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These metrics only detect actively septic joint replacements and may miss detecting biofilm-embedded bacteria that suppress neutrophil signaling and persist as a \u201chidden\u201d subset of implants with a dormant infection. We hypothesize that previously infected joint replacements have a high prevalence of dormant infection that can be distinguished from aseptic revision joint replacements (replaced for instability, loosening, wear, and fracture) by the persistent inflammatory response within synovial fluid and\/or circulating plasma, and that detecting a dormant infection indicates an increased risk of infection relapse.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This is an observational cohort study using synovial fluid and plasma proteomics of 96 immuno-oncology mediators (Olink Proteomics, Sweden) with three-year clinical follow-up from a single academic medical center (Stanford University, USA). Thirty patients undergoing revision joint replacement: culture-positive actively septic joint replacements (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20097), aseptic revision joint replacements (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200912), and re-implantations of joint replacements previously classified as infection-free by 2018 Musculoskeletal Infection Society (MSIS) criteria (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200911). Differential expression, unsupervised clustering, Euclidean distance mapping, principal-component analysis, and gene-set variation analysis were used to define the inflammatory signature of dormant infection present in joint replacements with a prior infection. The identified biomarkers of dormant infection were correlated with the three-year incidence of infection relapse.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Eight of eleven MSIS-cleared joint replacements (73%) clustered with culture-positive active infections despite normal ESR, CRP, and scant synovial neutrophils revealing the synovial inflammatory signature of dormant infection. A nine-analyte synovial panel consisting of PDGF-B, CXCL5, CXCL11, MCP-2 (CCL8), ANGPT1, TIE2, EGF, NOS3, and Gal-1 distinguished dormant infection from truly aseptic cases with 100% specificity and positive predictive value (sensitivity 22%, negative predictive value 74%). Synovial CXCL5 over-expression was a universal hallmark of both active and dormant infection, whereas matched plasma profiles showed no discriminatory power for all immuno-oncology mediators tested. Dormant infections exhibited downregulation of granulocyte activation and T-cell proliferation pathways (FDR\u2009&lt;\u20090.001), mirroring immune evasion programs seen in cancer microenvironments. After a mean of 3 years follow-up, infection relapse occurred in 22% of the biomarker-positive dormant infections, but relapse did not occur in any of the biomarker-negative aseptic cases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Profiling of the persistent inflammatory response within the synovial fluid of two-stage re-implantations classified as \u201cinfection-free\u201d by the MSIS criteria unmasked a clinically silent reservoir of biofilm-embedded bacteria that suppress clinical diagnostic criteria of active infection and define the novel clinical state of dormant infection. We used that profile to identify a novel culture-free panel of rule-out biomarkers for determining which re-implantations were safe from infection relapse. These findings challenge the use of conventional clinical diagnostic criteria, which are over-reliant on acute phase reactants and neutrophil recruitment, and creates a new prognostic clinical paradigm that now includes a future with precision, immune-guided management of dormant infections likely present in many implant-associated infections.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-025-07425-y","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T10:51:42Z","timestamp":1765536702000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The presence of persistent synovial inflammation after \u201cEradication\u201d unmasks the \u201cUnseen\u201d dormant state of infection allowing the prediction of infection free survival in total joint replacements"],"prefix":"10.1186","volume":"23","author":[{"given":"Robert","family":"Manasherob","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shay I.","family":"Warren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Flanagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prerna","family":"Arora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyong","family":"Heo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon K. 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The Stanford Office of Technology and Licensing has submitted intellectual property regarding the diagnosis of implant-associated dormant infections based on these proteomic and functional findings (Docket #24\u2013143 and Docket #24\u2013240, US Patent Pending #63\/677,070, PCT-US25\/039107).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1392"}}