Identification of Infections in Hip Arthroplasty Loosening.

• ClinicalTrials.gov Identifier: NCT04773054
• Recruitment Status: Not yet recruiting
• First Posted: February 26, 2021
• Last Update Posted: February 26, 2021
• Sponsor: Istituto Ortopedico Rizzoli
• Information provided by (Responsible Party): Nicola Baldini, Istituto Ortopedico Rizzoli

Study Description

Brief Summary:

Recent data showed that the rate of periprosthetic infections in patients undergoing a hip arthroplasty revision for aseptic loosening is higher than what can be ascertained with conventional methods.

The study aims to assess the adequacy of next-generation sequencing of 16s ribosomal ribonucleic acid (rRNA) gene amplicons for identifying occult infections and improving the diagnostic workup. Moreover, additional testing has been planned in order to increase knowledge on the etiopathogenesis of infection.

Condition or disease	Intervention/treatment
Loosening, Prosthesis	Diagnostic Test: Microbiological analysis of periprosthetic tissue; Diagnostic Test: Histological analysis of periprosthetic tissue; Other: Characterization of tissue microbiota; Other: Characterization of gut microbiota; Other: Characterization of oral microbiota

Detailed Description:

Periprosthetic infection following hip arthroplasty is one of the main causes of implant failure that leads to multiple surgical interventions, prolonged hospitalization, and higher complication rate and mortality.

Recent data prove that the rate of periprosthetic infections is higher than what can be ascertained with conventional techniques and highlight as analytical methods that allow an early and accurate diagnosis may help clinicians identify effective treatment and mitigate the devastating consequences.

New technologies based on culture-independent assays, i.e., the next-generation sequencing (NGS) of 16s rRNA gene amplicons, have entered medical microbiology as an alternative to traditional bacterial identification methods. NGS has been proven to detect microorganisms in culture-negative periprosthetic joint infection and seems to be a valid adjunct in identifying causative pathogens in samples from patients undergoing a hip arthroplasty revision for aseptic loosening.

The microbiota profiling using NGS may also help identify patients prone to develop infections. In predisposing clinical conditions, i.e., obesity and diabetes, the metabolic and nutritional alterations modify the composition and the immunomodulatory properties of intestinal microbiota. Saprophytic, non-pathogenic microorganisms usually found in the intestine and oral cavity can be transferred to other areas becoming a potential source of periprosthetic infection.

Additionally, microorganisms may live in the periprosthetic microenvironment without giving signs of overt infection. However, bacterial products, i.e., "microbe-associated molecular patterns" (MAMPs) or "pathogen-associated molecular patterns "(PAMPs), adhere to the implant surface or the wear particles and may elicit a local inflammatory response characterized by the presence of cells capable of producing cytokines that promote osteoclastogenesis, periprosthetic resorption and consequent loosening of the implant.

In summary, the current knowledge suggests that the hip arthroplasty loosening, classified as aseptic according to the preoperative clinical and laboratory investigations, could be directly or indirectly associated with infectious pathogenesis even if the microbial cultures on periprosthetic tissues are negative.

The investigators designed a small-scale study to assess the adequacy of NGS for identifying occult infections and improving the diagnostic workup in patients undergoing a hip arthroplasty revision for aseptic loosening. Moreover, additional testing has been planned to enhance knowledge on the role of unusual or difficult-to-cultivate microorganisms in the etiopathogenesis of implant failure.

Study Design

• Study Type: Observational
• Estimated Enrollment: 6 participants
• Observational Model: Cohort
• Time Perspective: Cross-Sectional
• Official Title: Application of Advanced High-sensitivity Technologies for Identifying Infections in Patients With Aseptic Loosening of Hip Arthroplasty.
• Estimated Study Start Date: June 1, 2021
• Estimated Primary Completion Date: December 31, 2021
• Estimated Study Completion Date: December 31, 2021

Groups and Cohorts

Intervention Details:

• Diagnostic Test: Microbiological analysis of periprosthetic tissue
  Microbiological culture of tissue samples collected intraoperatively from the newly-formed joint capsule, between prosthesis stem and femoral bone, and between the acetabular prosthesis and iliac bone.
• Diagnostic Test: Histological analysis of periprosthetic tissue
  Histological assessment of cellular reactivity associated with the infection on tissue samples collected intraoperatively from the newly-formed joint capsule, between prosthesis stem and femoral bone, and between the acetabular prosthesis and iliac bone.
• Other: Characterization of tissue microbiota
  Assessment of tissue microbiome composition using the "next-generation sequencing" of DNA extracted from samples collected intraoperatively from the newly-formed joint capsule, between prosthesis stem and femoral bone, and between the acetabular prosthesis and iliac bone.
• Other: Characterization of gut microbiota
  Assessment of gut microbiome composition using the "next-generation sequencing" of DNA extracted from stool samples.
• Other: Characterization of oral microbiota
  Assessment of oral microbiome composition using the "next-generation sequencing" of DNA extracted from a buccal swab obtained by rubbing the mucosa of cheeks, gingivae, and palate.

