Metagenomics to Identify Pathogens in Diabetic Foot Ulcers and the Potential Impact for Clinical Care.

PURPOSE OF REVIEW: Diabetes mellitus may affect every third adult American by 2050, and about one-third will develop a diabetic foot ulcer (DFU) during their lifetime. The current standard of care results in healing of less than 50% of all DFUs. Many individuals with DFU develop limb-threatening infection which place them at risk for additional morbidity and mortality. We review research associated with culture-independent next-generation sequencing techniques pertaining to diabetic foot ulcers and their potential for clinical application. RECENT FINDINGS: Diabetic foot ulcers are a growing problem and clinicians are limited by their reliance on conventional culture. Metagenomic sequencing technology provides an unparalleled viewpoint of the polymicrobial constituency of DFU. The microbiome techniques used to study the microbial constituency of DFU may offer insight to improve care for these patients, but without standardized approaches in research based on real-world clinical practices, a significant knowledge gap will remain.

Postoperative healing in the diabetic foot is impacted by discharge destination.

The aim of this study was to evaluate the impact of discharge destination on diabetes-related limb salvage surgery outcomes post-hospitalisation. This was a single-centre, observational, descriptive study of 175 subjects with diabetes who underwent limb salvage surgery of a minor foot amputation or wide incision and debridement for an acutely infected diabetic foot ulcer (DFU). Comparisons were made between subjects discharged home vs a skilled nursing facility (SNF) for 12 months postoperatively. Univariate, multivariate, and time-to-event analyses were performed. The SNF discharge group (n = 40) had worse outcomes with longer healing time (P = .022), more rehospitalisations requiring a podiatry consult (P = .009), increase of subsequent ipsilateral major lower-extremity amputation (P = .028), and a higher mortality rate (P = .012) within the 12-month postoperative period. There was no significant difference between the cohorts in surgically cleared osteomyelitis (P = .8434). The Charlson Comorbidity Index values for those discharged home and those in a short-term nursing facility were similar (P = .3819; home x ¯ =5.33 ± 2.84 vs SNF x ¯ =5.75 ± 2.06). The planned discharge destination after limb salvage surgery among people with an acutely infected DFU should be an added risk factor for healing outcomes. Patients discharged to SNFs experience additional morbidity and mortality compared with patients discharged home post-hospitalisation.

Multidrug resistant organism predicts ulcer recurrence following surgical management of diabetic foot osteomyelitis.

Diabetic foot ulcers commonly precede diabetic foot osteomyelitis (DFO) and once the latter occurs, surgical management is often performed. The presence of osteomyelitis is an independent risk factor for the development of re-ulceration. We investigated the relationship between causative organisms in osteomyelitis and 1-year diabetic foot outcomes (re-ulceration, amputation, and death) following surgical management in an observational cohort of 223 patients. Univariate and multivariate analyses were performed for available demographic, clinical, and laboratory data. In addition, random forest plots were used to identify microbiologic predictors of 1-year outcomes. Patients with osteomyelitis managed surgically were younger and exhibited more painful peripheral neuropathy than outpatients with diabetes alone (both P < .0001). Osteomyelitis proximal margin cultures were diverse, at times polymicrobial, and included multidrug-resistant organisms in 13.9% of the cohort. In patients who underwent surgery, 44.5% experienced a re-ulceration on the same foot within 12 months of surgery. The presence of multidrug-resistant organisms on proximal bone culture was found to be a significant predictor of diabetic foot ulcer recurrence in univariate modelling (P < .001) and importance rankings. This is the first study to use prediction modelling to identify a relationship between multidrug-resistant organisms and diabetic foot ulcer recurrence following DFO.

Updates on Diabetic Foot and Charcot Osteopathic Arthropathy.

