Periprosthetic Joint Infections: Diagnostic Accuracy and Cost-effectiveness Analysis of Serum and Synovial Markers (DECISION)

March 14, 2024 updated by: Istituto Ortopedico Rizzoli

Diagnostic Accuracy and Cost-effectiveness Analysis of Serum and Synovial Fluid Markers for the Diagnosis of Periprosthetic Hip and Knee Joint Infections

Total joint replacement (TJR) is an increasing effective procedure in orthopedics. However, TJR failure due to aseptic or septic loosening remains an important problem, often due to predisposing factors of the patient, which determine the need to perform a revision surgery. In light of the recent conclusions emerged on the still open problems concerning the diagnostic accuracy of serum and synovial fluid markers in the diagnosis of peri-prosthetic joint infection (PJI), the project aims at evaluating the diagnostic accuracy and cost-effectiveness of the combination of serum and/or synovial markers in the diagnosis of PJI. Through a diagnostic clinical study on patients hospitalized for revision surgery the project would provide evidences on the potentiality of the combination of some markers in accelerating the PJI diagnosis for the best selection of surgical strategy, choosing the suitable cutoff thresholds to mitigate the effect of some factors on markers' discriminatory capability.

Study Overview

Status

Recruiting

Conditions

Detailed Description

Total joint arthroplasties (TJA) are constantly increasing in older and multi-morbid patients; knee and hip joints are the most frequently treated due to high incidence of osteoarthritis in these joints. The indication to TJA is now extended to younger and active patients with high functional demands and longer life expectancy. Because of these, an increase in revision surgeries and a PJI risk is also expected. The type of revision surgery (RS) approach and of antimicrobial treatments is based on the presence or absence of infection: one-stage revision with maintenance/replacement of prosthesis in combination with debridement and irrigation (aseptic RS); and two-stage revision with prosthesis removal, debridement and irrigation, the possible use of a temporary spacer, and the potential reimplantation after weeks or months (septic RS).

Today, PJI remains an important dangerous and devastating complication; it has been reported for hip and knee joints an incidence of 0.2-1.5%, prosthesis failure of 15-25%, revision success rate of 80-95% and annual cost per infection of $20,000-$40,000. The timely and most accurate diagnosis is essential for the correct treatment of PJI as patients undergoing revision need extensive physical, psychological and economic supports. Following the definition and standardization of diagnostic major and minor criteria for PJI by the Musculoskeletal Infection Society (MSIS) an improvement in the diagnosis and treatment of PJI was observed. Recently, the International Consensus Group on PJI revised MSIS criteria defining that patients should be considered to have PJI in the presence of one of the major criteria or three of five minor criteria. Finally, an evidence-based and validated criteria for hip and knee PJI definition to diagnose patients within the preoperative period was published in 2018. Patients with an aggregate score of more than or equal to 6 are considered infected, while a 2-5 score requires the inclusion of intraoperative findings (positive histology, purulence and single positive culture) for confirming or refuting the diagnosis. A 4-5 score is inconclusive, and a score of less than or equal to 3 is not infected.

During the last International Consensus Meeting on Musculoskeletal Infection, various questions on PJI were discussed and among them the working groups (WG) provided recommendations based on limited (4 - due to small numbers) and moderate (12 and 19) levels of evidence: WG4, on which patient-specific factors influence the thresholds for serum and synovial markers in acute and chronic PJI; WG12, on which serum tests have the best diagnostic accuracy for PJI and if the combination of any number of tests increase the diagnostic accuracy; WG19, if the profile of organisms causing surgical site infection or PJI following orthopaedic procedures changed over recent years. The WG4 highlighted that no inflammatory arthritis (IA)-specific factors are known to influence the thresholds for serum and synovial markers in PJIs. It appears that in IA patients there are overlaps in values of synovial markers such as alphadefensin, white blood cell count (sWBC) and C-reactive protein (CRP), limiting their usefulness in differentiating septic from aseptic patients. The WG12 stated that it is evident that diagnosis of PJI cannot be based solely on serological tests and that CRP and erythrocyte sedimentation rate (ESR) are well-researched screening tests and have high sensitivity when used alone. However, the combination of serological tests has shown to improve diagnostic accuracy, but the identification of the optimal combination needs further investigations. Finally, the WG19 recommended to perform further investigations regarding the profile of microorganism with next generation sequencing (NGS), as it may confer significant antibiotic selection implications.

Among pre-operative test on synovial fluid, alpha-defensin showed the highest degree of accuracy in the diagnosis of PJI when measured by laboratory-based immunoassay rather than lateral flow test, suggesting that care must be taken with interpretation of the lateral flow test when relying on its results for the intra-operative diagnosis. Synovial fluid could be tested for other newly markers such calprotectin and cathelicidin LL-37, whose sensitivity and specifity are to be defined or for microbiological tests.

Synovial fluid analysis for WBC and %PMN has high sensitivity and specificity in diagnosing PJI, and it represents an easy and widespread available method. Our meta-analysis evaluated: 1) accuracy in terms of sensitivity and specificity of synovial fluid WBC and %PMN tests in the diagnosis of PJI after total knee (TKA) and hip (THA) arthroplasty; 2) which test yielded superior test performance; and 3) the influence of study characteristics such as anatomic site and threshold value on the diagnostic accuracy of these tests. The meta-analysis results revealed that both synovial fluid WBC and %PMN have a high specificity and sensitivity in detecting PJI, and no clear superiority of one test over the other exists. In addition, an anatomic site effect was demonstrated on sensitivity of synovial fluid %PMN, suggesting that cutoff thresholds should be identified separately for TKA and THA. The differences in bearing surfaces and the possibility of fretting corrosion in dual taper stem designs might substantially alter automated synovial fluid analysis in THA compared to TKA.

