Identification of New Biological Marker for Diagnosis of Periprosthetic Infections

Management of prosthetic joint infections involves long antibiotic therapy and, in most cases, additional revision surgery with worsening of life quality for patients and high costs for health system. Prosthetic joint infections occur at a rate of 1-2% but their incidence grows up to 15-20% after the first revision surgery. Gram positive cocci, particularly staphylococci, are the main pathogens responsible for these infections. Diagnostic workflow is rather complicated, since a gold standard assay characterized by high sensitivity and specificity has not been recognized. Consequently, the diagnosis is based on fulfillment of a series of major and minor criteria derived from biochemical, hematological, microbiological, histological analyses combined with clinical and radiological observations. Therefore, it is evident that there is an urgent need to find early markers of infection, characterized by high sensitivity and specificity able to differentiate between aseptic failure and prosthetic joint infections caused by both high and low virulent microorganisms.

In the recent years, presepsin has been described as a marker for sepsis also able to discriminate sepsis severity. Presepsin is a fragment of soluble receptor CD14 which is released from monocyte surface during inflammation. The new inflammatory marker TREM-1 links the activity of presepsin to other actors of inflammation process like Toll Like Receptors, monocytes, inflammatory cytokines like IL-1 and IL-6, the chemokine CCL2. Presepsin activity is also related to suPAR an inflammatory marker, we have recently shown to be associated with prosthetic joint infections. Another potential marker of infection is osteopontin (OPN), a multifunctional protein with pro-inflammatory properties, which correlates with mortality and is associated to suPAR in inflammatory response. Similarly, receptor CD163, highly expressed by macrophages during inflammation has been proposed as a promising serum marker of inflammation. Equally important in inflammatory process is the role played by neutrophils, which represent the first line of defense against infection, being able to kill bacteria by producing oxygen reactive species (ROS). Recently ROS have been correlated with serum Advanced Glycation End Products(AGEs) that are increased by oxidative stress. AGEs are able to interact with their receptor RAGE, which exists in its soluble forms in plasma. For this reason, RAGE might be used as serum biomarker to diagnose infection and related oxidative stress. Despite the amount of scientific papers on the role of the above mentioned molecules, a panel combining them for diagnosis of prosthetic joint infections is not yet available.

Aim of the study will be to evaluate new biological markers of prosthetic joint infection in order to improve diagnostic workflow to support and integrate data from microbiological, hematological and clinical examination.

At this purpose, differences in serum concentrations of IL-6, TREM-1, CCL2, MMP-9, OPN, IL-1RA, GP-130, C5a, sRAGE, urokinases and presepsin between infected and not infected patients will be evaluated by measuring sensitivity, specificity, positive and negative predictive values, likelihood ratio for each parameter. Moreover, concentration of each biomarker will be correlated with markers routinely used for diagnosis of these infections.

A total of 130 patients will be enrolled in the study: 65 patients with diagnosis of aseptic failure, and 65 diagnosed with infection of prosthetic implant.