{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T09:52:03Z","timestamp":1784627523382,"version":"3.55.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T00:00:00Z","timestamp":1689552000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Identifying novel biomarkers that are both specific and sensitive to periprosthetic joint infection (PJI) has the potential to improve diagnostic accuracy and ultimately enhance patient outcomes. Therefore, the aim of this systematic review is to identify and evaluate the effectiveness of novel biomarkers for the diagnosis of PJI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We searched the MEDLINE, EMBASE, PubMed, and Cochrane Library databases from January 1, 2018, to September 30, 2022, using the search terms \u201cperiprosthetic joint infection,\u201d \u201cprosthetic joint infection,\u201d or \u201cperiprosthetic infection\u201d as the diagnosis of interest and the target index, combined with the term \u201cmarker.\u201d We excluded articles that mentioned established biomarkers such as CRP, ESR, Interleukin 6, Alpha defensin, PCT (procalcitonin), and LC (leucocyte cell count). We used the MSIS, ICM, or EBJS criteria for PJI as the reference standard during quality assessment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We collected 19 studies that analyzed fourteen different novel biomarkers. Proteins were the most commonly analyzed biomarkers (nine studies), followed by molecules (three studies), exosomes (two studies), DNA (two studies), interleukins (one study), and lysosomes (one study). Calprotectin was a frequently analyzed and promising marker. In the scenario where the threshold was set at \u226550-mg\/mL, the calprotectin point-of-care (POC) performance showed a high sensitivity of 98.1% and a specificity of 95.7%.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>None of the analyzed biomarkers demonstrated outstanding performance compared to the established parameters used for standardized treatment based on established PJI definitions. Further studies are needed to determine the benefit and usefulness of implementing new biomarkers in diagnostic PJI settings.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2023.1210345","type":"journal-article","created":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T13:27:40Z","timestamp":1689600460000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":33,"title":["Novel diagnostic markers for periprosthetic joint infection: a systematic review"],"prefix":"10.3389","volume":"13","author":[{"given":"Melanie","family":"Schindler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nike","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guenther","family":"Maderbacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene K.","family":"Sigmund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Alt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Rupp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3050","DOI":"10.1007\/s00167-016-4303-y","article-title":"EKA survey: diagnosis of prosthetic knee joint infection","volume":"24","author":"Ahmad","year":"2016","journal-title":"Knee Surg. Sports Traumatol Arthrosc"},{"key":"B2","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1016\/j.ajic.2010.03.017","article-title":"Patients' experiences of acquiring a deep surgical site infection: an interview study","volume":"38","author":"Andersson","year":"2010","journal-title":"Am. J. Infect. Control"},{"key":"B3","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1007\/s00402-019-03232-5","article-title":"Laboratory-based versus qualitative assessment of \u03b1-defensin in periprosthetic hip and knee infections: a systematic review and meta-analysis","volume":"140","author":"Balato","year":"2020","journal-title":"Arch. Orthop Trauma Surg."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2131","DOI":"10.1007\/s11999-014-4078-8","article-title":"Comparative epidemiology of revision arthroplasty: failed THA poses greater clinical and economic burdens than failed TKA","volume":"473","author":"Bozic","year":"2015","journal-title":"Clin. Orthop Relat. Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2028","DOI":"10.3748\/wjg.v19.i13.2028","article-title":"Measurement of calprotectin in ascitic fluid to identify elevated polymorphonuclear cell count","volume":"19","author":"Burri","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"15094","DOI":"10.1038\/s41598-022-19034-6","article-title":"Gut permeability may be associated with periprosthetic joint infection after total hip and knee arthroplasty","volume":"12","author":"Chisari","year":"2022","journal-title":"Sci. Rep."},{"key":"B7","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1016\/j.arth.2022.01.066","article-title":"How does a \u201cDry tap\u201d impact the accuracy of preoperative aspiration results in predicting chronic periprosthetic joint infection","volume":"37","author":"Christensen","year":"2022","journal-title":"J. Arthroplasty"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2455","DOI":"10.1016\/j.arth.2022.07.002","article-title":"Cell-free deoxyribonucleic acid: a potential biomarker of chronic periprosthetic knee joint infection","volume":"37","author":"Cobra","year":"2022","journal-title":"J. Arthroplasty"},{"key":"B9","doi-asserted-by":"publisher","first-page":"102909","DOI":"10.1016\/j.otsr.2021.102909","article-title":"Diagnostic accuracy of the BJI InoPlex\u2122 (Diaxonhit) immunoassay on blood samples for periprosthetic joint infection in complex microbiological situations. preliminary results of 24 cases in a French reference center for complex bone and joint infection (CRIOAC)","volume":"107","author":"Dartus","year":"2021","journal-title":"Orthop Traumatol Surg. Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"18","DOI":"10.3390\/ijms18081796","article-title":"Immune-response patterns and next generation sequencing diagnostics for the detection of mycoses in patients with septic shock-results of a combined clinical and experimental investigation","volume":"8","author":"Decker","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1007\/s00402-020-03427-1","article-title":"Synovial neutrophilic gelatinase-associated lipocalin in the diagnosis of periprosthetic joint infection after total knee arthroplasty","volume":"140","author":"Dijkman","year":"2020","journal-title":"Arch. Orthop Trauma Surg."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1705","DOI":"10.2106\/JBJS.20.02229","article-title":"Sequencing of circulating microbial cell-free DNA can identify pathogens in periprosthetic joint infections","volume":"103","author":"Echeverria","year":"2021","journal-title":"J. Bone Joint Surg. Am."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1883","DOI":"10.1007\/s00402-020-03388-5","article-title":"Analysis of synovial biomarkers with a multiplex protein microarray in patients with PJI undergoing revision arthroplasty of the hip or knee joint","volume":"140","author":"Fr\u00f6schen","year":"2020","journal-title":"Arch. Orthop Trauma Surg."},{"key":"B14","doi-asserted-by":"publisher","first-page":"612","DOI":"10.3390\/jcm10040612","article-title":"Soluble pecam-1 as a biomarker in periprosthetic joint infection","volume":"10","author":"Fuchs","year":"2021","journal-title":"J. Clin. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1016\/j.arth.2021.12.040","article-title":"Synovial biomarkers to detect chronic periprosthetic joint infection: a pilot study to compare calprotectin rapid test, calprotectin ELISA immunoassay and leukocyte esterase test","volume":"37","author":"Grassi","year":"2022","journal-title":"J. Arthroplasty"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e394","DOI":"10.1097\/CCM.0000000000003658","article-title":"Enhanced performance of next-generation sequencing diagnostics compared with standard of care microbiological diagnostics in patients suffering from septic shock","volume":"47","author":"Grumaz","year":"2019","journal-title":"Crit. Care Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1186\/s13073-016-0326-8","article-title":"Next-generation sequencing diagnostics of bacteremia in septic patients","volume":"8","author":"Grumaz","year":"2016","journal-title":"Genome Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1146\/annurev-pathmechdis-012418-012751","article-title":"Clinical metagenomic next-generation sequencing for pathogen detection","volume":"14","author":"Gu","year":"2019","journal-title":"Annu. Rev. Pathol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1186\/s12887-022-03433-9","article-title":"An evaluation of ascitic calprotectin for diagnosis of ascitic fluid infection in children with cirrhosis","volume":"22","author":"Honar","year":"2022","journal-title":"BMC Pediatr."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1007\/s00264-020-04753-0","article-title":"Evaluation of myeloperoxidase in synovial fluid as a biomarker for chronic periprosthetic joint infection","volume":"44","author":"Ikeda","year":"2020","journal-title":"Int. Orthop"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.687065","article-title":"sCD28, sCD80, sCTLA-4, and sBTLA are promising markers in diagnostic and therapeutic approaches for aseptic loosening and periprosthetic joint infection","volume":"12","author":"Jubel","year":"2021","journal-title":"Front. Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2223","DOI":"10.1016\/j.arth.2020.03.016","article-title":"Synovial fluid d-Lactate-A novel pathogen-specific biomarker for the diagnosis of periprosthetic joint infection","volume":"35","author":"Karbysheva","year":"2020","journal-title":"J. Arthroplasty"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2871","DOI":"10.1016\/j.arth.2016.05.033","article-title":"Intraoperative diagnosis of periprosthetic joint infection using a novel alpha-defensin lateral flow assay","volume":"31","author":"Kasparek","year":"2016","journal-title":"J. Arthroplasty"},{"key":"B24","doi-asserted-by":"publisher","first-page":"3287","DOI":"10.1007\/s00167-020-06154-7","article-title":"The projected volume of primary and revision total knee arthroplasty will place an immense burden on future health care systems over the next 30 years","volume":"29","author":"Klug","year":"2021","journal-title":"Knee Surg. Sports Traumatol Arthrosc"},{"key":"B25","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/j.arth.2021.10.018","article-title":"Hospital