{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T19:09:50Z","timestamp":1778180990692,"version":"3.51.4"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,3,8]],"date-time":"2025-03-08T00:00:00Z","timestamp":1741392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000133","name":"Agency for Healthcare Research and Quality","doi-asserted-by":"publisher","award":["T32HS000063"],"award-info":[{"award-number":["T32HS000063"]}],"id":[{"id":"10.13039\/100000133","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Joint Biology Consortium","award":["NIH\/NIAMS 5P30"],"award-info":[{"award-number":["NIH\/NIAMS 5P30"]}]},{"name":"Joint Biology Consortium","award":["AR070253"],"award-info":[{"award-number":["AR070253"]}]},{"name":"JBC Microgrant"},{"DOI":"10.13039\/100017980","name":"Peabody Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017980","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014731","name":"Global Lyme Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006823","name":"Boston Children's Hospital Medical Staff Organization Faculty Innovated Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006823","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005295","name":"American Academy of Pediatrics Ken Graff Young Investigator","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005295","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,3,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Pyogenic musculoskeletal infections, such as septic arthritis and osteomyelitis, require prompt recognition and treatment but can be challenging to distinguish from Lyme or inflammatory arthritis. Our goal was to identify cytokine biomarkers of musculoskeletal infections.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Using 2 multicenter prospective cohorts of children undergoing emergency department evaluation for musculoskeletal infection, we selected children \u226421 years of age with a musculoskeletal infection (cases) matched by age and sex to children with Lyme and inflammatory arthritis (controls). We performed a 45-cytokine\/chemokine panel using the Olink proximity extension assay platform and used receiver operator curve analysis to evaluate the discriminative ability of each cytokine. Using forward stepwise logistic regression, we derived a 3-cytokine panel and compared the accuracy with 5 commonly available plasma biomarkers.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We included 47 children with musculoskeletal infection, 48 with Lyme arthritis, and 49 with inflammatory arthritis. Interleukin-6 had the highest accuracy for musculoskeletal infection (area under the curve [AUC], 0.84; 95% CI, 0.77\u20130.91). A 3-cytokine biosignature panel (interleukin-6, interleukin-17A, and colony stimulating factor\u20131) had the highest overall accuracy (AUC, 0.90; 95% CI, 0.84\u20130.96) and performed better than 5 common plasma biomarkers (white blood cell count, absolute neutrophil count, C-reactive protein, erythrocyte sedimentation rate, and procalcitonin; P &amp;lt; .05 for all comparisons).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Plasma cytokines can distinguish musculoskeletal infections from Lyme or inflammatory arthritis and may assist initial decision-making for children undergoing evaluation for musculoskeletal infection.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ofid\/ofaf139","type":"journal-article","created":{"date-parts":[[2025,3,8]],"date-time":"2025-03-08T17:50:32Z","timestamp":1741456232000},"source":"Crossref","is-referenced-by-count":1,"title":["Utility of Cytokine Biomarkers for the Diagnosis of Pediatric Pyogenic Musculoskeletal Infections"],"prefix":"10.1093","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8928-5588","authenticated-orcid":false,"given":"Alexandra T","family":"Geanacopoulos","sequence":"first","affiliation":[{"name":"Division of Emergency Medicine, Boston Children's Hospital, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pui Y","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children's Hospital, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Todd W","family":"Lyons","sequence":"additional","affiliation":[{"name":"Division of Emergency Medicine, Boston Children's Hospital, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kailey E","family":"Brodeur","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children's Hospital, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachael K","family":"Aresco","sequence":"additional","affiliation":[{"name":"Division of Emergency Medicine, Boston Children's Hospital, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Monuteaux","sequence":"additional","affiliation":[{"name":"Division of Emergency Medicine, Boston Children's Hospital, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ron L","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital , Seattle, Washington ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea T","family":"Cruz","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine , Houston, Texas ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter A","family":"Nigrovic","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children's