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It is difficult to treat a disease that has not been properly diagnosed. Fracture-related infection (FRI) is a feared complication after surgical fracture care. One of its challenges is establishing the right diagnosis which can be difficult because FRI can present itself in many different ways. Sometimes the clinical scenario is clear and the diagnosis can be made on clinical examination only. This is the case with confirmatory clinical criteria such as a fistula or pus drainage from the wound. It is also possible for the presence of an FRI to be more obscured and for suggestive signs such as redness, swelling or pain to be mimicking a non-infected condition (such as posttraumatic arthrosis or a non-infected delayed fracture union). This thesis aims to improve the diagnostic process for FRI. The diagnostic value of serum inflammatory markers, imaging modalities, histopathological examination, tissue and sonication fluid sampling, and microbiological and molecular biological techniques are being evaluated. White blood cell (WBC) scintigraphy + SPECT/CT is the most accurate diagnostic imaging modality, followed by FDG-PET/CT. In late FRI, serum inflammatory markers such as C-reactive protein (CRP), leukocyte count (LC) and erythrocyte sedimentation rate (ESR) are insufficiently accurate to reliably confirm or rule out the presence of an FRI. Culturing of surgically obtained deep-tissue samples is one of the most important diagnostic steps in FRI management. The culture of phenotypically indistinguishable pathogens from at least two separate deep-tissue/implant specimens is considered a confirmatory criterion for FRI. In addition, the antibiotic susceptibility of the identified pathogens will guide the choice of antimicrobial treatment. It is of upmost importance to apply a structured tissue sampling protocol for diagnosing FRI. Despite stricter criteria for pathogen identification, a structured tissue sampling approach for fracture-related infection led to increased microbiological identification with more certainty of causative pathogens compared to a historic ad hoc sampling approach. Simple measures such as an adequate number of deep-tissue samples and use of a dedicated surgical sampling kit can be easily implemented in every hospital. This set of measurements will lead to more trustworthy culture results and consequently a more targeted FRI treatment. A systematic review of validation studies on sonication fluid cultures, molecular techniques and histopathology as diagnostic criteria for FR concluded that there is yet little evidence on their diagnostic accuracy for FRI. The outcome of the investigated diagnostic modalities for FRI as presented in this thesis are implemented in a Dutch guideline and have led to the design of a prospective trial on imaging modalities for FRI (The IFI Trial).

Introduction: Diagnosing Fracture-Related Infections (FRI) based on clinical symptoms alone can be challenging and additional diagnostic tools such as serum inflammatory markers are often utilized. The aims of this study were 1) to determine the individual diagnostic performance of three commonly used serum inflammatory markers: C-Reactive Protein (CRP), Leukocyte Count (LC) and Erythrocyte Sedimentation Rate (ESR), and 2) to determine the diagnostic performance of a combination of these markers, and the additional value of including clinical parameters predictive of FRI.Methods: This cohort study included patients who presented with a suspected FRI at two participating level I academic trauma centers between February 1st 2009 and December 31st 2017. The parameters CRP, LC and ESR, determined at diagnostic work-up of the suspected FRI, were retrieved from hospital records. The gold standard for diagnosing or ruling out FRI was defined as: positive microbiology results of surgically obtained tissue samples, or absence of FRI at a clinical follow-up of at least six months. The diagnostic accuracy of the individual serum inflammatory markers was assessed. Analyses were done with both dichotomized values using hospital thresholds as well as with continuous values. Multivariable logistic regression analyses were performed to obtain the discriminative performance (Area Under the Receiver Operating Characteristic, AUROC) of (1) the combined inflammatory markers, and (2) the added value of these markers to clinical parameters.Results: A total of 168 patients met the inclusion criteria and were included for analysis. CRP had a 38% sensitivity, 34% specificity, 42% positive predictive value (PPV) and 78% negative predictive value (NPV). For LC this was 39%, 74%, 46% and 67% and for ESR 62%, 64%, 45% and 76% respectively. The diagnostic accuracy was 52%, 61% and 80% respectively. The AUROC was 0.64 for CRP, 0.60 for LC and 0.58 for ESR. The AUROC of the combined inflammatory markers was 0.63. Serum inflammatory markers combined with clinical parameters resulted in AUROC of 0.66 as opposed to 0.62 for clinical parameters alone.Conclusion: The added value of CRP, LC and ESR for diagnosing FRI is limited. Clinicians should be cautious when interpreting the results of these tests in patients with suspected FRI.