Diabetic foot ulcer (DFU) is the most frequent cause of hospitalization among diabetic patients, and lower extremity amputation is the most feared consequence of this disorder, with disastrous effects on patient health and quality of life [1
]. Previous studies identified that the healing of foot ulcers is a complex,dynamic and multifactorial process that involves the interaction of diabetes complications, ulcer characteristics, and malnutrition, and the complexities of the healing process can be compounded by the patient’s social-economic status, level of self-care and age [2
]. Although preliminary studies had suggested that ageing could increase the risk of delayed healing in DFU patients [4
], data from middle-aged patients remains greatly limited. Moreover, the overall prevalence of diabetes and early-onset diabetes has sharply increased in recent decades in both China and other developing countries [9
], and it is likely that the number of DFUs among middle-aged patients aged 45–64 years will similarly increase. More importantly, DFUs in middle-aged working adults can cause unemployment, disability, and even death in the prime of life, contributing to increased family, social,and health care burdens [11
]. Therefore, it is very important to understand the clinical phenotypes of DFUs in middle-aged patients to inform the design of a new approach to diminishing the adverse outcomes of DFU in middle-aged patients.
To our knowledge, there has been no systematic and comprehensive study conducted on the clinical features of and predictors of outcomes in middle-aged DFU patients. Thus, the aims of the present study were as follows: 1) to explore the phenotypes and outcomes of DFUs in middle-aged patients, comparing those phenotypes and outcomes with those in the elderly and 2) to assess the variables that best predict poor outcomes in middle-aged patients.
DFUs, a severe complication of diabetes, tend to heal poorly and require long and intensive treatment, and they eventually lead to a high risk of amputation and even death. Abundant evidence has demonstrated that early recognition of diabetic foot problems and a coordinated intervention with a multidisciplinary foot care team may significantly improve patient outcomes [23
]. Although previous studies revealed that age, an easily measured risk factor, was strongly associated with the risk of amputation and death in patients with DFU [6
], the data on the phenotypes and outcomes in middle-aged patients were limited. The present study, to the best of our knowledge, was the first to show that middle-aged patients with DFUs made worse lifestyle choices, such as smoking and consuming alcohol, and had worse glucose control; they also had more severe ulcers and were more likely to have the complications of microangiopathy than elderly patients. However, these patients eventually had better healing rates and a lower risk of major amputation and mortality.
Many studies have noted significant discrepancies in clinical characteristics and coronary angiography results between middle-aged patients with premature myocardial infarction and elderly patients [26
], but little evidence has emerged regarding the clinical phenotypes of DFUs in non-elderly patients. This study showed that the DFUs of middle-aged patients were larger and deeper than those of elderly patients. The mechanism causing more severe ulcers in these patients remains unknown, which might be partly explained by following two aspects. Previous studies had suggested that those patients with DPN and DR may experience a delay in detecting foot problems and exhibit poor self-management of the wound because of their loss of protective sensation and their poor vision, resulting in a greater severity of the ulcer by the time they visit a doctor [20
]. Moreover, long-term hyperglycaemia and smoking may weaken immunity and impair the functioning of inflammatory cells that are important to bactericidal activity [1
], thus further increasing the ulcer size and depth. The middle-aged patients with DFU, despite experiencing severe DFUs, had higher rates of healing and lower rates of mortality and major amputation. The reason for these better outcomes in middle-aged patients is not yet clear but might be partly explained by the lower incidence of PAD and the higher eGFR values among these patients. The results of this and other studies have shown that younger subjects have more adequate blood supply to their lower limbs than older subjects, and that greater blood supply is vital for tissue repair and regeneration and combating ulcer infections [32
]. On the other hand, Zubair et al. [33
] found that DFU healing was worse in patients with impaired renal function than in those who had normal renal function. In addition to other biological factors, ageing itself is characterized by the degeneration of organ function, impaired immunity, and a decreased ability to cope with external stress and to regenerate granulation tissue [34
The proportion of middle-aged patients with DFUs far exceeded the amount expected based on their relatively young age and short duration of diabetes. Furthermore, DFUs in these patients might lead to decreased social activities, anxiety and depression, and even suicide. Therefore, it was crucial to clarify the risk factors associated with adverse outcomes in these patients. Our findings have suggested four easily recognizable and modifiable risk factors that contribute to poor outcomes in these patients, namely, severe infections, solitary living conditions, cigarettes and increased WBC counts. It is nearly universally agreed among researchers that more severe infections are correlated with poorer outcomes in DFU patients [35
]. In addition, amputation and mortality in DFU patients were reduced by early identification of infection and application of antimicrobial therapy. Furthermore, this study also revealed that 43.4% of middle-aged patients had a history of smoking, and the risk of adverse outcomes for patients who smoked was 2.6 times higher than that of those who had never smoked. Similarly, a prospective cohort study with Canadian patients with type 2 diabetes demonstrated that patients who smoked had a risk of developing foot gangrene or requiring amputation that was 4.2 times higher than that of those who did not smoke [15
], implying that smoking cessation may be critical for the improvement of the prognosis of DFUs. Although numerous clinical studies found an independent relationship between living alone and patient outcomes following myocardial infarction [37
], the relation between living alone and DFU prognosis remains to be clarified. Yu et al. [36
] failed to find any significant relationship between living alone and DFU outcomes in a larger cohort study of 669 individuals with an average age of 64 years. However, our results showed an independent positive association between living alone and DFU outcomes in patients with an average age of 54.58 years. This discrepancy is likely due to differences in phenotypes at different ages. Thus, more studies are needed in the future to clarify the relationship between living alone and DFU outcomes.
There are some limitations of the current study. First, the study was based in a single centre, limiting its generalizability; therefore, additional large-scale research is needed. In addition, retrospective surveys have inherent deficiencies. A prospective intervention study is needed to establish the direction of causality. Finally, standardized diabetic foot self-care is involved in multiple aspects of DFU outcomes, but the majority of variables in this study were based on the prevention of high-risk foot ulcers and not ulcer care; the relationship between foot self-care and DFU prognosis needs to be clarified by investigating other variables.
In conclusion, DFU is relativly common in middle-aged patients with diabetes,and these patients have unique clinical characteristics, such as deeper and larger ulcers, worse glucose control, more smoking, more alcohol consumption, and more microangiopathy involvement, but ultimately have better healing rates and alower risk of major amputation and mortality. Although severe infections,solitary living conditions,cigarettes, and increased WBC counts,were independent predictors of adverse outcome in middle-aged patients, further investigation is needed to clarify whether intervention regarding these modifiable risk factors could improve healing and survival rates in these DFU patients.
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