Diabetic Foot Infections: Immune Dysfunction, Laboratory Diagnosis, and Clinical Impact
Abstract
Diabetes mellitus (DM) enhances the risk of diabetic foot infections (DFIs) due to hyperglycemia-induced immune dysfunction and compromised wound healing. This review explores the mechanisms connecting immune dysfunction to DFIs, outlines the primary causative pathogens, assesses laboratory diagnostic methods, and proposes strategies to enhance DFI management, especially in resource-constrained environments. A systematic literature review was performed using PubMed, Scopus, ScienceDirect, and Google Scholar, with additional backward reference list searching. Publications from 2012 to 2024 were included. Out of 60 identified records, 24 duplicates were excluded, and 36 records were screened. Ultimately, 20 eligible publications were incorporated into the qualitative thematic synthesis. The evidence suggests that chronic hyperglycemia impairs neutrophil chemotaxis, phagocytosis, and cytokine responses, while promoting NETosis, oxidative stress, and mitochondrial dysfunction, thus contributing to the onset and persistence of DFIs. These infections are often polymicrobial, frequently involving Staphylococcus aureus, including methicillin-resistant strains, Pseudomonas aeruginosa, Escherichia coli, and other multidrug-resistant organisms. Conventional culture and antimicrobial susceptibility testing remain essential, although molecular methods and inflammatory biomarkers can supplement diagnosis but encounter resource-related implementation challenges. Enhancing laboratory capacity, local microbiological surveillance, timely targeted therapy, and multidisciplinary care may improve DFI management and mitigate severe outcomes, such as treatment failure and amputation.
References
2. Yunus R, Wijayati F, Askrening A, Rahayu DYS, Hasan FE, Trees T, et al. Diabetes Mellitus and Bacterial Infections: A Review of Main Infections in DM Patients. Public Health of Indonesia. 2024;10(1): 73–97. https://doi.org/10.36685/phi.v10i1.777.
3. Casqueiro J, Casqueiro J, Alves C. Infections in patients with diabetes mellitus: A review of pathogenesis. Indian journal of endocrinology and metabolism. 2012;16(Suppl1): S27. https://doi.org/10.4103/2230-8210.94253.
4. Sohail MU, Mashood F, Oberbach A, Chennakkandathil S, Schmidt F. The role of pathogens in diabetes pathogenesis and the potential of immunoproteomics as a diagnostic and prognostic tool. Frontiers in Microbiology. 2022;13: 1042362. https://doi.org/10.3389/fmicb.2022.1042362.
5. Jafar MDN, Edriss MDH, Nugent MDK. The effect of short-term hyperglycemia on the innate immune system. The American journal of the medical sciences. 2016;351(2): 201–211. https://doi.org/10.1016/j.amjms.2015.11.011.
6. Farhan A, Hassan G, Ali SHL, Yousaf Z, Shafique K, Faisal A, et al. Spontaneous NETosis in diabetes: A role of hyperglycemia mediated ROS and autophagy. Frontiers in Medicine. 2023;10: 1076690. https://doi.org/10.3389/fmed.2023.1076690.
7. Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of type 2 diabetes mellitus. International journal of molecular sciences. 2020;21(17): 6275. https://doi.org/10.3390/ijms21176275.
8. Mendes JJ, Neves J. Diabetic foot infections: current diagnosis and treatment. Journal of Diabetic Foot Complications. 2012; 26–45.
9. Maity S, Leton N, Nayak N, Jha A, Anand N, Thompson K, et al. A systematic review of diabetic foot infections: pathogenesis, diagnosis, and management strategies. Frontiers in Clinical Diabetes and Healthcare. 2024;5: 1393309. https://doi.org/10.3389/fcdhc.2024.1393309.
10. Rajab AAH, Hegazy WAH. What’s old is new again: insights into diabetic foot microbiome. World journal of diabetes. 2023;14(6): 680. https://doi.org/10.4239/wjd.v14.i6.680.
11. Macdonald KE, Boeckh S, Stacey HJ, Jones JD. The microbiology of diabetic foot infections: a meta-analysis. BMC infectious diseases. 2021;21(1): 770. https://doi.org/10.1186/s12879-021-06516-7.
12. Alhubail A, Sewify M, Messenger G, Masoetsa R, Hussain I, Nair S, et al. Microbiological profile of diabetic foot ulcers in Kuwait. Plos one. 2020;15(12): e0244306. https://doi.org/10.1371/journal.pone.0244306.
13. Senneville É, Albalawi Z, Van Asten SA, Abbas ZG, Allison G, Aragón‐Sánchez J, et al. IWGDF/IDSA guidelines on the diagnosis and treatment of diabetes‐related foot infections (IWGDF/IDSA 2023). Diabetes/metabolism research and reviews. 2024;40(3): e3687. https://doi.org/10.1093/cid/ciad527.
14. Rubitschung K, Sherwood A, Crisologo AP, Bhavan K, Haley RW, Wukich DK, et al. Pathophysiology and molecular imaging of diabetic foot infections. International journal of molecular sciences. 2021;22(21): 11552. https://doi.org/10.3390/ijms222111552.
15. Holt RIG, Cockram CS, Ma RCW, Luk AOY. Diabetes and infection: review of the epidemiology, mechanisms and principles of treatment. Diabetologia. 2024;67(7): 1168–1180. https://doi.org/10.1007/s00125-024-06102-x.
16. Matheson EM, Bragg SW, Blackwelder RS. Diabetes-related foot infections: diagnosis and treatment. American family physician. 2021;104(4): 386–394.
17. Darwitz BP, Genito CJ, Thurlow LR. Triple threat: how diabetes results in worsened bacterial infections. Infection and immunity. 2024;92(9): e00509-23. https://doi.org/10.1128/iai.00509-23.
18. Sethi SM, Khanum I, Javed U, Sabir S. Impact of Infection on Glycemic Control in Diabetic Patients; a Hospital-based Cohort Study in Pakistan. Afro-Egyptian Journal of Infectious and Endemic Diseases. 2022;12(4): 321–328. https://doi.org/10.21608/aeji.2022.156178.1246.
19. Salari N, Karami MM, Bokaee S, Chaleshgar M, Shohaimi S, Akbari H, et al. The prevalence of urinary tract infections in type 2 diabetic patients: a systematic review and meta-analysis. European journal of medical research. 2022;27(1): 20. https://doi.org/10.1186/s40001-022-00644-9.
20. Lauri C, Leone A, Cavallini M, Signore A, Giurato L, Uccioli L. Diabetic foot infections: the diagnostic challenges. Journal of clinical medicine. 2020;9(6): 1779. https://doi.org/10.3390/jcm9061779.
21. Spichler A, Hurwitz BL, Armstrong DG, Lipsky BA. Microbiology of diabetic foot infections: from Louis Pasteur to ‘crime scene investigation’. BMC medicine. 2015;13(1): 2. https://doi.org/10.1186/s12916-014-0232-0.