PURPOSE OF REVIEW: Diabetes mellitus affects approximately 30.8 million people currently living in the USA. Chronic diabetes complications, including diabetic foot complications, remain prevalent and challenging to treat. We review clinical diagnosis and challenges providers may encounter when managing diabetic foot ulcers and Charcot neuroarthropathy. RECENT FINDINGS: Mechanisms controlling these diseases are being elucidated and not fully understood. Offloading is paramount to heal and manage diabetic foot ulcers and Charcot neuroarthropathy. Diabetic foot ulcers recur and the importance of routine surveillance and multidisciplinary approach is essential. Several predictors of failure in Charcot foot include a related diabetic foot ulcer, midfoot or rearfoot location of the Charcot event, and progressive bony changes on interval radiographs. Patients with diabetic foot ulcer and/or Charcot neuroarthropathy are in need of consistent and regular special multidisciplinary care. If not diagnosed early and managed effectively, morbidity and mortality significantly increase.

Residential Address Amplifies Health Disparities and Risk of Infection in Individuals With Diabetic Foot Ulcers.

OBJECTIVE: To determine the association between social determinants of health (SDOH) and a diagnosis of diabetic foot ulcer (DFU) infection. RESEARCH DESIGN AND METHODS: Targeted interrogation of electronic health record data using novel search engines to analyze individuals with a DFU infection during a 5-year period (2013-2017) was performed. We extracted geolocated neighborhood data and SDOH characteristics from the National Neighborhood Data Archive and used univariate and multiple logistic regression to evaluate associations with outcomes in the population with diabetes. RESULTS: Among 4.3 million people overall and 144,564 individuals with diabetes seen between 2013 and 2017, 8,351 developed DFU, of which cases 2,252 were complicated by a DFU infection. Sex interactions occurred, as men who experienced a DFU infection more frequently identified as having nonmarried status than their female counterparts. For the population with DFU infection, there were higher rates for other SDOH, including higher neighborhood disadvantaged index score, poverty, nonmarriage, and less access to physician/allied health professionals (all P < 0.01). In multiple logistic regression, those individuals who developed DFU infection came from neighborhoods with greater Hispanic and/or foreign-born concentrations (odds ratio 1.11, P = 0.015). CONCLUSIONS: We found significant differences in neighborhood characteristics driving a higher risk for DFU infection in comparisons with the grouping of individuals with diabetes overall, including increased risk for individuals with Hispanic and/or foreign-born immigration status. These data strongly support the need to incorporate SDOH, particularly ethnic and immigration status, into triage algorithms for DFU risk stratification to prevent severe diabetic foot complications and move beyond biologic-only determinants of health.

Primary prevention of cardiovascular complications in type II diabetes patients using aspirin: a complicated tale.

Diabetes is a disease that affects 23 million in the United States alone. Within the past 20 years, there has been remarkable research performed concerning primary prevention of cardiovascular events in type II diabetes patients. The American Diabetes Association along with a government panel made recommendations that diabetes patients at a high risk of cardiovascular events should be on a low-dose aspirin regimen. However, more recent data show that aspirin has no clinical benefit to the diabetic patient as compared with a control group. Looking at research performed by groups in Japan, the United States, namely, the Primary Prevention Project, and a group in Ireland, we learn that there is no significant difference between diabetes patients who take aspirin and those who do not with respect to cardiovascular events. These studies are criticized by some newer research, and the prevailing thought about them call into question the results they obtained.Furthermore, we learn that many type II diabetes patients are not properly participating in an aspirin regimen or they are overusing aspirin, and these variables appear to confound the situation. One study showed that up to 50% of diabetes patients do not have their diabetes under control and are therefore increasing their risk for a multitude of complications arising from diabetes, including cardiovascular events.Finally, we learn of an upcoming project studying aspirin from Bayer, Inc. Much of the information presented in this article demonstrates the need for more and better research revolving around primary prevention of cardiovascular events in type II diabetes patients using aspirin.

Tackling diabetic foot: limb salvage during the COVID-19 pandemic.

