Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Orthop. Dec 18, 2019; 10(12): 424-433
Published online Dec 18, 2019. doi: 10.5312/wjo.v10.i12.424
Pilot study of a novel serum mRNA gene panel for diagnosis of acute septic arthritis
Blake J Schultz, Timothy Sweeney, Malcolm R DeBaun, Melissa Remmel, Uros Midic, Purvesh Khatri, Michael J Gardner
Blake J Schultz, Malcolm R DeBaun, Michael J Gardner, Department of Orthopedic Surgery, Stanford University, Redwood City, CA 94063, United States
Timothy Sweeney, Melissa Remmel, Uros Midic, Inflammatix, Inc, 863 Mitten Road, Suite 104, Burlingame, CA 94010, United States
Purvesh Khatri, Institute for Immunity, Transplantation and Infections, Center for Biomedical Research, Department of Medicine, Stanford University, Stanford, Redwood City, CA 94305, United States
Author contributions: Sweeney T, Remmel M, Midic U, Khatri P ran the laboratory tests and performed data analysis and interpretation. Schultz BJ, DeBaun MR and Gardner MJ organized and ran the clinical trial. All authors provided critical feedback and helped shape the research, analysis and manuscript. All authors have read and approve of the final submitted manuscript.
Institutional review board statement: All specimens from the patients were obtained after their informed consent and ethical permission was obtained for participation in the study.
Conflict-of-interest statement: The authors report no relevant conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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:
Corresponding author: Blake J Schultz, MD, Surgeon, Department of Orthopedic Surgery, Stanford University, 450 Broadway Street Pavilion C, 4th Floor, Redwood City, CA 94063, United States.
Telephone: +1-650-4975281
Received: August 14, 2019
Peer-review started: August 14, 2019
First decision: August 30, 2019
Revised: September 19, 2019
Accepted: October 18, 2019
Article in press: October 18, 2019
Published online: December 18, 2019

Septic 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.


To study whether the SMS holds diagnostic validity in determining the etiology of acute arthritis.


We 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.


A 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.


In 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.

Keywords: Biomarkers, Bioinformatics, Infection, Septic arthritis, Medical technology, Diagnostics

Core tip: Acute septic arthritis is an orthopedic emergency. The current gold standard diagnostic tool is synovial fluid culture, but this can take days to results, so decisions about surgery are made with imperfect information. A novel diagnostic “Sepsis MetaScore” (SMS) based on an mRNA signature has been identified that uses a blood sample to rapidly identify differentiate septic vs aseptic inflammation. Our pilot study showed the SMS had higher diagnostic accuracy than current standard of care inflammatory labs, showing potential for use as a rule-out test for septic arthritis, helping to minimize misdiagnosis and avoid unnecessary surgeries.