The efficacy of inflammatory markers in diagnosing infected diabetic foot ulcers and diabetic foot osteomyelitis: Systematic review and meta-analysis

Abstract

Background Diabetes foot ulcer (DFU) is a complication of diabetes mellitus. Accurate diagnosis of DFU severity through inflammatory markers will assist in reducing impact on quality of life. We aimed to ascertain the diagnostic test accuracy of commonly used inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), procalcitonin (PCT), and white cell count (WCC) for the diagnosis and differentiation between DFU grades based on the International Working Group on the Diabetic Foot classification system. Methods This systematic review explored studies that investigated one or more of the above-listed index tests aiding in diagnosing infected DFU. This review was registered on PROSPERO database (ID = CRD42021255618) and searched 5 databases including an assessment of the references of included studies. Records were manually screened as per Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A total of 16 studies were included which were assessed for quality using QUADAS-2 tool and meta-analysed using Meta-Disc v1.4. Results CRP had the greatest area under the curve (AUC) of 0.893 for diagnosing grade 2 DFU. This returned a pooled sensitivity and specificity of 77.4% (95% CI: 72% to 82%) and 84.3% (95% CI: 79% to 89%) respectively. In terms of diagnosing grade 3 DFU, procalcitonin had the highest AUC value of 0.844 when compared with other markers. The pooled sensitivity of PCT was calculated as 85.5% (95% CI: 79% to 90%) and specificity as 68.9% (95% CI: 63% to 75%). Conclusion CRP and PCT are the best markers for diagnosing grade 2 and grade 3 DFU respectively. Other markers are also valuable when used in conjunction with clinical judgement. The findings accentuate the necessity of further research to establish standardised cut-off values for these inflammatory markers in diagnosing diabetic foot ulcers.

Biochemical and patient factors as predictors for multiple surgeries in diabetic foot disease

“…We assessed for the rise in a group of markers called acute phase reactants (in particular CRP, leukocytes and thrombocytes) which the liver produces at a variable rate during states of acute and chronic inflammation. 17,18 As may be expected, this study found that inflammatory markers and acute phase reactants were raised at these patients' first presentation (mean leukocytes = 8.8±3.2 in single surgery and 9.73±4.7 in multiple surgeries; mean thrombocytes = 315.9±127.7 in single surgery and 336.07±136.3 in multiple surgeries; mean CRP = 46.8±60.1 in single surgery and 97.8±92.1 in multiple surgeries). However, a raised CRP was the only marker to be significantly associated with the requirement for further surgery, with binomial regression modelling showing a value of >84mg/L being significantly associated with requiring multiple surgical procedures.…”

“…We assessed for the rise in a group of markers called acute phase reactants (in particular CRP, leukocytes and thrombocytes) which the liver produces at a variable rate during states of acute and chronic inflammation 17,18 …”

IWGDF/IDSA guidelines on the diagnosis and treatment of diabetes‐related foot infections (IWGDF/IDSA 2023)

“…62 A more recent systematic review and meta-analysis published in 2022 found that PCT had the highest diagnostic test accuracy when compared to that of ESR, WBC and ESR with sensitivity, specificity, and AUC of 0.85, 0.67 and 0.844 at a cut-off value of 0.33 ng/mL. 63,95 Given the lack of inter-operator variability, the use of either ESR, CRP, or PCT as a sole biomarker for the detection of DFO in a patient with soft tissue DFI is not appropriate, but their use in combination with other diagnostic tests may be useful. A large-scale retrospective single-centre study with high risk of bias that used the results of culture and/or histology of bone samples as a reference standard found that ESR >60 mm/hr plus CRP ≥80 mg/L had a high positive predictive value, but a modest negative predictive value, for the diagnosis of DFO.…”

The infected diabetes‐related foot: Comparison of erythrocyte sedementation rate/albumin and C‐reactive protein/albumin ratios with erythrocyte sedimentation rate and C‐reactive protein to differentiate bone and soft tissue infections

“…In previous studies C‐reactive protein (CRP) and erythrocyte sedimentation rate (ESR) have been shown to perform better than newer biomarkers such as procalcitonin and interleukins to diagnose 3,4 . However, a recent meta‐analysis has shown that procalcitonin may have superior performance to both ESR and CRP in differentiating grade 2 and grade 3 diabetes‐related foot ulcerations 5 . Previous studies have also described the utility of ESR and CRP in monitoring OM 6,7 .…”

“…3,4 However, a recent meta-analysis has shown that procalcitonin may have superior performance to both ESR and CRP in differentiating grade 2 and grade 3 diabetes-related foot ulcerations. 5 Previous studies have also described the utility of ESR and CRP in monitoring OM. 6,7 Recently, several authors have evaluated the ratio of CRP and albumin to identify total joint infections, 8 infection versus inflammation in patients with systemic lupus erythematosus 9 and OM in diabetes-related foot infections 10 as well as to predict death.…”