance medicine measures have been implemented in order to avoid the risk of contagion though with the risk of underestimating more severe conditions of DM and its complications, such as diabetic foot ulcers (DFU). [7][8][9][10] The aim of the study was to evaluate the clinical-demographic differences between a cohort of patients with DFU hospitalised in the pre-pandemic 3-year period and a cohort of patients hospitalised for DFU in the most recent 2-year pandemic period.

| MATERIALS AND METHODS
The clinical and demographic data of 111 patients from the prepandemic period 2017-2019 (Group A) and 86 patients from the pandemic period 2020-2021 (Group B) affected by DFU, admitted to the division of Endocrinology and Metabolism of the University Hospital of Palermo, were retrospectively evaluated. The clinical assessment of the type, staging and grading of the lesion, and the infective complications from DFU was performed according to the most recent recommendations of the International Working Group on the Diabetic Foot (IWGDF). 11,12 In both patient groups, we evaluated anthropometric and demographic data, such as age, sex, body mass index (BMI), type and duration of DM, clinical parameters such as type of ulcer (neuropathic, ischaemic, or neuro-ischaemic ulcer), grade and stage of the lesion according to the Texas wound classification system, the severity of infection according to Infectious Diseases Society of America (IDSA) classification, the presence of systemic inflammatory response syndrome (SIRS) in accordance with the recommendations of the main scientific societies in the sector, and the presence of osteomyelitis and its outcome in terms of major or minor amputation and revascularisation. [12][13][14][15][16] The Texas classification is a descriptive classification, rather than a scoring system, which classifies DFUs according to depth (grade from 0 to 3), presence of infection (stage B), ischaemia (stage C), or both (stage D). 13 Ischaemic ulcer was defined by the clinical evaluation of absent pulses, ankle-brachial index (ABI) less than 0.9, and evidence of low arterial flow at triphasic pedal Doppler. 17 The decision to revascularise was based on clinical evaluation by a deputed vascular surgeon, low ABI (<0.5), low or absent arterial flow at triphasic pedal Doppler, and execution of computed tomography angiography only in cases of large ulcers that cannot consent to perform Doppler according to the guidelines on the diagnosis and treatment of peripheral arterial diseases. 17 In addition, biochemical parameters, such as glycated haemo-

| Statistical analysis
A statistical analysis was performed using the SPSS version 20. The normality test was assessed using the Kolmogorov-Smirnov test.
Numerical data were presented as mean � standard deviation (SD) or median and interquartile range. Analyses of variables were performed using the chi-square or Fisher's exact test for categorical variables and the independent t-test or Mann-Whitney test for continuous variables according to their distribution. A p value of <0.05 was considered statistically significant.

| RESULTS
The clinical, demographic, and biochemical data are shown in Table 1.
As expected, longer foot ulcer duration was observed in group B compared to group A (p < 0.001). Patients hospitalised in the pandemic period had significantly higher indices of inflammation (WBC p < 0.001; ESR p = 0.030; CRP p = 0.001). In Group B, a significantly higher prevalence of male subjects (p = 0.009) was observed compared to group A. In Group B, a higher prevalence of ischaemic and neuro-ischaemic ulcers was observed compared to neuropathic ulcers (neuropathic ulcer in Group A 36.9% vs. Group B 10.5%; neuro-ischaemic ulcer Group A 53.2% vs. Group B 74.4% p < 0.001). In Group B, a significantly higher prevalence of deep ulcers with the involvement of the osteo-articular plane was observed compared to Group A (superficial ulcers in Group A 50.5% vs. Group B 18.6%; ulcer involving tendons/capsules Group A 36% vs. Group B 58.1%; ulcer with bone involvement Group A 12.6% vs. Group B 20.9%, p < 0.001) ( Table 1). In Figure 1, grading of DFU shows the significant difference (p < 0.001) in the frequency of all lesions from pre-ulcerative ones to those involving superficial, tendon/capsule, and bone. Patients hospitalised during the pandemic period showed a higher prevalence of SIRS than the limit of statistical significance (SIRS Group A 12.6% vs. Group B 23.3% p = 0.05).
Revascularisation and minor or major amputation outcome data are shown in Table 2   amputation rates and mortality in patients with DFU before and during the pandemic. 28 To avoid late referral and the risk of major amputation, the scientific community developed a tool to be adopted during the pandemic period and beyond in the case of similar condition, the COVID-19 fast-track pathway. 29 This tool is useful for clinicians to distinguish non-limb from limb-threatening conditions.

| Limitations and strength of the study
The strength of our study is to be considered the observation of a series of monocentric patients, all hospitalised for acute DFU conditions and compared taking into consideration the 2-year pandemic and an immediately preceding 3-year period to avoid the bias linked to a different territorial microbiological spectrum, different antibiotic resistances, and different procedural methods. The limits include the small number of the sample and the retrospective observation.

| Conclusions
Our study documented a greater severity of ulcers in terms of deep tissue involvement, systemic inflammatory involvement, and severity of ischaemia, requiring a significantly higher number of revascularisations and more expensive therapy but without increasing the amputation rate observed in the pandemic period. The main message of our study is that the collaboration of several professional figures is confirmed as fundamental as is the timeliness of diagnosis and intervention in the diagnostic and therapeutic pathway of DFU, which were probably deficient due to the pandemic emergency. had full access to all the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. The datasets generated during and/or analysed in the current study are available from the corresponding author upon reasonable request.