METAGENOS: Assessing the Performance of Shotgun Metagenomics in the Diagnosis of Complex Prosthetic Joint Infections
Study Details
Study Description
Brief Summary
Prosthetic joint infection (PJI) is one of the most serious and devastating complications of orthopaedic surgery, leading to a high risk of recurrence and disability, as well as increased mortality and management costs (Kurtz et al., 2012; Huang et al., 2020b). The significant increase in the number of prostheses fitted worldwide goes hand in hand with an increase in cases of infection (Kapadia et al., 2016; Kurtz et al., 2018).
Microbiological diagnosis of PJI is therefore an important issue in the orthopaedic management of patients, and must be as early and exhaustive as possible. A wide range of bacteria can be responsible for chronic PJI. Despite the optimisation of conventional culture approaches, culture of samples is negative in 5 to 30% of cases (Corvec et al., 2012; Tande and Patel, 2014). Improving diagnostic performance therefore requires the development of molecular technologies, including shotgun metagenomics, considered to be the 'microbiology of the future'. The sensitivity of this approach has been estimated at around 95% for the diagnosis of PJI (Cai et al., 2020; Fang et al., 2020; Huang et al., 2020a). However, the majority of these studies were performed on only one sample per patient, which is insufficient for the diagnosis of PJI according to international (Parvizi and Gehrke, 2014) and national (SPILF, 2009) consensus recommendations.
The multicentre METAGENOS study will assess the performance of shotgun metagenomics using four samples per patient, which is what makes it original.
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Detailed Description
Prosthetic joint infection (PJI) is one of the most serious and devastating complications of orthopaedic surgery, leading to a high risk of recurrence and disability, as well as increased mortality and management costs (Kurtz et al., 2012; Huang et al., 2020b). Despite improvements in antibiotic prophylaxis procedures and surgical asepsis measures, the significant increase in the number of prostheses fitted worldwide has been accompanied by an increase in the number of infections. The infection rate has been estimated at between 1% and 2% after hip and knee arthroplasty (Kapadia et al., 2016; Kurtz et al., 2018).
Appropriate diagnosis and medical and surgical management of PJI are therefore essential to preserve and/or restore adequate motor function, minimise the risk of complications and prevent excessive morbidity. The microbiological diagnosis of PJI must be as early and exhaustive as possible in order to introduce rapid and effective antibiotic therapy and avoid the development of a biofilm (gangue around the material) or chronic infection (quiescent bacteria).
However, the diagnosis of PJI can be difficult to make in certain situations. Learned societies have established a definition of PJI and defined diagnostic scores combining clinical, biological, anatomopathological and cytological criteria. An initial definition was approved in 2011 by the Musculoskeletal Infection Society (MSIS) (Parvizi et al., 2011). This definition was modified and subject to an international consensus review in 2013 (Parvizi and Gehrke, 2014) (MSIS diagnostic score). In 2018, an international consensus meeting reviewed and adapted the MSIS score (Parvizi et al., 2018). This adapted score is more appropriate to current Medical Biology practices and to the non-accessibility of all diagnostic tests in laboratories (leucocyte esterase, alpha-defensin, ...).
In this definition of PJI, the positivity of 2 intra-operative samples to the same bacterial species is considered to be a major criterion. A wide range of bacteria can cause PJI: aerobic/anaerobic/intracellular/mycobacterial; somePJI can be polymicrobial. It is therefore essential to accurately identify these pathogens in order to administer appropriate antibiotic therapy and avoid chronicity of infection (Tande and Patel, 2014). Despite the optimisation of practices, culture of samples is negative in 5 to 30% of cases, despite the presence of diagnostic criteria for PJI (Corvec et al., 2012; Tande and Patel, 2014). The most common causes are a lack of culture sensitivity, prior antibiotic administration and/or the presence of difficult or slow-growing pathogens. In these cases, intravenous broad-spectrum antibiotic therapy is administered, resulting in additional management costs (Wang et al., 2020), the occurrence of adverse treatment effects (Triffault-Fillit et al., 2018) and the risk of acquiring resistance or intestinal dysbiosis (Levast et al., 2021).