Hospital, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]},{"name":"Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital , Boston, Massachusetts ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6369-3997","authenticated-orcid":false,"given":"Lise E","family":"Nigrovic","sequence":"additional","affiliation":[{"name":"Division of Emergency Medicine, Boston Children's Hospital, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,3,8]]},"reference":[{"key":"2025052712083961100_ofaf139-B1","first-page":"e2112","article-title":"Distinguishing pediatric Lyme arthritis of the hip from transient synovitis and acute bacterial septic arthritis: a systematic review and meta-analysis","volume":"10","author":"Cruz","year":"2018","journal-title":"Cureus"},{"key":"2025052712083961100_ofaf139-B2","doi-asserted-by":"crossref","first-page":"e695","DOI":"10.1542\/peds.2012-2531","article-title":"Distinguishing Lyme from septic knee monoarthritis in Lyme disease-endemic areas","volume":"131","author":"Deanehan","year":"2013","journal-title":"Pediatrics"},{"key":"2025052712083961100_ofaf139-B3","doi-asserted-by":"crossref","first-page":"e881","DOI":"10.1097\/PEC.0000000000002455","article-title":"Validation of septic knee monoarthritis prediction rule in a Lyme disease endemic area","volume":"38","author":"Grant","year":"2022","journal-title":"Pediatr Emerg Care"},{"key":"2025052712083961100_ofaf139-B4","doi-asserted-by":"crossref","first-page":"e0182577","DOI":"10.1371\/journal.pone.0182577","article-title":"The burden of septic arthritis on the U.S. inpatient care: a national study","volume":"12","author":"Singh","year":"2017","journal-title":"PLoS One"},{"key":"2025052712083961100_ofaf139-B5","doi-asserted-by":"crossref","first-page":"740285","DOI":"10.3389\/fsurg.2021.740285","article-title":"Diagnostic criteria for the painful swollen pediatric knee: distinguishing septic arthritis from aseptic effusion in a non-Lyme endemic area","volume":"8","author":"Thomas","year":"2021","journal-title":"Front Surg"},{"key":"2025052712083961100_ofaf139-B6","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S1521-6942(02)00106-7","article-title":"Septic arthritis","volume":"17","author":"Nade","year":"2003","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"2025052712083961100_ofaf139-B7","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1097\/01241398-200303000-00006","article-title":"Septic arthritis of the hip in infancy: long-term follow-up","volume":"23","author":"Dobbs","year":"2003","journal-title":"J Pediatr Orthop"},{"key":"2025052712083961100_ofaf139-B8","doi-asserted-by":"crossref","first-page":"112","DOI":"10.3928\/0090-4481-20060201-11","article-title":"Pediatric orthopedic infections: early detection and treatment","volume":"35","author":"Kocher","year":"2006","journal-title":"Pediatr Ann"},{"key":"2025052712083961100_ofaf139-B9","doi-asserted-by":"crossref","first-page":"122","DOI":"10.5312\/wjo.v13.i2.122","article-title":"Developments in diagnosis and treatment of paediatric septic arthritis","volume":"13","author":"Donders","year":"2022","journal-title":"World J Orthop"},{"key":"2025052712083961100_ofaf139-B10","doi-asserted-by":"crossref","first-page":"13463","DOI":"10.1038\/s41598-022-16509-4","article-title":"A systems immunology approach to investigate cytokine responses to viruses and bacteria and their association with disease","volume":"12","author":"Lin","year":"2022","journal-title":"Sci Rep"},{"key":"2025052712083961100_ofaf139-B11","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/art.42680","article-title":"Elevation of IL-17 cytokines distinguishes Kawasaki disease from other pediatric inflammatory disorders","volume":"76","author":"Brodeur","year":"2024","journal-title":"Arthritis Rheumatol"},{"key":"2025052712083961100_ofaf139-B12","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1186\/s12879-021-06470-4","article-title":"Interleukin 6 as a marker of severe bacterial infection in children with sickle cell disease and fever: a case-control study","volume":"21","author":"Rinc\u00f3n-L\u00f3pez","year":"2021","journal-title":"BMC Infect Dis"},{"key":"2025052712083961100_ofaf139-B13","doi-asserted-by":"crossref","first-page":"e162","DOI":"10.1097\/PCC.0000000000001092","article-title":"Utility of assessing cytokine levels for the differential diagnosis of pneumonia in a pediatric population","volume":"18","author":"Zhou","year":"2017","journal-title":"Pediatr Crit Care Med"},{"key":"2025052712083961100_ofaf139-B14","doi-asserted-by":"crossref","first-page":"631308","DOI":"10.3389\/fimmu.2021.631308","article-title":"Future biomarkers for infection and inflammation in febrile children","volume":"12","author":"Zandstra","year":"2021","journal-title":"Front Immunol"},{"key":"2025052712083961100_ofaf139-B15","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.3201\/eid2612.200920","article-title":"Pediatric Lyme Disease Biobank, United States, 2015-2020","volume":"26","author":"Nigrovic","year":"2020","journal-title":"Emerg Infect Dis"},{"key":"2025052712083961100_ofaf139-B16","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.annemergmed.2022.04.009","article-title":"A