Alpha-Defensin and Synovial Proteins to Improve Detection of Pediatric Septic Arthritis

Study Overview
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Brief Summary
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Differentiating between septic arthritis and other causes of joint inflammation in pediatric patients is challenging and of the utmost importance because septic arthritis requires surgical debridement as part of the treatment regimen. The current gold standard to diagnose septic arthritis in children is a positive synovial fluid culture; however, joint cultures may take several days to return. If a bacterial infection is present, it requires immediate surgical intervention in order to prevent lasting articular cartilage damage. Frequently surgeons must decide whether to surgically debride a joint before culture results are available. There is no single lab test or clinical feature that reliably indicates bacterial infection over other causes of joint inflammation. The alpha-defensin assay has shown high sensitivity and specificity for joint infection in other studies.The purpose of this study is to determine the sensitivity and specificity of several synovial biomarkers for diagnosing pediatric septic arthritis.

Detailed Description
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The purpose of this study is to determine if alpha-defensin and other proteins present in joint fluid may be able to rapidly diagnose bacterial joint infections. Patients with suspected joint infection typically undergo joint aspiration so that tests can be performed to help diagnose joint infection, including gram stain, cell count, and culture. Patients under 18 years old that are undergoing sampling of their joint fluid due to suspicion of infection or inflammation will be enrolled in this multi-center trial. Joint fluid will also be sampled from normative controls made up of patients who are undergoing an unrelated procedure without inflammation or infection. Joint fluid from patients with suspected inflammation/infection and from normative controls will be analysed for presence of alpha-defensin, leukocyte esterase, neutrophil elastase, synovial C-reactive protein, and synovial lactate. The alpha-defensin assay has shown high sensitivity and specificity for joint infection in other studies. Additionally a Staphylococcus spp antigen panel, Candida spp antigen panel, Enterococcus faecalis assay, BACTAlert culture, cell count plus differential, gram stain, and aerobic, anaerobic, and fungal cultures will be done using synovial fluid. A synovial fluid PCR for Kingella kingae will be performed if the patient is under eight years of age. Blood tests will include cell count and differential, erythrocyte sedimentation rate, C-reactive protein, procalcitonin, and D-dimer, as well as relevant inflammatory or rheumatologic marker tests. Results from these tests will be compared to joint fluid culture which the gold standard for diagnosing bacterial infection. The study includes 1 visit per patient, the standard of care visit in which the patient would be undergoing joint aspiration or arthroscopy. Once data has been collected, the sensitivity and specificity will be determined for these experimental tests both individually and in combination.

Official Title
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Alpha-Defensin and Synovial Proteins to Improve Detection of Pediatric Septic Arthritis

Conditions
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Joint Infection, Infection of Hip Joint (Disorder), Infection of Shoulder Joint, Septic Arthritis

Intervention / Treatment
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* Diagnostic Test: Synovial Alpha-defensin assay
* Diagnostic Test: Synovial Neutrophil elastase assay
* Diagnostic Test: Synovial lactate assay
* Diagnostic Test: Synovial C-reactive Protein (CRP)
* Diagnostic Test: Synovial Staphylococcus spp antigen panel
* Diagnostic Test: Synovial Candida spp antigen panel
* Diagnostic Test: Synovial Enterococcus faecalis assay
* Diagnostic Test: Synovial bacterial culture by BacT/Alert
* Diagnostic Test: Synovial Cell count + differential (CBC)
* Diagnostic Test: Synovial Gram Stain
* Diagnostic Test: Synovial Leukocyte Esterase Test Strips
* Diagnostic Test: Synovial PCR for Kingella kingae
* Diagnostic Test: Serum Cell count + differential (CBC)
* Diagnostic Test: Serum erythrocyte sedimentation rate (ESR)
* Diagnostic Test: Serum C-reactive Protein (CRP)
* Diagnostic Test: Serum D-dimer
* Diagnostic Test: Serum Procalcitonin
* Diagnostic Test: Blood Cultures
* Diagnostic Test: Optional blood testing per standard of care (ASO, anti-strep, ANA, anti-DS-DNA, HLA-B27, RF, Lyme and other inflammatory/ rheumatologic markers )