Purpose: Lower extremity amputation resulting from diabetic foot ulcer, with neuropathic and/or ischemic etiologies, remains a devastating and costly complication of diabetes mellitus. This study evaluated changes in care delivery of diabetic foot ulcer patients during the COVID-19 pandemic. A longitudinal assessment evaluating the ratio of major lower extremity amputation to minor lower extremity amputations after implementation of novel strategies to combat access restrictions was compared to the pre-COVID-19 era. Methods: The ratio of major to minor lower extremity amputation (i.e. the high-to-low ratio) was assessed at two academic institutions, the University of Michigan, and University of Southern California, in a population of patients with diabetes who had direct access to multidisciplinary foot care clinics in the 2 years prior to the pandemic and the first 2 years of the COVID-19 pandemic. Results: Patient characteristics and volumes including patients with diabetes and those with a diabetic foot ulcer were similar between eras. In addition, inpatient diabetic foot-related admissions were similar, but were suppressed by government shelter in placed mandates and subsequent COVID-19 variants surges (e.g. delta, omicron). In the control group, the Hi-Lo ratio increased every 6 months by an average of 11.8%. Meanwhile, following STRIDE implementation during the pandemic, the Hi-Lo ratio reduced by (-)11% (p < 0.001) and doubled limb salvage efforts as compared to the baseline era. The reduction of the Hi-Lo ratio was not influenced significant by patient volumes or inpatient admissions for foot infections. Conclusion: These findings signify the importance of podiatric care in the at-risk diabetic foot population. Through strategic planning and rapid implementation of at-risk diabetic foot ulcer triage, multidisciplinary teams were able to maintain accessible care during the pandemic which resulted in a reduction of amputations. Furthermore, this manuscript highlights the value of the Hi-Lo ratio as an indicator of institutional limb salvage efforts.

Empirical Antibiotic Therapy in Diabetic Foot Ulcer Infection Increases Hospitalization.

Background: We evaluated the outcomes associated with initial antibiotic management strategies for infected diabetic foot ulcers (DFUs) diagnosed in an outpatient multidisciplinary center. Methods: Consecutive outpatient individuals with infected DFUs, stratified according to Infectious Diseases Society of America infection severity, were followed for 1 year from the initial antibiotic administration to treat acute infection. The main outcomes were hospitalization rates for a diabetes-related foot complication within 30 days of diagnosis and requiring an amputation or death during follow-up. Outcomes were analyzed by regression analysis, accounting for demographics, clinical characteristics, and antibiotic therapy. Results: Among 147 outpatients with infected DFUs, 116 were included. Infections were categorized as mild (68%), moderate (26%), and severe (6%). Empirical antibiotics (not culture-guided) were prescribed as initial treatment in 39 individuals, while 77 received culture-based antibiotics. There were no differences in demographic or clinical characteristics between the antibiotic administration groups, except for a higher body mass index and prevalence of chronic kidney disease in the empirical cohort. Forty-two infected DFU patients required hospitalization within 30 days of diagnosis for the same reason. The relative risk for hospitalizations was 1.87 greater in those with mild infections when treated with empirical antibiotics compared with culture-directed antibiotics. There were no differences in amputations and/or death at 1 year follow-up. Conclusions: These data support obtaining tissue culture to guide antibiotic therapy, regardless of DFU infection severity, to decrease hospitalizations.

Comorbid status in patients with osteomyelitis is associated with long-term incidence of extremity amputation.

INTRODUCTION: Osteomyelitis is associated with significant morbidity, including amputation. There are limited data on long-term amputation rates following an osteomyelitis diagnosis. We sought to determine the incidence of amputation in patients with osteomyelitis over 2 years. RESEARCH DESIGN AND METHODS: Observational cohort study of 1186 inpatients with osteomyelitis between 2004 and 2015 and stratified by osteomyelitis location status to evaluate the impact on amputation, mortality rates, readmission data, and inpatient days. RESULTS: Persons with diabetes had 3.65 times greater probability of lower extremity amputation (p<0.001), readmission (p<0.001), and longer inpatient stay (p<0.001) and had higher 2-year mortality (relative risk (RR) 1.23, p=0.0027), adjusting for risk factors. Male gender (RR 1.57, p<0.001), black race (RR 1.41, p<0.05), former smoking status (RR 1.38, p<0.01), myocardial infarction (RR 1.72, p<0.001), congestive heart failure (RR 1.56, p<0.001), peripheral vascular disease (RR 2.25, p<0.001) and renal disease (RR 1.756, p<0.001) were independently associated with amputation. Male gender (RR 1.39, p<0.01), black race (RR 1.27, p<0.05), diabetes (RR 2.77, p<0.001) and peripheral vascular disease (RR 1.59, p<0.001) had increased risk of lower, not upper, extremity amputation. CONCLUSIONS: Patients with osteomyelitis have higher rates of amputation and hospitalization. Clinicians must incorporate demographic and comorbid risk factors to protect against amputation.

