Discussion
Difference in parameters
The present study indicates that the patients with future DFU occurrence had distinctive characteristics in a set of parameters that were considered in this investigation. Significantly higher proportions of patients with any of the following characteristics: neuropathy, history of ulceration, presence of callus, nail ingrowth, foot swelling, and limited ankle and MTP joint mobilities were shown to have an incident of future DFU. However, the effect sizes were found to be small indicating that these criteria may not be used for effective patient stratification. On the other hand, we showed that a significantly higher proportions of patients with impaired sensitivity to touch ended up having future incident of DFU. To be more precise, the higher the degree of impairment to touch, the higher the proportion of patients with DFU incident in that group. With a medium effect size, this indicates that this parameter has the potential for stratifying patients into four groups based on the sensitivity level to touch where each group showed a significantly higher prevalence of future DFU proportionate to the sensitivity level to touch sensation.
The significantly higher proportion of participants with impaired sensitivity to monofilament or history of ulcer incurred future DFU that is in line with the previous studies for neuropathy30 or for history of ulcer30–32 in European populations.
Out of all biomechanical parameters, limited ankle mobility that can indicate excessive load on the forefoot during ambulation was found to be significantly more prevalent in the group with future DFU occurrence that is in line with the results of the previous study in Europe.33
The results of this study highlighting the significantly older age and longer duration of diabetes of the group vulnerable to future DFU occurrence are in line with the previous finding for age in European31 and for the duration of diabetes in European30 31 and Middle Eastern34 populations. This indicates similarities in the generic characteristics between the studied group and the patient population in previous studies.30 31 34
However, the results of the current study which indicate that significantly higher proportion of patients who incur future DFU had callus or swollen feet contradicts the previous studies on south European population for callus30 31 or swollen foot30 31 where no such observations were reported.
These distinct differences in foot characteristics of patients with future DFU that were found in the current study can indicate a different etiology of ulceration in the studied group. In addition to the fact that the previous studies reported on a different demographic (ie, European30 vs African population in the current study), in few a combination of patients recruited from a hospital and a community setting was studied.30 However, our study which had a focus on patients in a hospital setting indicates that with regards to identifying the patient group vulnerable to foot ulceration, attention need to be paid to patients with callus and swollen feet (edema).
Parameters associated with increased risk (hazard) and likelihood (odds) of DFU occurrence
The results of the current study in which association between older age and longer duration of diabetes on increasing the likelihood of DFU occurrence were found, are in line with the study conducted on the pooled patient data from Europe and North America.16 This can be the results of the deterioration in the soft tissue due to prolonged exposure to high blood sugar level, reflected in the significantly higher risk for future DFU occurrence for patients with higher duration of diabetes or higher blood glucose levels that were found in the current study. These reults of the current study are also in agreement with the findings from studies in North America.35 36 Although the observed association between swollen feet and increased risk of future DFU occurrence in present study is in line with the findings of previous studies in North America,35 contrary to that study35 in the current study presence of callus was associated with increased risk of DFU occurrence.
On the other hand, onychomycosis was previously reported to have strong association with nail ingrowth37; hence, the results of the current study where nail ingrowth was associated with the future DFU occurrence are in agreement with a previous study on North American population.35
The significantly higher risk and more likelihood of future DFU occurrence for patients with impaired sensation to monofilament or with history of ulceration that is found in the present study are in line with the studies in North America35 36 or Europe16 indicating the notion that DFU occurrence is linked to the damages in the soft tissue which patient does not recognize as a result of impaired sensation. This can be further backed up by the result of the current study where a significantly higher likelihood of future DFU occurrence for patients with increased VPT was observed in accordance with previous study in Europe.38
Furthermore in line with other findings of the current study with regards to neuropathy, impaired sensation to touch21 showed significant association with future DFU occurrence in the present study. While the value of Ipswich touch test to accurately assess loss of protective sensation was previously established,39 the present study indicates that the risk of future DFU occurrence significantly increases as the level of impairment to touch sensation increases. Furthermore, the ulcer-free survival time also showed to significantly decrease as the sensitivity to touch decreases. Hence, touch sense could be used to stratify patient based on the risk of future DFU occurrence.