In this context, "classic" molecular techniques are routinely used to overcome the limitations of culture for microbiological detection: bacterial-specific (including PCR targeting Staphylococcus aureus) or non-specific (bacterial universal PCR targeting the gene encoding 16S rDNA) (Figure 1). The latter approach was previously evaluated by the CRIOGO group (3Centre de Référence en Infections Ostéo-articulaires du Grand Ouest") with detection performance deemed disappointing in the context of PJI (sensitivity of 73.3%, specificity of 95.5%) (Bémer et al., 2014). Innovative molecular techniques for Next Generation Sequencing (NGS) are being developed (Goswami et al., 2021), including shotgun metagenomics (sequencing of all the genetic material in a sample). Recent studies have evaluated the sensitivity of shotgun metagenomics in PJI, estimated at between 90.2% and 93.0% compared with bacterial culture (Street et al., 2017; Ivy et al., 2018) and at around 95% compared with the MSIS diagnostic score (Cai et al., 2020; Fang et al., 2020; Huang et al., 2020a).
However, these few recent studies evaluating shotgun metagenomics have only been carried out on a single sample per patient, which is insufficient according to the recommendations of the international (Parvizi and Gehrke, 2014) and national (SPILF, 2009) consensuses on the management of PJI. In fact, four or even five intraoperative samples must be taken and analysed in microbiology to make the diagnosis of PJI. This high number of samples improves the sensitivity and completeness of bacterial detection and facilitates the interpretation of positive cultures for potentially contaminating skin bacteria (coagulase-negative Staphylococci, Cutibacterium acnes, etc.). To date, only one study has assessed the performance of shotgun metagenomics applied to several intraoperative samples per patient (d'Humières et al., 2022). Further studies are therefore needed to refine the performance of shotgun metagenomics in the context of PJI and to better assess the contribution of this costly technique, which requires considerable expertise to perform and interpret.
The setting up of a prospective, multicentre study in centres associated with the CRIOGO will make it possible to assess the performance of shotgun metagenomics in the management of chronic PJI. The performance of shotgun metagenomics will be assessed on the basis of four different samples per patient, in six centers specialising in the diagnosis of PJI, which makes the METAGENOS study unique compared with other studies. At the end of the project, the aim is to define the indications for using this innovative technique and to harmonise future regional practices.
Study Design
Outcome Measures
Primary Outcome Measures
- PJI diagnosis [from samples taken during surgery. Shotgun metagenomics will be performed at the end of the inclusion of all patients, i.e. one year after the start of the study]
PJI diagnosis (positive/negative) obtained by shotgun metagenomics and by the adapted MSIS criteria (gold standard)MSIS diagnostic score (gold standard).
Secondary Outcome Measures
- PJI diagnosis (positive/negative) obtained by shotgun metagenomics and by culture [from samples taken during surgery. Shotgun metagenomics will be performed at the end of the inclusion of all patients, i.e. one year after the start of the study]
- Presence/absence of a bacterial species (by culture and/or shotgun metagenomics) in a patient sample considered infected according to the appropriate MSIS score [: from samples taken during surgery. Shotgun metagenomics will be performed at the end of the inclusion of all patients, i.e. one year after the start of the study]
- Resistance/sensitivity to antibiotics tested [immediate post-operative period (usually within 3-15 days following surgery)]
- PJI diagnosis (positive/negative) obtained by shotgun metagenomics and by culture in case of presence/absence of antibiotic therapy the month before surgery [from samples taken during surgery. Shotgun metagenomics will be performed at the end of the inclusion of all patients, i.e. one year after the start of the study]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Male or female ≥ 18 years
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Patients being considered for surgery for suspected chronic PJI (time between joint replacement surgery and patient inclusion > 3 months)
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Social security affiliation
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No objection to participating in the study
Exclusion Criteria:
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Suspicion or documentation (positive blood cultures) of acute bacteremia at time of inclusion
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Patients under guardianship or trusteeship
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Pregnant or breastfeeding woman
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Patient deprived of liberty by legal or administrative decision
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Patients in psychiatric care
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
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| 1 | Brest university hospital | Brest | France | 29200 |
Sponsors and Collaborators
- University Hospital, Brest
Investigators
- Principal Investigator: Rachel CHENOUARD, Dr, Angers HU
- Principal Investigator: Stéphane CORVEC, PhD, Nantes HU
- Principal Investigator: Chloé PLOUZEAU, Dr, Poitier HU
- Principal Investigator: Vincent CATTOIR, PhD, Rennes HU
- Principal Investigator: Marie-Frédérique LARTIGUE, Tours HU
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 29BRC22.0208