The NIDDK Diabetic Foot Consortium.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diabetic Foot Consortium (DFC) was established in September 2018 by the NIDDK to build an organization to facilitate the highest quality of clinical research on diabetic foot ulcers (DFUs) that will answer clinically significant questions to improve DFU healing and prevent amputations. The initial focus of the DFC is to develop and validate biomarkers for DFUs that can be used in clinical care and research. The DFC consists of a data coordinating center (DCC) for operational oversight and statistical analysis, clinical sites for participant recruitment and evaluation, and biomarker analysis units (BAUs). The DFC is currently studying biomarkers to predict wound healing and recurrence and is collecting biosamples for future studies through a biorepository. The DFC plans to address the challenges of recruitment and eligibility criteria for DFU clinical trials by taking an approach of "No DFU Patient Goes Unstudied." In this platform approach, clinical history, DFU outcome, wound imaging, and biologic measurements from a large number of patients will be captured and the in-depth longitudinal data set will be analyzed to develop a computational-based DFU risk factor profile to facilitate scientifically sound clinical trial design. The DFC will expand its platform to include studies of the role of social determinants of health, such as food insecurity, housing instability, limited health literacy, and poor social support. The DFC is starting partnerships with the broad group of stakeholders in the wound care community.

CC chemokine receptor 4 contributes to innate NK and chronic stage T helper cell recall responses during Mycobacterium bovis infection.

Cysteine-cysteinyl chemokine receptor 4 (CCR4) is expressed by a variety of T-cell subsets and leukocytes. This study examined the participation of CCR4 in response to pulmonary infection with Mycobacterium bovis Bacille-Calmette-Guerin (BCG). Constitutive and induced CCR4 agonist expression was detected among large mononuclear cells. The course of infection and mobilization of effector cell populations were then analyzed in CCR4 knockout (CCR4(-/-)) mice. Compared with controls, CCR4(-/-) mice displayed delayed innate stage (<2 weeks) bacterial clearance and reduced late stage inflammation. Innate impairment was associated with reduced natural killer cell activation. In the adaptive phase, CCR4(-/-) mice generated effector T cells in draining lymph nodes and accumulated effector T cells in lungs, which resulted in normal adaptive stage bacterial elimination at 2 to 4 weeks. However, during the late stage, CCR4(-/-) mice had reduced interferonγ+CD4(+)α/ß+ (Th1) and interleukin (IL)-17+CD4(+)α/ß+ (Th17) T helper cells in lungs. In contrast, IL-17+ γ/δ T cells in lungs were unaffected. When challenged with mycobacterial antigen- (Ag-) Ag-coated beads to elicit a recall granulomatous response, CCR4(-/-) mice displayed abrogated recall granuloma formation and reduced interferon γ+ Th1 cells. These findings indicate that CCR4 supports innate natural killer cell activation and sustains later CD4(+) Th effector/memory antimycobacterial responses in the lung but is redundant in the early adaptive elimination phase.

Emerging Diabetic Foot Ulcer Microbiome Analysis Using Cutting Edge Technologies.

One of the most prevalent complications of diabetes mellitus are diabetic foot ulcers (DFU). Diabetic foot ulcers represent a complex condition placing individuals at-risk for major lower extremity amputations and are an independent predictor of patient mortality. DFU heal poorly when standard of care therapy is applied. In fact, wound healing occurs only approximately 30% within 12 weeks and only 45% regardless of time when standard of care is utilized. Similarly, diabetic foot infections occur in half of all DFU and conventional microbiologic cultures can take several days to process before a result is known. DFU represent a significant challenge in this regard because DFU often demonstrate polymicrobial growth, become resistant to preferred antibiotic therapy, and do not inform providers about long-term prognosis. In addition, conventional culture yields may be affected by the timing of antibiotic administration and collection of tissue for analysis. This may lead to suboptimal antibiotic administration or debilitating amputations. The microbiome of DFU is a new frontier to better understand the interactions between host organisms and pathogenic ones. Newer molecular techniques are readily available to assist in analyzing the constituency of the microbiome of DFU. These emerging techniques have already been used to study the microbiome of DFU and have clinical implications that may alter standard of care practice in the near future. Here emerging molecular techniques that can provide clinicians with rapid DFU-related-information and help prognosticate outcomes in this vulnerable patient population are presented.