costs for unsuccessful two-stage revisions for periprosthetic joint infection","volume":"37","author":"Kurtz","year":"2022","journal-title":"J. Arthroplasty"},{"key":"B26","doi-asserted-by":"publisher","first-page":"3238","DOI":"10.1016\/j.arth.2018.05.042","article-title":"Are we winning or losing the battle with periprosthetic joint infection: trends in periprosthetic joint infection and mortality risk for the Medicare population","volume":"33","author":"Kurtz","year":"2018","journal-title":"J. Arthroplasty"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1186\/s12879-021-06721-4","article-title":"The concordance between preoperative aspiration and intraoperative synovial fluid culture results: intraoperative synovial fluid re-cultures are necessary whether the preoperative aspiration culture is positive or not","volume":"21","author":"Li","year":"2021","journal-title":"BMC Infect. Dis."},{"key":"B28","doi-asserted-by":"publisher","first-page":"819","DOI":"10.2217\/bmm-2016-0034","article-title":"Concentrations of neutrophil-derived proteins in meconium and their correlations","volume":"10","author":"Lisowska-Myjak","year":"2016","journal-title":"biomark. Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/S0883-5403(03)00453-4","article-title":"Role of core biopsy in diagnosing infection before revision hip arthroplasty","volume":"19","author":"Malhotra","year":"2004","journal-title":"J. Arthroplasty"},{"key":"B30","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1302\/0301-620X.103B1.BJJ-2020-1381.R1","article-title":"The EBJIS definition of periprosthetic joint infection","author":"McNally","year":"2021","journal-title":"Bone Joint J."},{"key":"B31","doi-asserted-by":"publisher","first-page":"383","DOI":"10.3109\/17453674.2014.927729","article-title":"Similar success rates for single and multiple debridement surgery for acute hip arthroplasty infection","volume":"85","author":"Moojen","year":"2014","journal-title":"Acta Orthop"},{"key":"B32","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1002\/jor.24913","article-title":"Noninvasive diagnostic of periprosthetic joint infection by urinary peptide markers: a preliminary study","volume":"39","author":"Omar","year":"2021","journal-title":"J. Orthop Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1093\/cid\/cis803","article-title":"Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the infectious diseases society of America","volume":"56","author":"Osmon","year":"2013","journal-title":"Clin. Infect. Dis."},{"key":"B34","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1186\/s13643-021-01626-4","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"10","author":"Page","year":"2021","journal-title":"Syst. Rev."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1016\/j.arth.2014.03.009","article-title":"Definition of periprosthetic joint infection","volume":"29","author":"Parvizi","year":"2014","journal-title":"J. Arthroplasty"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1016\/j.arth.2018.02.078","article-title":"The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria","volume":"33","author":"Parvizi","year":"2018","journal-title":"J. Arthroplasty"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2992","DOI":"10.1007\/s11999-011-2102-9","article-title":"New definition for periprosthetic joint infection: from the workgroup of the musculoskeletal infection society","volume":"469","author":"Parvizi","year":"2011","journal-title":"Clin. Orthop Relat. Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1111\/j.1469-0691.2011.03758.x","article-title":"Cost analysis of debridement and retention for management of prosthetic joint infection","volume":"19","author":"Peel","year":"2013","journal-title":"Clin. Microbiol. Infect."},{"key":"B39","doi-asserted-by":"publisher","first-page":"742","DOI":"10.2106\/JBJS.17.01005","article-title":"Alpha defensin lateral flow test for diagnosis of periprosthetic joint infection: not a screening but a confirmatory test","volume":"100","author":"Renz","year":"2018","journal-title":"J. Bone Joint Surg. Am."},{"key":"B40","first-page":"342","article-title":"Preoperative aspiration culture (PAC) for the diagnosis of infection in a prosthetic knee joint","volume":"6","author":"Rodriguez-Merchan","year":"2018","journal-title":"Arch. Bone Jt Surg."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1622","DOI":"10.1097\/CORR.0000000000001214","article-title":"Projections of primary TKA and THA in Germany from 2016 through 2040","volume":"478","author":"Rupp","year":"2020","journal-title":"Clin. Orthop Relat. Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"516","DOI":"10.3390\/jcm9020516","article-title":"Extracellular vesicle isolation and characterization from periprosthetic joint synovial fluid in revision total joint arthroplasty","volume":"9","author":"R\u00fcwald","year":"2020","journal-title":"J. Clin. Med."},{"key":"B43","doi-asserted-by":"publisher","first-page":"S21","DOI":"10.2106\/00004623-200300001-00006","article-title":"Modes of failure and preoperative evaluation","author":"Saleh","year":"2003","journal-title":"J. Bone Joint Surg. Am."