The significant associations between impaired sensitivities and tolerances to temperature stimuli with the risk and likelihood of future DFU occurrence that observed in the present study indicate the importance of assessing small fiber function in identifying the risk of future DFU and are in line with previous study on small cohort of patients.40
With regards to the biomechanical parameters, the association between limited MTP joint mobility and increased likelihood of future DFU occurrence is in line with the results of the previous findings in large cohorts from North America.14 This could be affiliated to the increased pressure on the forefoot that is observed as the significant association between the peak plantar pressure at the first MTH during shod walking and the DFU occurrence were reported in North American population.41
The fact that the ulcerated participants showed higher plantar pressure at the fifth MTH can be attributed to some morphological changes as a result of motor nerve damage in this group of patients where this leads to applying less load at the outer side of the forefoot. Investigating the motor neurons in patients with diabetes warrants further analyses in future studies.
While several categorical and continuous parameters were shown to increase the risk and likelihood of DFU in the current study, it can be argued that collecting all these parameters may not be feasible in a clinical setting. Hence, development of a model using proportionate hazard multiple regression analysis deemed necessary to reveal the minimum number of parameters which can predict the DFU with highest accuracy discussed as follows.
Survival analysis (Cox regression model to identify ulcer-free survival)
The Cox regression model containing six parameters (including four categorical–out of which two were significant predictors and two continuous–both were significant predictors) was found to be worthwhile for predicting the incident of diabetic foot ulceration.
Two categorical parameters, nail ingrowth and dry skin indicate that patients with each of these characteristics have significantly higher (four times more) risk of future ulcer occurrence compared with those without these characteristics.
In the present study, VPT was found to be a significant contributor to predicting the future DFU occurrence, and it indicates that increase in VPT by 1 V would increase the chance of ulceration by 7%.
Cox proportional hazard multiple regression analyses indicated that the final prediction model of foot ulceration included four significant (p<0.05) parameters, including: nail ingrowth, dry skin, VPT, and TTT to warm stimuli, plus the two non-significant (p>0.05), including neuropathy and foot swelling. The overall model showed to be a worthwhile model that can predict ulceration risk with a prognosis power of 0.62.
Strength and limitations
The present study is unique as it reports on a wide range of foot-related parameters along with the clinical and lifestyle characteristics to identify the risk factors for future DFU occurrence in large cohort of patients with diabetes in Africa. The prognosis power of the model proposed in the current study (0.62) is lower than the values of 0.73 reported in other studies for western populations.31 However in the current study when, a prognostic model was developed using only the three parameters (namely: absent pedal pulse, history of ulcer, and monofilament insensitivity) that were suggested based on a systematic review,16 the prognosis accuracy was found to be much lower.
Despite the difference in the prevalence of diabetic foot ulceration across African countries,7 it can be argued that there are similarities in ethnicity, socioeconomic conditions, and culture between Tanzania and Eastern, Central, and Western Africa. Hence, a similar model to the one that was developed in the current study may be applied to patients from those populations.
Clinical implications and future directions
The results of this study indicated that a few parameters significantly associated with and contributed to predicting the risk of DFU occurrence, except the nail ingrowth, the rest of parameters were related to neuropathy. This highlights the importance of considering both the sensory and autonomic peripheral neuropathy associated with large and small fiber impairment together.
The results on VPT (HR: 1.07) indicate the importance of assessing the impairment in A-alpha/beta as the nerves that are functional in sensing touch and vibration sensations.42 The impairment in C-fibers that is responsible for input from high threshold stimuli43 44 indicated by the findings of the current study in which a high TTT to hot stimuli (HR: 1.001) are among the predictors of risk of future DFU occurrence. The results of the current study also indicated the importance of VPT and touch sensation in assessing the risk of DFU occurrence.
The impairment of small unmyelinated C-fibers of the peripheral nervous system that are responsible for cutaneous sensations and for mediating thermal sensations44 45 is reported in the current study, which is in line with the previous observations in patients with diabetic neuropathy and with DFU.15 46
The current study further indicates impairment of small fiber as mediator of autonomic functions such as sweating44 indicated by the importance of skin status (dry skin HR=4.48) in predicting the risk of future DFU occurrence. This is related to decreased activity of sweat glands and a dry skin,47 48 which make the dry skin vulnerable to cracks and fissures leading to ulceration.
Although previous studies indicate that the small fiber impairment precede large fiber complications in people with diabetes,48 the results of present study indicate that the measurements related to small fiber impairment provide as a strong prognostic tool to assess the risk of DFU occurrence.
Although in the current study a vast range of parameters were collected from each participant, the inclusion of further parameters to reflect the microcirculatory49 and mechanical properties of the plantar soft tissue50 could have resulted in achieving a higher prognosis power in predicting the DFU occurrence.