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria- Septic Cases and Inflamed, Non-Septic Comparators: Synovial fluid is obtained to assess for infection or inflammatory/rheumatologic disease (all medium and large joints will be included: hip, knee, ankle, shoulder, subtalar, elbow, and wrist joints) Patients with recent antibiotic exposure are eligible to participate but will be analyzed separately Inclusion Criteria- Normative Controls: Patients undergoing a procedure unrelated to infection (the procedure may be arthroscopy, or an open or percutaneous bony or soft tissue procedure) Exclusion Criteria- All Participants: Family declines to participate/consent Patients with a major joint trauma (such as a documented ligament tear or fracture) within the past 8 weeks are not eligible to have that joint aspirated, but could have another joint aspirated Exclusion Criteria- Normative Controls: A history of recent infection (within the past 3 months) Received antibiotics in the past 7 days

Ages Eligible for Study
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Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants are assigned as either cases of infection/inflammation, or normative controls, and receive the same diagnostic testing for the duration of the study.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inflamed/Infected Joint<br>Patients undergoing joint aspiration/debridement due to suspicion of septic joint or rheumatologic/inflammatory condition | Diagnostic Test: Synovial Alpha-defensin assay<br>* One of the synovial fluid (joint fluid) tests that will be performed by the outside lab, CD Diagnostics.<br>Diagnostic Test: Synovial Neutrophil elastase assay<br>* One of the synovial fluid (joint fluid) tests that will be performed by the outside lab, CD Diagnostics.<br>Diagnostic Test: Synovial lactate assay<br>* Synovial Fluid (joint fluid) will be sent out to CD Diagnostics for this test.<br>Diagnostic Test: Synovial C-reactive Protein (CRP)<br>* One of the synovial fluid (joint fluid) tests that will be performed by the outside lab, CD Diagnostics.<br>Diagnostic Test: Synovial Staphylococcus spp antigen panel<br>* One of the synovial fluid (joint fluid) tests that will be performed by the outside lab, CD Diagnostics.<br>Diagnostic Test: Synovial Candida spp antigen panel<br>* One of the synovial fluid (joint fluid) tests that will be performed by the outside lab, CD Diagnostics.<br>Diagnostic Test: Synovial Enterococcus faecalis assay<br>* One of the synovial fluid (joint fluid) tests that will be performed by the outside lab, CD Diagnostics.<br>Diagnostic Test: Synovial bacterial culture by BacT/Alert<br>* The synovial fluid (joint fluid) sent to CD Diagnostics for testing will also be cultured to see if any organisms grow.<br>Diagnostic Test: Synovial Cell count + differential (CBC)<br>* One of the synovial fluid (joint fluid) tests that will be performed by the outside lab, CD Diagnostics.<br>Diagnostic Test: Synovial Gram Stain<br>* This will be performed by CD Diagnostics if any organisms are present in the synovial fluid.<br>Diagnostic Test: Synovial Leukocyte Esterase Test Strips<br>* These test strips will be tested at the hospital where the patient is being seen, a few drops of synovial fluid will be used on the strip.<br>Diagnostic Test: Synovial PCR for Kingella kingae<br>* In participants < 8 years old, a sample of synovial fluid will be tested for Kingella kingae using PCR.<br>Diagnostic Test: Serum Cell count + differential (CBC)<br>* A blood test performed at the hospital.<br>Diagnostic Test: Serum erythrocyte sedimentation rate (ESR)<br>* A blood test performed at the hospital.<br>Diagnostic Test: Serum C-reactive Protein (CRP)<br>* A blood test performed at the hospital.<br>Diagnostic Test: Serum D-dimer<br>* A blood test performed at the hospital.<br>Diagnostic Test: Serum Procalcitonin<br>* A blood test performed at the hospital.<br>Diagnostic Test: Blood Cultures<br>* Blood will be cultured at the hospital to see if any organisms grow.<br>Diagnostic Test: Optional blood testing per standard of care (ASO, anti-strep, ANA, anti-DS-DNA, HLA-B27, RF, Lyme and other inflammatory/ rheumatologic markers )<br>* In patients with suspected inflammation/infection, there are other blood tests which may be standard of care and used for diagnosis.<br>|