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0268076","article-title":"Activated polymorphonuclear derived extracellular vesicles are potential biomarkers of periprosthetic joint infection","volume":"17","author":"Sallai","year":"2022","journal-title":"PloS One"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1086\/592973","article-title":"Prolonged bacterial culture to identify late periprosthetic joint infection: a promising strategy","volume":"47","author":"Sch\u00e4fer","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"B46","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1302\/2046-3758.119.BJR-2022-0078.R1","article-title":"Diagnosing periprosthetic joint infections : a comparison of infection definitions: EBJIS 2021, ICM 2018, and IDSA 2013","volume":"11","author":"Sigmund","year":"2022","journal-title":"Bone Joint Res."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.3390\/biomedicines9091128","article-title":"Serum inflammatory biomarkers in the diagnosis of periprosthetic joint infections","volume":"9","author":"Sigmund","year":"2021","journal-title":"Biomedicines"},{"key":"B48","doi-asserted-by":"publisher","first-page":"245","DOI":"10.33549\/physiolres.930448","article-title":"Calprotectin - a pleiotropic molecule in acute and chronic inflammation","volume":"53","author":"Str\u00edz","year":"2004","journal-title":"Physiol. Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.arth.2018.09.047","article-title":"Evaluation of lipocalin-2 as a biomarker of periprosthetic joint infection","volume":"34","author":"Vergara","year":"2019","journal-title":"J. Arthroplasty"},{"key":"B50","doi-asserted-by":"publisher","first-page":"2226","DOI":"10.2106\/JBJS.18.01483","article-title":"LTF, PRTN3, and MNDA in synovial fluid as promising biomarkers for periprosthetic joint infection: identification by quadrupole orbital-trap mass spectrometry","volume":"101","author":"Wang","year":"2019","journal-title":"J. Bone Joint Surg. Am."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.2106\/JBJS.20.01089","article-title":"Diagnostic utility of a novel point-of-Care test of calprotectin for periprosthetic joint infection after total knee arthroplasty: a prospective cohort study","volume":"103","author":"Warren","year":"2021","journal-title":"J. Bone Joint Surg. Am."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1016\/j.arth.2022.01.082","article-title":"Calprotectin lateral flow test: consistent across criteria for ruling out periprosthetic joint infection","volume":"37","author":"Warren","year":"2022","journal-title":"J. Arthroplasty"},{"key":"B53","doi-asserted-by":"publisher","first-page":"529","DOI":"10.7326\/0003-4819-155-8-201110180-00009","article-title":"QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies","volume":"155","author":"Whiting","year":"2011","journal-title":"Ann. Intern. Med."},{"key":"B54","doi-asserted-by":"publisher","first-page":"2203","DOI":"10.1097\/CORR.0000000000001838","article-title":"What are the long-term outcomes of mortality, quality of life, and hip function after prosthetic joint infection of the hip? a 10-year follow-up from Sweden","volume":"479","author":"Wildeman","year":"2021","journal-title":"Clin. Orthop Relat. Res."},{"key":"B55","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1016\/j.arth.2003.11.011","article-title":"The value of hip aspiration versus tissue biopsy in diagnosing infection before exchange hip arthroplasty surgery","volume":"19","author":"Williams","year":"2004","journal-title":"J. Arthroplasty"},{"key":"B56","doi-asserted-by":"publisher","first-page":"992","DOI":"10.2106\/JBJS.15.01142","article-title":"The alpha-defensin immunoassay and leukocyte esterase colorimetric strip test for the diagnosis of periprosthetic infection: a systematic review and meta-analysis","volume":"98","author":"Wyatt","year":"2016","journal-title":"J. Bone Joint Surg. Am."},{"key":"B57","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1177\/230949901302100225","article-title":"Review article: joint aspiration for diagnosis of periprosthetic infection","volume":"21","author":"Yee","year":"2013","journal-title":"J. Orthop Surg. (Hong Kong)"},{"key":"B58","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.jinf.2019.05.015","article-title":"Performance of synovial fluid d-lactate for the diagnosis of periprosthetic joint infection: a prospective observational study","volume":"79","author":"Yermak","year":"2019","journal-title":"J. Infect."},{"key":"B59","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1007\/s11999-013-3089-1","article-title":"The 2013 frank stinchfield award: diagnosis of infection in the early postoperative period after total hip arthroplasty","volume":"472","author":"Yi","year":"2014","journal-title":"Clin. Orthop Relat. Res."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2023.1210345\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T13:27:44Z","timestamp":1689600464000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2023.1210345\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,17]]},"references-count":59,"alternative-id":["10.3389\/fcimb.2023.1210345"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2023.1210345","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,17]]},"article-number":"1210345"}}