Diagnostic value of procalcitonin,erythrocyte sedimentation rate (ESR),quantitative C-reactive protein (CRP) and clinical findings associated with osteomyelitis in patients with diabetic foot

1. Introduction

There are various reports of the prevalence and incidence of diabetic foot ulcers. The incidence ranges from 1 to 4 percent and the prevalence is between 3.5 and 10.5 percent in these individuals [1]. According to epidemiological studies, 2.5% of diabetic people suffer from ulcer annually and 15% of all diabetic people develop diabetic foot ulcer at least once in their lifetime. 20% of diabetics are referred to the hospital for problems with their legs [2]. In England, 50% of the causes of hospitalization of diabetic patients in the hospital are problems with the leg [3]. Diabetic foot ulcer has a profound effect on the quality of life of patients and imposes a huge burden on health care centers [4, 5]. Diabetic foot ulcers cause lower limb amputation in 85% of cases [6]. Also, mortality rate in diabetic foot ulcer patients is twice as high as other diabetic patients [7]. Osteomyelitis as a complication of diabetic foot is one of the most common and important health problems in the world. The risk of serious complications in diabetic patients with bone involvement increases by about 20 to 66%. Given these issues, diagnosis and timely treatment have a significant role in reducing mortality and the rate of amputation. Diagnosis is routinely done by clinical symptoms. When clinical symptoms are misleading, laboratory tests can help diagnose the infection. Clinically, there are different categories for diabetic foot. For example, in the Wagner classification of Grade zero, there is no wound. Grade 1 contains superficial wounds that affect the thickness of the skin, but does not interfere with subcutaneous tissue. Grade 2 is a deep wound which penetrates the ligaments and muscles, but does not involve bone involvement and abscess formation. There are deep wounds associated with osteomyelitis and abscess formation, often associated with osteomyelitis in Grade 3. There are localized gangrene in Grade 4 diffuse gangrene in Grade 5 [8]. In some studies, increase of inflammatory markers such as ESR-CRP, PCT has been considered as markers for osteomyelitis occurring in diabetic foot ulcers, with variable results [9, 10]. It seems that using these laboratory factors is beneficial to predict osteomyelitis. MRI is also the best imaging to detect osteomyelitis in diabetic patients, which can help us diagnose precisely and timely [11, 12, 13, 14]. Procalcitonin is a new parameter for the diagnosis of bacterial, fungal infections. In healthy people, the level of pro-calcitonin is very low ( 0.1 ng/ml) and is not detectable by standard methods. In an infected person, pro-calcitonin level increases rapidly within 2–6 hours and then reaches a maximum within 6–12 hours. other markers like CRP, in addition to being non-specific, its blood level increases about 20 hours after the onset of the infection [15, 16]. CRP is an acute phase protein. During infectious and inflammatory processes, this marker is used as an auxiliary device for the diagnosis of musculoskeletal infections [15, 16]. In patients with infectious diabetic foot ulcers, this marker is increased compared with non-infectious ulcers [14]. Previous studies have shown procalcitonin is a superior laboratory finding for the diagnosis of diabetic foot infection [17], but the diagnostic role of procalcitonin in osteomyelitis is not clear and in limited studies its diagnostic role has been investigated. In the study of Gunalpuzun et al. and Jeandrot et al. PCT is proposed as a diagnostic marker for diabetic foot ulcer infection [17]. In contrast of these studies, in a study by Glaudemans and colleagues, it has suggested that PCT does not have much diagnostic value and is not specific [9]. Given the contradictory studies on the diagnostic value of inflammatory markers, especially PCT, in predicting osteomyelitis in diabetic foot ulcers, and regarding to importance of rapid diagnosis and treatment of osteomyelitis in patients with diabetic foot ulcers to prevent of amputation, this study was designed to assess the diagnostic and prognostic value of laboratory markers such as ESR, CRP, PCT in the diagnosis of osteomyelitis in diabetic foot ulcers.

Patients were divided into two groups of patients with and without osteomyelitis and based on MRI findings. There were 45 patients in each group. In the group of patients with osteomyelitis, 13 (28.9%) were female and 32 (71.1%) were male, and in the non-osteomyelitis group, 14 (31.1%) were female and 31 (68.9%) Were male (Table 1). The mean age in the osteomyelitis group was 58.2 ± 11.1 years and in the non-osteolytic group 61.2 ± 9.7 years (Table 1).

There was no statistically significant difference between the two groups in terms of sex and age ( p = 0.818, p = 118). In terms of residence in the group of patients with osteomyelitis, 32 (28.9%) were rural and 13 (71.1%) were urban and in the non-osteomyelitis group, 20 (31.1%) were rural and 25 (68.9%) were urban. There was a significant difference between the two groups ( p = 0.01).

The duration of hospitalization in the patients with osteomyelitis was 22.9 ± 3.6 days and in the non-osteomyelitis group 11.8 days ± 2.8 years.

There was a statistically significant difference between the two groups ( 0.001). Other demographic characteristics in the two groups are presented in Table 4.

The duration of ulceration was 51.2 ± 59.6 days in the patients with osteomyelitis and 51.4 ± 22.6 days in the non-osteomyelitis group (Table 5). There was a statistically significant difference between the two groups ( p = 0.001).

In the two group of patients, the diameter of ulcer was between 1 to 3 cm. There was a significant difference between the two groups ( 0.001). The most common lesions in the patients with osteomyelitis were on the foot of the sole (35.5%) and in the patients without osteomyelitis were on the tip of the fingers (28.8%), which was not statistically significant.

