The manuscript offers a nuanced examination of how biomarkers like CXCL5, SERPINB3, and Neutrophil Elastase can foretell the healing trajectory of diabetic foot ulcers (DFUs). It synthesizes data from multiple clinical studies, underscoring that a high level of CXCL5 correlates with non-healing ulcers, while decreased SERPINB3 levels indicate a quicker healing process. Such insights could revolutionize treatment protocols, offering a more tailored and effective approach to managing DFUs.
For further details, please refer to the manuscript here.
Some key findings:
- CXCL6: Downregulated in non-healing ulcers with high predictive accuracy (AUC: 0.965; sensitivity: 87.27%; specificity: 95.56%).
- ENA-78 (CXCL5): Downregulated in non-healing DFUs; predictive value indicated by an AUC of 0.705.
- SERPINB3: Downregulated in rapidly healing ulcers, with a predictive AUC of 0.665.
- Neutrophil Elastase and CitH3: Associated with delayed wound healing in DFUs.
- Other Biomarkers: Elevated levels of sICAM-1, endothelin-1, lactate concentration, and MMP-9/TIMP-1 ratio were also associated with delayed healing in various studies.
Clinical studies that reported potential biomarkers for predicting hard-to-heal DFUs
| Author, year, country | Wound characteristics | Definition of hard-to-heal | Specimen-related information | Analysis methods | Biomarkers | Accuracy of prediction |
|---|---|---|---|---|---|---|
| Wang et al., 2019, USA(11) | Diabetic neuropathic wounds Texas Grading System (grade 2-3) Exclusion: Ischemia, infection, and immunological disorder | Non-healing: Ulcer persisted or increased in size, new ulcers appeared, amputations were required, or the patient died. | Wound exudates (swab) | ELISA | CXCL6 ↓ | AUC: 0.965 Cutoff value: 846.90 ng/mL Sensitivity: 87.27% Specificity: 95.56% |
| Li et al., 2019, China (17) | Diabetic neuropathic wounds Texas Grading System (grade 2-3) | Nonhealing: The ulcer persisted or was even enlarged, development of new ulcers, amputations, or death | Wound exudates (swab) and plasma | Protein array; candidate markers were then analyzed using ELISA | ENA-78 | AUC: 0.705 (95% CI 0.608–0.801, P<0.001) Cutoff value: 1792.00 ng/mL Sensitivity: 45.90% Specificity: 89.58% |
| Li et al., 2013, China (18) | Diabetic neuropathic wounds Texas Grading System (grade 1-3) Wound duration: 14 to 90 days Size: >0.5 cm² Exclusion: Arteriopathy of the lower limbs | Poor healers: A decrease in wound area <82% in 4 weeks | Serum samples at the first clinic visit and the end of 4-week treatment | ELISA for MMP-9, MMP-2, TIMP-1 and TIMP-2 | MMP-9/TIMP-1 ratio ↑ | AUC: 0.658 (Sensitivity: 63.6%; specificity: 58.6%) |
| Fadini et al., 2014, Italy (13) | Diabetic neuropathic wounds Exclusion: Ischemia, systematic infection | Non-healing: Ulcer persisted or was even enlarged in 6 months | Skin biopsy | Proteomics analysis, ELISA, Real-time RT-PCR | SerpinB3 ↓ | AUC: 0.665 Sensitivity: 75%; Specificity: 62.5% Cutoff value: 1.13 ng/mL/total protein µg/µl |
| Fadini et al., 2016, Italy (16) | Diabetic neuropathic wounds Exclusion: Ischemia, systematic infection | Non-healing: Ulcer persisted or was even enlarged in 6 months | Serum samples | ELISA (elastase, NGAL, lactoferrin, PR-3) | Neutrophil elastase ↑ | AUC: 0.815 (95% CI 0.686–0.944) (ulcer infection) |
| Yang et al., 2020, China (23) | Diabetic wounds Exclusion: Traumatic amputation, Buerger’s disease, vasculitis, acute arterial occlusion | Non-healing: Did not heal in one year with multidisciplinary management of DFU | Peripheral blood plasma and wound tissues | ELISA (NET-related markers, elastase level) | CitH3 ↑, Neutrophil elastase ↑ | AUC: 0.84 [95% CI 0.76–0.90] |
| Loffle et al., 2011, Germany (20) | Diabetic ulcer located below the ankle Not receiving any antimicrobial treatments in 3 months | Healing: within no soft-tissue infection group: Healed within 6-month follow-up period | Wound fluid (swab) | Wound fluid lactate concentration | Lactate concentration ↑ | NA |
| Vieceli Dalla Sega et al., 2022, Italy (21) | Ischemic ulcer that requires percutaneous transluminal angioplasty and foot surgery | Optimal healing: healed at 3 months; Others: new limb revascularization, new lesions or recurrence | Peripheral blood serum | Multiplex immunoassay: sCD40L, IFN-γ2, IFN-γ, 1RA, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-18, TNF-α, Angiopoietin-2, Endoglin, Endothelin-1, sE-Selectin, Thrombomodulin, s-RAGE, sICAM-1, P-Selectin, sVCAM-1, and PAI-1; ELISA: vWF | Various biomarkers | Decision tree accuracy for lower risk of new lesion: 0.812 (95% CI=0.6192–0.937) (sCD40L<18 pg/mL and thrombomodulin levels ≥2 pg/mL) |
| MacDonald et al., 2019, USA (22) | Infected diabetic foot ulcer | Persistent infections at week 12 | Wound tissue debridement | 16S rRNA genomic seq (microbial species) and qPCR (bacterial abundance) | Higher abundance of Bacteroidales and Streptococcaceae; Low level of Actinomycetales | NA |
| Min et al., 2020, USA(19) | Vascularized plantar neuropathic DFU Duration: >4 weeks Size: >0.5 cm² Exclusion: Receiving antibiotics over 2 weeks | Non-healing wounds: <50% closed by week 4 | Plantar skin swab, ulcer debridement of the wound edge before wound cleansing. | 16S rRNA next generation sequencing | Gram-positive anaerobic cocci ↑ | NA |
Leave a Reply