Outcome Measures

Primary Outcome Measures :

1. Identification of microorganisms by microbiological cultures (number of patients with positive microbiological culture). [ Time Frame: Within two week of admission ]
   Tissue samples will be sent for microbiological cultures and treated for the isolation of aerobic and anaerobic pathogens. The existence of two positive cultures will be considered to be diagnostic for periprosthetic infection; a single positive culture may occur from a contaminating organism and will be considered in conjunction with other markers of infection, including histological features.
2. Number of patients with histological features of periprosthetic infection [ Time Frame: Within two week of admission ]
   The presence of a periprosthetic infection will be established according to the number of polymorphonuclear cells (PMN) counted in ten high-power fields (HPF) (400 × magnification, field diameter 0.54 mm)- Uninfected: 0-5 PMNs in 10 HPFs; borderline, but probably not infected: 6-10 PMNs for 10 HPF; borderline, but probably infected: >10 PMNs for 10 HPFs (but not > 5 PMNs in a single HPF); infected > 5 for HPF.
3. Identification of microorganisms by next-generation sequencing (NGS) (number of patients with positive NGS). [ Time Frame: Through study completion, an average of 6 months. ]
   The NGS will be employed to characterize the overall microbiome profile in tissue samples, and bioinformatics used to determine the taxonomic and phylogenetic affiliation, alpha-diversity (ecological diversity of a single sample according to the number of different taxa and their relative abundances), and beta-diversity (differences in microbial community composition between samples).

Secondary Outcome Measures :

1. Characterization of taxonomic and phylogenetic affiliation of gut microbiota [ Time Frame: Through study completion, an average of 6 months. ]
   The NGS technology will be employed to characterize the overall microbiome profile in stool samples, and bioinformatics used to determine the taxonomic and phylogenetic affiliation.
2. Characterization of alpha-diversity and beta-diversity of gut microbiota [ Time Frame: Through study completion, an average of 6 months. ]
   The NGS technology will be employed to characterize the overall microbiome profile in stool samples, and bioinformatics used to determine alpha-diversity (ecological diversity of a single sample according to the number of different taxa and their relative abundances) and beta-diversity (differences in microbial community composition between samples).
3. Characterization of taxonomic and phylogenetic affiliation of oral microbiota [ Time Frame: Through study completion, an average of 6 months. ]
   The NGS technology will be employed to characterize the overall microbiome profile in oral swab, and bioinformatics used to determine the taxonomic and phylogenetic affiliation.
4. Characterization of alpha-diversity and beta-diversity of oral microbiota [ Time Frame: Through study completion, an average of 6 months. ]
   The NGS technology will be employed to characterize the overall microbiome profile in oral swab, and bioinformatics used to determine alpha-diversity (ecological diversity of a single sample according to the number of different taxa and their relative abundances) and beta-diversity (differences in microbial community composition between samples
5. Number of patients with inflammatory cellular reactivity related to bacterial products. [ Time Frame: Through study completion, an average of 6 months. ]
   The inflammatory cellular reactivity proved by the presence of activated macrophages and Toll-like-receptor positive cells.

Biospecimen Retention:   Samples With DNA

tissue, oral mucosa, stools

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Hospitalized patients admitted at the 1st Orthopaedic and Traumatology Unit of the Istituto Ortopedico Rizzoli (Bologna, Italy).

Criteria

Inclusion Criteria:

Hip arthroplasty revision for aseptic loosening, diagnosis determined as probable according to the following criteria:

• pain and/or functional impairment;
• radiographic signs of osteolysis following wear of the implant components, or cortical reaction, or periprosthetic bone resorption;
• negative evaluation by the infectious disease specialist.

Exclusion Criteria:

• presence of a sinus tract communicating with the arthroplasty;
• bacteria isolation from aspirates or blood cultures performed preoperatively;
• serum C-reactive protein higher than 10 mg/L;
• recurrent implant dislocations;
• prosthetic fracture;
• medical history for septic arthritis, osteomyelitis;
• infections in anatomic areas other than hip;
• antibiotic therapy in the 15 days prior to surgery (with the exception of preoperative antibiotic prophylaxis);
• chronic treatment with immunosuppressive drugs;
• medical contraindications for executing sample collection.

Contacts and Locations

Contacts

Contact: Giorgia Borciani, M.Sc.; +39 0516366748; giorgia.borciani@ior.it

Locations

Italy

Istituto Ortopedico Rizzoli

Bologna, Italy, 40136

Contact: Nicola Baldini, M.D. +39 051 6366560 nicola.baldini@ior.it

Sub-Investigator: Alberto C Di Martino, M.D.

Sub-Investigator: Giorgia Borciani, M.Sc.

Sponsors and Collaborators

Istituto Ortopedico Rizzoli

Investigators

• Principal Investigator: Nicola Baldini; University of Bologna, Istituto Ortopedico Rizzoli

More Information

Publications:

Goswami K, Parvizi J. Culture-negative periprosthetic joint infection: is there a diagnostic role for next-generation sequencing? Expert Rev Mol Diagn. 2020 Mar;20(3):269-272. doi: 10.1080/14737159.2020.1707080. Epub 2019 Dec 24.

Tarabichi M, Shohat N, Goswami K, Alvand A, Silibovsky R, Belden K, Parvizi J. Diagnosis of Periprosthetic Joint Infection: The Potential of Next-Generation Sequencing. J Bone Joint Surg Am. 2018 Jan 17;100(2):147-154. doi: 10.2106/JBJS.17.00434.

Pajarinen J, Jamsen E, Konttinen YT, Goodman SB. Innate immune reactions in septic and aseptic osteolysis around hip implants. J Long Term Eff Med Implants. 2014;24(4):283-96.

• Responsible Party: Nicola Baldini, Professor, Director of the Research Innovation & Technology Department, Istituto Ortopedico Rizzoli
• ClinicalTrials.gov Identifier: NCT04773054
• Other Study ID Numbers: TAS-ASEPTIC
• First Posted: February 26, 2021
• Last Update Posted: February 26, 2021
• Last Verified: February 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Nicola Baldini, Istituto Ortopedico Rizzoli:

Hip arthroplasty; Infection; Microbiota; Next Generation Sequencing

Additional relevant MeSH terms:

Infections; Prosthesis Failure; Postoperative Complications; Pathologic Processes