According to Table 3, in the group of patients with osteomyelitis, 34 (75.5%) and in the patients without osteomyelitis, 24 (53.3%) had diabetic neuropathy, which was statistically significant ( P = 0.028). The values of ESR, CRP and procalcitonin between the two groups were statistically significant ( 0.001). In the group of patients with osteomyelitis, 8 (17.7%), 21 (46.7%) and 16 (35.6%) had Wagner, 3, 4 and 5, respectively, and in the non-osteomyelitis group 33 (73.4%), 12 (26.6%) and 0 were Wagner’s 3, 4 and 5, respectively (Table 2). There was a statistically significant difference between the two groups It was seen ( 0.001).

In order to evaluate the diagnostic value of Procalcitonin, ESR, CRP and clinical findings in osteomyelitis diabetic foot patients, 90 patients with diabetic foot ulcer with Wagner’s stage 3 to 5 hospitalized in the Shahid Beheshti Hospital of Kashan in 2016 were studied. According to the analysis, the procalcitonin content 0.085 was the best cut-off point, which had sensitivity of 100%, specificity 97.9%, positive predictive value of 97.8%, and negative predictive value of 100%. The ESR 53.5 mm/hr was the best cut-off point with sensitivity of 84.4%, specificity 91.1%, positive predictive value 90.5%, and negative predictive value of 85.4%, as well as a CRP value of 5.19 was the best cut-off point that had sensitivity of 86.7%, pecifity 73.3%, positive predictive value of 76.5% and negative predictive value of 84.6%.

In study of Mutluoglu M and et al. in Turkey, in 24 patients with diabetic foot ulcers, the serum level and the association of inflammatory markers with the probability of occurrence of osteomyelitis were investigated. In 13 cases with osteomyelitis, the level of procalcitonin 66.7 ± 43.4 pg/ml was reported. In contrast to our study, there was no significant difference in procalcitonin levels between the two groups, but ESR significantly increased in osteomyelitis cases like our study, and ESR 48 mm/h had the sensitivity 72% and the specificity 84% for osteomyelitis, and ESR was preferred to other inflammatory markers such as procalcitonin and CRP osteomyelitis [16]. Bubul-Avicl and et al. used the procalcitonin to detect osteomyelitis in children with fever and limping they found the specificity and sensitivity of 100% and 43.5%, that procalcitonin diagnostic value was preferred to other inflammatory markers such as WBC, ESR, CRP. However, because of its low sensitivity, procalcitonin was not a screening test suitable for the diagnosis of bone infections in children [18]. In the study of Ertugrul and et al., unlike our study, there was no difference in the rate of WBC in diabetic foot with or without osteomyelitis, but other indicators such as CRP, wound size and diabetic nephropathy, as our study, were significantly different in patients with osteomyelitis [19]. Another study showed that CRP had a sensitivity of 85% and 65% specificity in the diagnosis of osteomyelitis in diabetic patients, and stated that ESR above 70 mm/h in the case with clinical suspicion of osteomyelitis in diabetic patients had the highest accuracy in predicting the presence or absence of osteomyelitis is [13]. As in our study, Fleischer and his colleagues were observed increased CRP, ESR and WBC in osteomyelitis cases compared with patients without osteomyelitis, and also suggested inflammatory serum markers had some predictive value about the occurrence of osteomyelitis. The ESR above the 80 mm/h and CRP values above 3 mg/dl with a sensitivity of 85% had a high diagnostic value for osteomyelitis, and these markers were strongly associated with the occurrence of osteomyelitis. It was found also that adding ESR and CRP to wound characteristics, such as depth, increased the detection rate of osteomyelitis by 55% compared with the depth of the wound alone. In addition, studying the level of these markers during workup and the initial treatment of osteomyelitis is valuable [20]. In the study of Gunalpuzun and et al., the sensitivity and specificity of PCT in the Diabetic foot infection group with a cut-off value of 0.88 ng/ml were 77% and 100% respectively, but in our study, the best cut off point was 0.85 ng/ml with sensitivity and specificity of 100% and 97.8%. In the case of ESR with a cut-off value of 40.5 mm/h, the sensitivity and specificity of 77% were reported, which in our study with a cutoff point of 53.5 mm/hr, the sensitivity and specificity of 84.4% and 91.1% were reported. In the case of CRP with a cut-off value of 32.3 mg/dL, the sensitivity was 29% and 100% specificity, but in our study, CRP with a cutoff point of 19.5 mg/dl had a sensitivity of 86.7% and 73.3%. This study suggests PCT as a diagnostic marker for diabetic foot ulcer infection [17]. In a study by Jeandrot et al., it was suggested that a PCT serum level could be used as a marker for diagnosis of diabetic foot ulcer, but further evaluations are required [19]. In a study by Glaudemans and colleagues, it was finally suggested that serologic tests such as ESR are useful in diabetic foot ulcer diagnosis, but contrary to the results of our study, PCT does not have much diagnostic value in this field [9]. In the study of Jafari et al. [21], procalcitonin, white blood cells, ESR and C reactive protein (CRP) were significantly increased in the diabetic foot with infectious ulcer compared to the diabetic foot with non-infectious ulcer. The best cutting point, sensitivity and specificity for ESR were 40.5 mmHg, 90% and 94%, respectively, and for CRP, respectively, 7.1 mg/dL, 80% and 74%, respectively, and for procalcitonin 0.12, 70% and 74% respectively. In the study of Asten et al. [22]. In patients with diabetic foot ulcers, the level of PCT in the osteomyelitis group was significantly higher than that of the non-osteomyelitis group ( P = 0.049), which is similar to our study, but in contrast to our study. There was no a significant difference between the two groups according to other inflammatory markers.

5. Conclusion

Serum procalcitonin level seems to play a key role in the diagnosis of osteomyelitis in diabetic patients. Also, ESR and CRP have a diagnostic value for osteomyelitis in diabetic patients, but the PCT diagnostic value is higher than the two mentioned markers.