Outcomes of Hallux Amputation Versus Partial First Ray Resection in People with Non-Healing Diabetic Foot Ulcers: A Pragmatic Observational Cohort Study.

There are few data comparing outcomes after hallux amputation or partial first ray resection after diabetic foot ulcer (DFU). In a similar context, the choice to perform one of these two surgeries is attributable to clinician preference based on experience and characteristics of the patient and the DFU. Therefore, the purpose of this study was to determine the more definitive surgery between hallux amputation and partial first ray resection. We abstracted data from a cohort of 70 patients followed for a 1-year postoperative period to support clinical practice. We also attempted to identify patient characteristics leading to these outcomes. Our results suggested no statistical difference between the type of surgery and outcomes such as recurrence of DFU and amputation at 3, 6, and 12 months or death. However, there was a statistically significantly increased likelihood of re-ulceration for patients with CAD who underwent hallux amputation (p = 0.02). There was also a significantly increased likelihood of re-ulceration for people with depression or a history when the partial ray resection was performed (p = 0.02). Patients with prior amputation showed a higher probability of undergoing another re-amputation with partial ray resection (p = 0.01). Although the trends that emerge from this project are limited to what is observed in this statistical context, where the number of patients included and the number of total observations per outcome were limited, it highlights interesting data for future research to inform clinical decisions to support best practices for the benefit of patients.

On diabetic foot ulcer knowledge gaps, innovation, evaluation, prediction markers, and clinical needs.

Diabetic foot ulcers (DFUs) remain a very prevalent and challenging complication of diabetes worldwide due to high morbidity, high risks of lower extremity amputation and associated mortality. Despite major advances in diabetes treatment in general, there is a paucity of FDA approved technologies and therapies to promote successful healing. Furthermore, accurate biomarkers to identify patients at risk of non-healing and monitor response-to-therapy are significantly lacking. To date, research has been slowed by a lack of coordinated efforts among basic scientists and clinical researchers and confounded by non-standardized heterogenous collection of biospecimen and patient associated data. Novel technologies, especially those in the single and 'multiomics' arena, are being used to advance the study of diabetic foot ulcers but require pragmatic study design to ensure broad adoption following validation. These high throughput analyses offer promise to investigate potential biomarkers across wound trajectories and may support information on wound healing and pathophysiology not previously well understood. Additionally, these biomarkers may be used at the point-of-care. In combination with national scalable research efforts, which seek to address the limitations and better inform clinical practice, coordinated and integrative insights may lead to improved limb salvage rates.

Deferring Amputation in Diabetic Foot Osteomyelitis: Doing More Harm Than Good?

In a cohort of patients with diabetic foot osteomyelitis who were recommended to undergo below-knee amputation, those who deferred amputation and chose medical therapy were more likely to die during the follow-up time compared with those who proceeded with amputation.

Clinical insights into Charcot foot.

Charcot neuropathic arthropathy (CN) is a devastating condition resulting in non-reducible foot deformity that places patients with distal peripheral neuropathy at risk for the development of chronic neuropathic foot ulcers, major lower extremity amputation, and even death. The condition is often misdiagnosed early in its presentation because of a lack of knowledge among members of the medical community. Consequently, initial therapies for the condition are fewer and patients who present in more advanced stages of the condition are more difficult to manage. We now understand that CN is a multifactorial process resulting in unregulated osteoclastogenesis and bony destruction. Classically, the patient will present with an edematous, erythematous foot with increased temperature. These non-specific findings lead to a multitude of differential diagnoses. However, there are no diagnostic biomarkers or pathognomonic clinical signs to distinguish this condition from other common foot ailments seen in the context of peripheral neuropathy. Advancing our understanding of this condition, while educating the medical community about its devastating impact, is needed to advance and improve outcomes for patients affected by CN.

