Goswami, Karan; (2025) The role of metagenomic sequencing for the identification of organism(s) in the setting of periprosthetic joint infection. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

INTRODUCTION: Periprosthetic joint infection (PJI) is a devastating complication after total joint arthroplasty, with culture-negative infections presenting a particular diagnostic and therapeutic challenge. Next generation sequencing (NGS) technologies have emerged as a promising novel tool for pathogen detection in the broader non-orthopaedic literature. This thesis systematically evaluates the potential clinical utility of NGS for organism identification and management of PJI. METHODS: The thesis employs a mixed-methods approach, incorporating a series of prospective observational studies, multicentre investigations, as well as observer-blinded analyses, to assess the performance of NGS from clinical samples. Comparative analyses between NGS and conventional culture were performed. Additional work extended to characterization of the native hip and knee joint microbiota, comparisons between sequencing modalities and longitudinal patient outcome analysis. RESULTS: NGS demonstrated higher sensitivity for pathogen detection compared to culture, and was able to identify organisms in the majority of culture-negative PJI cases. NGS also revealed polymicrobial profiles and antimicrobial resistance genes not routinely captured by culture. However, high rates of microbial DNA detection in presumed aseptic cases and even in primary osteoarthritic joints underscore concerns regarding specific and clinical interpretation of these findings. Longitudinal follow-up studies found that organisms detected by NGS at index surgery often correlated with subsequent treatment failures. DISCUSSION: The findings of this dissertation highlight the potential of NGS as an adjunctive diagnostic tool for the identification of organisms in culture-negative PJI. While the potential for integration of NGS into the diagnostic work-up of PJI marks an innovative development, further investigation is required since the clinical significance of these polymicrobial findings and their role in guiding antimicrobial management remain uncertain. Additional studies are necessary to validate clinically significant thresholds and optimize reporting frameworks before NGS can be integrated into evidence-based management of PJI.

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