Pilot study of a novel serum mRNA gene panel for diagnosis of acute septic arthritis

Abstract

BACKGROUNDSeptic arthritis is an orthopedic emergency requiring immediate surgical intervention. Current diagnostic standard of care is an invasive joint aspiration. Aspirations provide information about the inflammatory cells in the sample within a few hours, but there is often ambiguity about whether the source is infectious (e.g. bacterial) or non-infectious (e.g. gout). Cultures can take days to result, so decisions about surgery are often made with incomplete data. Novel diagnostics are thus needed. The “Sepsis MetaScore” (SMS) is an 11-mRNA host immune blood signature that can distinguish between infectious and non-infectious acute inflammation. It has been validated in multiple cohorts across heterogeneous clinical settings.AIMTo study whether the SMS holds diagnostic validity in determining the etiology of acute arthritis.METHODSWe conducted a blinded, prospective, non-interventional clinical study of the SMS. All patients undergoing work-up for a septic primary joint were enrolled. Patients proceeded through the normal standard-of-care pathway, including joint aspiration and inflammatory labs [white blood cell (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)]. Venous blood was also drawn into PAX gene RNA-stabilizing tubes and mRNAs were measured using Nano String nCounter™. SMS was calculated blinded to clinical results.RESULTSA total of 20 samples were included, of which 11 were infected based on aspiration or intra-operative cultures. The SMS had an area under the ROC curve (AUROC) of 0.87 for separating infectious from non-infectious conditions. For comparison, the AUROCs for ESR = 0.58, CRP = 0.6, and WBC = 0.59. At 100% sensitivity for infection, the specificity of the SMS was 40%, meaning nearly half of non-septic patients could have been ruled out for further intervention.CONCLUSIONIn this pilot study, SMS showed a high level of diagnostic accuracy in predicting septic joints compared to other diagnostic biomarkers. This quick blood test could be an important tool for early, accurate identification of acute septic joints and need for emergent surgery, improving clinical care and healthcare spending.

Comparison of Clinical Prediction Rules in Pre-school Aged Children With Septic Hip Arthritis Due to Different Pathogens

“…Furthermore, the model could be potentially improved by addition of more sensitive biomarkers such as procalcitonin or novel RNA signatures. [28][29][30][31] In addition, repeated CRP measurement could aid in the differentiation of bacterial infections. 32 Ideally, predictors should be readily available at the point-of-care.…”

“…In addition, clinical prediction rules should aim to influence clinical important decisions such as need for antibiotic treatment or hospital admission. Furthermore, the model could be potentially improved by addition of more sensitive biomarkers such as procalcitonin or novel RNA signatures 28–31 . In addition, repeated CRP measurement could aid in the differentiation of bacterial infections 32 .…”

Novel therapeutic interventions towards improved management of septic arthritis

“…The biodegradable electrosprayed nano/microparticles released high concentrations of antibiotics into the synovial knee tissue of rabbits for more than 2 weeks which was well above the MIC 90 for S. aureus . • Schulz et al [ 185 ] reported the use of a novel diagnostic method termed the “Sepsis MetaScore” (SMS) which is an 11-mRNA host immune blood signature. This represents a rapid blood test that can distinguish between bacterial inflammation and non-infectious causes of inflammation thus directing correct treatment to be followed at the earliest.…”

“…• Schulz et al [ 185 ] reported the use of a novel diagnostic method termed the “Sepsis MetaScore” (SMS) which is an 11-mRNA host immune blood signature. This represents a rapid blood test that can distinguish between bacterial inflammation and non-infectious causes of inflammation thus directing correct treatment to be followed at the earliest.…”

A Multi-mRNA Prognostic Signature for Anti-TNFα Therapy Response in Patients with Inflammatory Bowel Disease

“…This lack of biological and clinical heterogeneity, in turn, reduces the generalizability of findings. Using a multicohort analysis framework [17], we have repeatedly demonstrated that leveraging biologically, clinically, and technically heterogeneous cohorts identifies a more robust generalizable gene signature compared to using a single homogeneous cohort [18][19][20][21][22][23][24][25][26][27][28] and can be translated in a diagnostic test for use in clinics [29][30][31][32].…”