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      Inflammatory response in confirmed non-diabetic foot and ankle infections: A case series with normal inflammatory markers

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          Abstract

          BACKGROUND

          The distinction between foot and ankle wound healing complications as opposed to infection is crucial for the appropriate and efficacious allocation of antibiotic therapy. Multiple reports have focused on the diagnostic accuracy of different inflammatory markers, however, mainly in the diabetic population.

          AIM

          To evaluate the diagnostic accuracy of white cell count (WCC) and C-reactive protein (CRP) as diagnostic tools for this distinction in the non-diabetic cohort.

          METHODS

          Data was reviewed from a prospectively maintained Infectious Diseases Unit database of 216 patients admitted at Leicester University Hospitals–United Kingdom with musculoskeletal infections over the period between July 2014 and February 2020 (68 mo). All patients with confirmed diagnosis of diabetes were excluded while only those with confirmed microbiological or clinical diagnosis of foot or ankle infection were included in our study. For the included patients, we retrospectively retrieved the inflammatory markers (WCCs and CRP) at the time of presentation. Values of CRP 0-10 mg/L and WCC 4.0-11.0 × 10 9/L were considered normal.

          RESULTS

          After exclusion of patients with confirmed diabetes, 25 patients with confirmed foot or ankle infections were included. All infections were confirmed microbiologically with positive intra-operative culture results. 7 (28%) patients with osteomyelitis (OM) of the foot, 11 (44%) with OM of the ankle, 5 (20%) with ankle septic arthritis and 2 (8%) patients with post-surgical wound infection were identified. Previous bony surgery was identified in 13 (52%) patients, either a corrective osteotomy or an open reduction and internal fixation for a foot or ankle fracture with the infection developing on top of the existing metalwork. 21 (84%) patients did have raised inflammatory markers while 4 (16%) patients failed to mount an inflammatory response even with subsequent debridement and removal of metal work. CRP sensitivity was 84%, while WCC sensitivity was only 28%.

          CONCLUSION

          CRP has a relatively good sensitivity in the diagnosis of foot and ankle infections in non-diabetic patients, whereas WCC is a poor inflammatory marker in the detection of such cases. In presence of clinically high level of suspicion of foot or ankle infection, a normal CRP should not rule out the diagnosis of OM.

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          Most cited references40

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          Role of C-Reactive Protein at Sites of Inflammation and Infection

          C-reactive protein (CRP) is an acute inflammatory protein that increases up to 1,000-fold at sites of infection or inflammation. CRP is produced as a homopentameric protein, termed native CRP (nCRP), which can irreversibly dissociate at sites of inflammation and infection into five separate monomers, termed monomeric CRP (mCRP). CRP is synthesized primarily in liver hepatocytes but also by smooth muscle cells, macrophages, endothelial cells, lymphocytes, and adipocytes. Evidence suggests that estrogen in the form of hormone replacement therapy influences CRP levels in the elderly. Having been traditionally utilized as a marker of infection and cardiovascular events, there is now growing evidence that CRP plays important roles in inflammatory processes and host responses to infection including the complement pathway, apoptosis, phagocytosis, nitric oxide (NO) release, and the production of cytokines, particularly interleukin-6 and tumor necrosis factor-α. Unlike more recent publications, the findings of early work on CRP can seem somewhat unclear and at times conflicting since it was often not specified which particular CRP isoform was measured or utilized in experiments and whether responses attributed to nCRP were in fact possibly due to dissociation into mCRP or lipopolysaccharide contamination. In addition, since antibodies for mCRP are not commercially available, few laboratories are able to conduct studies investigating the mCRP isoform. Despite these issues and the fact that most CRP research to date has focused on vascular disorders, there is mounting evidence that CRP isoforms have distinct biological properties, with nCRP often exhibiting more anti-inflammatory activities compared to mCRP. The nCRP isoform activates the classical complement pathway, induces phagocytosis, and promotes apoptosis. On the other hand, mCRP promotes the chemotaxis and recruitment of circulating leukocytes to areas of inflammation and can delay apoptosis. The nCRP and mCRP isoforms work in opposing directions to inhibit and induce NO production, respectively. In terms of pro-inflammatory cytokine production, mCRP increases interleukin-8 and monocyte chemoattractant protein-1 production, whereas nCRP has no detectable effect on their levels. Further studies are needed to expand on these emerging findings and to fully characterize the differential roles that each CRP isoform plays at sites of local inflammation and infection.
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            Wound microbiology and associated approaches to wound management.