The aim of the project is to evaluate the diagnostic accuracy and cost-effectiveness of the combination of serum and/or synovial markers in the pre- or intraoperative (lateral flow test)/post- diagnosis of PJI. To such purpose a clinical diagnostic study on patients hospitalized for revision surgery based on the guidelines of MSIS will be carried out; the combinations of two or more markers with the highest diagnostic accuracies will be identified and evaluated in term of cost-effectiveness towards individual markers whose thresholds are based on the MSIS 2013 ICM. The significance of this research is to provide evidences on the potentiality of the combination of some markers in accelerating the PJI diagnosis for the best selection of surgical strategy to be followed. A prompt diagnosis and recognition of the etiological agent are crucial to define the appropriate antimicrobial therapy and to reduce to a minimum the cases of erroneous diagnosis and of consequent erroneous surgical conduct, with the need for subsequent re-operations, and multiplication of risk for patients and of costs for the health care system.

Study Type

Observational

Enrollment (Estimated)

270

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Bologna, Italy, 40134
        • Recruiting
        • IRCCS Istituto Ortopedico Rizzoli
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

A maximum number of n = 270 patients who will have to undergo hip or knee prosthetic revision surgery will be enrolled, of which n = 54 for late infection ascertained by previous microbiological analyzes, and n = 216 for prosthetic failure not from infection. Patients will be enrolled in the clinical study only after having signed and dated personally or by the patient's legal representative, the written informed consent. Therefore, enrollment in the study (exclusively of a diagnostic type) will not in any case influence the established diagnostic and therapeutic path.

Description

Inclusion Criteria:

  • Patients requiring hip or knee replacement surgery: i) for 'late' joint prosthesis infection, present for at least 90 days from the date of the arthroplasty (first surgical phase); II) for non-infectious causes (mobilization, wear, instability, misalignment, adverse reactions to local tissues or other aseptic causes), also present for at least 90 days, and which have not had other re-operations on the same joint, and which will be a one-step review;
  • Previous clinical data and laboratory and radiological examinations available.

Exclusion Criteria:

  • Patients affected by 'early' joint prosthesis infection, with clinical symptom latency of less than 90 days (in this specific subset of patients there is in fact still considerable heterogeneity and little consensus about the diagnostic levels of white blood cell count and percentage of neutrophils).
  • Patients suffering from joint prosthesis infection involving joints other than the hip or knee.
  • Severe cognitive impairment or psychiatric disorders;
  • Pregnant women.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Only
  • Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
White blood cell count (WBC, cells/μL)
Time Frame: 7 days
7 days
Erythrocyte sedimentation rate (ESR, mm/hour)
Time Frame: 7 days
7 days
C-reactive Protein (CRP, mg/L)
Time Frame: 7 days
7 days
D-dimer (ng/ml)
Time Frame: 7 days
7 days
IL-6 (pg/ml)
Time Frame: 7 days
7 days
Procalcitonin (ng/ml)
Time Frame: 2 months
2 months
Soluble Intercellular Adhesion Molecule-1 (sICAM-1, ng/L)
Time Frame: 7 days
7 days
Synovial WBC (sWBC, cells/μL)
Time Frame: 7 days
7 days
Percentage of polymorphonucleates (%PMM, %) in synovial fluid
Time Frame: 7 days
7 days
Synovial C-reactive Protein (sCRP, mg/L)
Time Frame: 7 days
7 days
Synovial alpha-defensin (positive or negative)
Time Frame: 7 days
7 days
Synovial leukocyte esterase (positive or negative)
Time Frame: 7 days
7 days
Synovial IL-6 (pg/ml)
Time Frame: 7 days
7 days
Synovial cathelicidin LL-37 (μg/ml)
Time Frame: 7 days
7 days
Synovial calprotectin (ng/ml)
Time Frame: 7 days
7 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum and synovial biomarkers cut-off for prosthetic joint infections
Time Frame: 2 months
Test various cut-off values for selected serum and synovial biomarkers for diagnosing PJI.
2 months
Assessment of antimicrobial resistances of isolated microrganisms
Time Frame: 2 months
Bacterial gene sequencing to indentify antimicrobial resistance by Ion AmpliSeqTM Antimicrobial Resistance (AMR) Research Panel.
2 months
Assessment of biofilm formation capability of isolated microrganisms
Time Frame: 2 months
Measure the level of cyclic dimeric bis- (3'-5 ') - guanosine monophosphate (c-di-GMP) which influences biofilm formation by proteomic analysis (MALDI-TOF).
2 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Istituto Ortopedico Rizzoli

Collaborators

IRCCS Azienda Ospedaliero-Universitaria di Bologna

Investigators

  • Principal Investigator: Gianluca Giavaresi, MD, Istituto Ortopedico Rizzoli

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 1, 2022

Primary Completion (Estimated)

April 30, 2025

Study Completion (Estimated)

May 31, 2025

Study Registration Dates

First Submitted

April 8, 2021

First Submitted That Met QC Criteria

April 22, 2021

First Posted (Actual)

April 26, 2021

Study Record Updates

Last Update Posted (Actual)

March 15, 2024

Last Update Submitted That Met QC Criteria

March 14, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 37/2021/Sper/IOR

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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