Making the equivocal unequivocal: standardization of clean margins in diabetic foot osteomyelitis.

BACKGROUND: The prevalence of diabetes mellitus continues to rise. Diabetic foot ulcers with osteomyelitis are a diabetes-related complication presenting a significant burden to this cohort. A cure to diabetic foot osteomyelitis remains elusive and standard of care has failed to improve outcomes. To advance research and better patient outcomes, the authors offer specific guidance with terminology to enhance operative dictations which may improve surgical practice and guide treatment. METHODS: A consecutive review of podiatric surgical dictations for inpatient diabetic foot osteomyelitis within a tertiary care facility was performed. Surgical descriptors of bone were standardized: density, anatomic structure, vascular thrombosis, color, and draining sinus. Correlations between the five categories and histopathological results were performed after kappa analysis for interrater reliability was performed. RESULTS: Kappa coefficient demonstrated high inter-reliability of surgical findings. This suggests potential agreement amongst surgeons performing similar procedures. It was also found that specific bone descriptors had moderate to strong correlation with clean histopathologic bone margins when biopsied. This further suggests that the use of standardized terms may help guide definitive therapy. CONCLUSIONS: The authors suggest a standardized approach which includes consistent descriptors of intraoperative bone. With use of standardized terms, vague and blanket descriptors are eliminated. This has potential to improve understanding of changes within bone as a result of infection and diabetes. Early and improved communication of intraoperative findings will enhance the multidisciplinary approach. This could potentially lead to changes in diabetic foot management and may limit hospital waste waiting for final cultures and pathology reports.

Describing Normative Foot Temperatures in Patients With Diabetes-Related Peripheral Neuropathy.

BACKGROUND: Prior research shows increased foot temperatures are predictive of diabetes-related foot complications. Our aim was to describe normative skin foot temperatures for individuals with diabetic peripheral neuropathy to better inform new technologies. We also explored for potential risk factors which correlate with changes in foot temperatures. METHODS: We conducted a retrospective chart review of adult patients >18 years of age with diabetes mellitus and clinically diagnosed diabetic peripheral neuropathy with pedal digital thermometry performed between 2009 and 2018. A total of 58 patients met these criteria. Univariate modeling was based on covariates that may affect foot temperature including age, peripheral arterial disease, toe pressure, seasonality of measurement, smoking pack-years, caffeine use, insulin use, and calcium channel blocker use. RESULTS: In patients with diabetic peripheral neuropathy, mean toe temperatures of 27.67°C (6.300°C), forefoot of 28.58°C (5.36°C), midfoot of 29.21°C (3.81°C), and rearfoot of 29.88°C(3.83°C) were demonstrated. A modest negative correlation between seasonality and toe and metatarsal temperatures (r = -0.38, P < .05; r = -0.43 P < .01, respectively) was demonstrated. Midfoot temperatures were modestly and positively correlated to the presence of small fiber symptoms (r = 0.33, P = .03). Positive modest correlation with rearfoot temperatures and amount of pack-year history (r = 0.30, P = .03) was seen. CONCLUSION: Normative foot temperatures in neuropathic patients were found to be inversely associated with seasonality at the toe and metatarsal level. Smoking and pack-year history demonstrate modest correlation previously unseen in temperature analyses and warrant further exploration. Normative temperatures in neuropathic patients can better inform new technologies for the prevention of diabetic foot ulcer and Charcot neuroarthropathy.

Eccrine Porocarcinoma: Avoiding Diagnostic Delay.

Skin cancer is the most common cancer within the United States. Reports estimate that 1 in 5 Americans will develop some form of skin cancer. Eccrine porocarcinoma is a rare type of skin cancer of sweat gland origin. Eccrine porocarcinoma is most commonly found on the lower extremities. Clinically it may appear similar to benign skin lesions and it has significant metastatic potential. The authors present a case report with 22 months' follow-up. It describes a multiyear delay in diagnosis involving 3 specialties, including primary care, dermatology, and wound physical therapy. Information is given on techniques when high-risk cutaneous cancers are suspected or encountered. A multispecialty treatment plan is discussed.Levels of Evidence: Level V.