            The majority of dermal wounds are colonized with aerobic and anaerobic microorganisms that originate predominantly from mucosal surfaces such as those of the oral cavity and gut. The role and significance of microorganisms in wound healing has been debated for many years. While some experts consider the microbial density to be critical in predicting wound healing and infection, others consider the types of microorganisms to be of greater importance. However, these and other factors such as microbial synergy, the host immune response, and the quality of tissue must be considered collectively in assessing the probability of infection. Debate also exists regarding the value of wound sampling, the types of wounds that should be sampled, and the sampling technique required to generate the most meaningful data. In the laboratory, consideration must be given to the relevance of culturing polymicrobial specimens, the value in identifying one or more microorganisms, and the microorganisms that should be assayed for antibiotic susceptibility. Although appropriate systemic antibiotics are essential for the treatment of deteriorating, clinically infected wounds, debate exists regarding the relevance and use of antibiotics (systemic or topical) and antiseptics (topical) in the treatment of nonhealing wounds that have no clinical signs of infection. In providing a detailed analysis of wound microbiology, together with current opinion and controversies regarding wound assessment and treatment, this review has attempted to capture and address microbiological aspects that are critical to the successful management of microorganisms in wounds.
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              Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update).

              The International Working Group on the Diabetic Foot (IWGDF) has published evidence-based guidelines on the prevention and management of diabetic foot disease since 1999. This guideline is on the diagnosis and treatment of foot infection in persons with diabetes and updates the 2015 IWGDF infection guideline. On the basis of patient, intervention, comparison, outcomes (PICOs) developed by the infection committee, in conjunction with internal and external reviewers and consultants, and on systematic reviews the committee conducted on the diagnosis of infection (new) and treatment of infection (updated from 2015), we offer 27 recommendations. These cover various aspects of diagnosing soft tissue and bone infection, including the classification scheme for diagnosing infection and its severity. Of note, we have updated this scheme for the first time since we developed it 15 years ago. We also review the microbiology of diabetic foot infections, including how to collect samples and to process them to identify causative pathogens. Finally, we discuss the approach to treating diabetic foot infections, including selecting appropriate empiric and definitive antimicrobial therapy for soft tissue and for bone infections, when and how to approach surgical treatment, and which adjunctive treatments we think are or are not useful for the infectious aspects of diabetic foot problems. For this version of the guideline, we also updated four tables and one figure from the 2016 guideline. We think that following the principles of diagnosing and treating diabetic foot infections outlined in this guideline can help clinicians to provide better care for these patients.
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                Author and article information

                Contributors
                Journal
                World J Orthop
                WJO
                World Journal of Orthopedics
                Baishideng Publishing Group Inc
                2218-5836
                18 March 2023
                18 March 2023
                : 14
                : 3
                : 136-145
                Affiliations
                Department of Trauma and Orthopedics, Leicester University Hospitals-NHS Trust, Leicester LE1 5WW, Leicestershire, United Kingdom
                Department of Trauma and Orthopedics, Leicester University Hospitals-NHS Trust, Leicester LE1 5WW, Leicestershire, United Kingdom
                Department of Trauma and Orthopedics, Leicester University Hospitals-NHS Trust, Leicester LE1 5WW, Leicestershire, United Kingdom. ahmedharoonbarakat@ 123456gmail.com
                Department of Trauma and Orthopedics, Leicester University Hospitals-NHS Trust, Leicester LE1 5WW, Leicestershire, United Kingdom
                Department of Infectious Diseases and Tropical Medicine, Leicester Royal Infirm, Leicester LE1 5WW, Leicestershire, United Kingdom
                Author notes

                Author contributions: Mangwani J and White H conceptualized the study design and aim; Ahmed AH and Ahmed S completed data collection and statistical analysis; Barakat A drafted the manuscript and reviewed it for final submission.

                Corresponding author: Ahmed Barakat, MBChB, MSc, Surgeon, Department of Trauma and Orthopedics, Leicester University Hospitals-NHS Trust, University Hospitals of Leicester Headquarters, Level 3, Balmoral Building, Leicester Royal Infirmary, Infirmary Square, Leicester LE1 5WW, Leicestershire, United Kingdom. ahmedharoonbarakat@ 123456gmail.com

                Article
                jWJO.v14.i3.pg136
                10.5312/wjo.v14.i3.136
                10044321
                be235f58-61f5-40bf-967b-a5df05eb4be7
                ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.

                This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

                History
                : 9 July 2022
                : 23 October 2022
                : 31 January 2023
                Categories
                Retrospective Study

                osteomyelitis,septic arthritis,surgical site infection,inflammatory markers,c-reactive protein,white cell count

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