| Active Comparator: Normative Control<br>Patient undergoing procedure unrelated to infection/inflammation | Diagnostic Test: Synovial Alpha-defensin assay<br>* One of the synovial fluid (joint fluid) tests that will be performed by the outside lab, CD Diagnostics.<br>Diagnostic Test: Synovial Neutrophil elastase assay<br>* One of the synovial fluid (joint fluid) tests that will be performed by the outside lab, CD Diagnostics.<br>Diagnostic Test: Synovial lactate assay<br>* Synovial Fluid (joint fluid) will be sent out to CD Diagnostics for this test.<br>Diagnostic Test: Synovial C-reactive Protein (CRP)<br>* One of the synovial fluid (joint fluid) tests that will be performed by the outside lab, CD Diagnostics.<br>Diagnostic Test: Synovial Staphylococcus spp antigen panel<br>* One of the synovial fluid (joint fluid) tests that will be performed by the outside lab, CD Diagnostics.<br>Diagnostic Test: Synovial Candida spp antigen panel<br>* One of the synovial fluid (joint fluid) tests that will be performed by the outside lab, CD Diagnostics.<br>Diagnostic Test: Synovial Enterococcus faecalis assay<br>* One of the synovial fluid (joint fluid) tests that will be performed by the outside lab, CD Diagnostics.<br>Diagnostic Test: Synovial bacterial culture by BacT/Alert<br>* The synovial fluid (joint fluid) sent to CD Diagnostics for testing will also be cultured to see if any organisms grow.<br>Diagnostic Test: Synovial Cell count + differential (CBC)<br>* One of the synovial fluid (joint fluid) tests that will be performed by the outside lab, CD Diagnostics.<br>Diagnostic Test: Synovial Gram Stain<br>* This will be performed by CD Diagnostics if any organisms are present in the synovial fluid.<br>Diagnostic Test: Synovial Leukocyte Esterase Test Strips<br>* These test strips will be tested at the hospital where the patient is being seen, a few drops of synovial fluid will be used on the strip.<br>Diagnostic Test: Synovial PCR for Kingella kingae<br>* In participants < 8 years old, a sample of synovial fluid will be tested for Kingella kingae using PCR.<br>Diagnostic Test: Serum Cell count + differential (CBC)<br>* A blood test performed at the hospital.<br>Diagnostic Test: Serum erythrocyte sedimentation rate (ESR)<br>* A blood test performed at the hospital.<br>Diagnostic Test: Serum C-reactive Protein (CRP)<br>* A blood test performed at the hospital.<br>Diagnostic Test: Serum D-dimer<br>* A blood test performed at the hospital.<br>Diagnostic Test: Serum Procalcitonin<br>* A blood test performed at the hospital.<br>Diagnostic Test: Blood Cultures<br>* Blood will be cultured at the hospital to see if any organisms grow.<br>Diagnostic Test: Optional blood testing per standard of care (ASO, anti-strep, ANA, anti-DS-DNA, HLA-B27, RF, Lyme and other inflammatory/ rheumatologic markers )<br>* In patients with suspected inflammation/infection, there are other blood tests which may be standard of care and used for diagnosis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitivity and specificity of experimental tests | Sensitivity and specificity have been selected as these are standard outcome tests when determining the utility of a diagnostic test. | Interim analysis at 2 years of study recruitment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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synovial biomarkers, alpha-defensin, diagnostics, pediatric