Culture-negative periprosthetic joint infection: an umbrella review of prevalence, diagnostic strategies, treatment, and methodological limitations

Abstract. Purpose: Culture-negative periprosthetic joint infection (CN-PJI) poses a significant clinical challenge because antimicrobial selection relies on guesswork rather than robust clinical data. This umbrella review summarizes the prevalence of CN-PJI, diagnostic strategies (including molecular assays), treatment approaches, and outcomes. Methods: We conducted an umbrella review of published systematic reviews and meta-analyses on CN-PJI in adult hip and/or knee arthroplasties. Searches of major bibliographic databases were conducted in December 2025; two reviewers screened studies and extracted data on prevalence, reported risk factors, diagnostic criteria, use of molecular tests, specimen matrix (synovial fluid, periprosthetic tissue, and/or sonication fluid), surgical strategy, antimicrobial selection, and clinical outcomes (infection control or failure). Methodological quality was assessed with AMSTAR 2. Results: Nine reviews were included. Reported CN-PJI prevalence varied widely (11.0 %–63.6 %), reflecting substantial heterogeneity in study populations, diagnostic definitions, microbiological workflows, and pre-analytical factors. Prior antibiotic exposure before sampling was repeatedly identified as an important contributor to culture negativity. Molecular diagnostics, predominantly NGS (next-generation sequencing)-based approaches, were evaluated in five out of nine reviews, with highly variable organism detection rates depending on assay type, specimen source, and study context. Where meta-analytic estimates were available, pooled sensitivity ranged from 0.81 to 0.93, and pooled specificity ranged from 0.92 to 0.97. Treatment strategies and outcome definitions were inconsistently reported across reviews; when extractable, two-stage exchange was the most frequently described surgical strategy. Conclusions: CN-PJI remains common and variable across settings. Molecular diagnostics improve pathogen detection but do not eliminate false negatives. Reported failure rates varied across reviews and appeared to be clinically relevant, although differences in outcome definitions, treatment protocols, and follow-up duration limited direct comparison.