clinical prediction rule for bacterial musculoskeletal infections in children with monoarthritis in Lyme endemic regions","volume":"80","author":"Lyons","year":"2022","journal-title":"Ann Emerg Med"},{"key":"2025052712083961100_ofaf139-B17","doi-asserted-by":"crossref","first-page":"100168","DOI":"10.1016\/j.mcpro.2021.100168","article-title":"Proximity extension assay in combination with next-generation sequencing for high-throughput proteome-wide analysis","volume":"20","author":"Wik","year":"2021","journal-title":"Mol Cell Proteomics"},{"key":"2025052712083961100_ofaf139-B18","doi-asserted-by":"crossref","first-page":"e102","DOI":"10.1093\/nar\/gkr424","article-title":"Homogeneous antibody-based proximity extension assays provide sensitive and specific detection of low-abundant proteins in human blood","volume":"39","author":"Lundberg","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"2025052712083961100_ofaf139-B19","doi-asserted-by":"crossref","first-page":"2676","DOI":"10.1002\/sim.4509","article-title":"Classification accuracy and cut point selection","volume":"31","author":"Liu","year":"2012","journal-title":"Stat Med"},{"key":"2025052712083961100_ofaf139-B20","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2307\/2531595","article-title":"Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach","volume":"44","author":"DeLong","year":"1988","journal-title":"Biometrics"},{"key":"2025052712083961100_ofaf139-B21","doi-asserted-by":"crossref","first-page":"e000262","DOI":"10.1136\/fmch-2019-000262","article-title":"Variable selection strategies and its importance in clinical prediction modelling","volume":"8","author":"Chowdhury","year":"2020","journal-title":"Fam Med Community Health"},{"key":"2025052712083961100_ofaf139-B22","doi-asserted-by":"crossref","first-page":"e2023061329","DOI":"10.1542\/peds.2023-061329","article-title":"Biomarkers for pediatric bacterial musculoskeletal infections in Lyme disease\u2013endemic regions","volume":"152","author":"Kahane","year":"2023","journal-title":"Pediatrics"},{"key":"2025052712083961100_ofaf139-B23","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.ajem.2018.05.040","article-title":"Interleukin-6 as a diagnostic marker for infection in critically ill patients: a systematic review and meta-analysis","volume":"37","author":"Iwase","year":"2019","journal-title":"Am J Emerg Med"},{"key":"2025052712083961100_ofaf139-B24","doi-asserted-by":"crossref","first-page":"340","DOI":"10.2174\/1567202611666140912120940","article-title":"Meta-analysis identifies tumor necrosis factor-alpha and interleukin-1 beta as diagnostic biomarkers for bacterial and aseptic meningitis","volume":"11","author":"Panato","year":"2014","journal-title":"Curr Neurovasc Res"},{"key":"2025052712083961100_ofaf139-B25","doi-asserted-by":"crossref","first-page":"a016295","DOI":"10.1101\/cshperspect.a016295","article-title":"IL-6 in inflammation, immunity, and disease","volume":"6","author":"Tanaka","year":"2014","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2025052712083961100_ofaf139-B26","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.3389\/fimmu.2020.01558","article-title":"Biology of interleukin-17 and its pathophysiological significance in sepsis","volume":"11","author":"Ge","year":"2020","journal-title":"Front Immunol"},{"key":"2025052712083961100_ofaf139-B27","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.coi.2005.11.006","article-title":"Colony-stimulating factor-1 in immunity and inflammation","volume":"18","author":"Chitu","year":"2006","journal-title":"Curr Opin Immunol"},{"key":"2025052712083961100_ofaf139-B28","doi-asserted-by":"crossref","first-page":"2119.e3","DOI":"10.1016\/j.ajem.2019.158416","article-title":"Inflammatory markers limitations in the diagnosis of pediatric calcaneal osteomyelitis","volume":"37","author":"Ingersoll","year":"2019","journal-title":"Am J Emerg Med"},{"key":"2025052712083961100_ofaf139-B29","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1097\/BPO.0000000000000390","article-title":"Septic arthritis of the elbow in children: clinical presentation and microbiological profile","volume":"36","author":"Nduaguba","year":"2016","journal-title":"J Pediatr Orthop"}],"container-title":["Open Forum Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ofid\/advance-article-pdf\/doi\/10.1093\/ofid\/ofaf139\/62342185\/ofaf139.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ofid\/article-pdf\/12\/4\/ofaf139\/62342185\/ofaf139.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ofid\/article-pdf\/12\/4\/ofaf139\/62342185\/ofaf139.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T16:09:17Z","timestamp":1748362157000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ofid\/article\/doi\/10.1093\/ofid\/ofaf139\/8063829"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,8]]},"references-count":29,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,3,27]]}},"URL":"https:\/\/doi.org\/10.1093\/ofid\/ofaf139","relation":{},"ISSN":["2328-8957"],"issn-type":[{"value":"2328-8957","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,4]]},"published":{"date-parts":[[2025,3,8]]},"article-number":"ofaf139"}}