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To address this, we developed a multiplex assay to assess the humoral immune proteome against <jats:italic>S. aureus<\/jats:italic> in patients with musculoskeletal infections. We found initial evidence that antibodies against some antigens (autolysins: Amd, Gmd; secreted immunotoxins: CHIPS, SCIN, Hla) were associated with protection, whereas antibodies against the iron\u2010regulated surface determinant (Isd) proteins (IsdA, IsdB, IsdH) were aligned with adverse outcomes. To formally test this, we analyzed antibody levels and 1\u2010year clinical outcomes of 194 patients with confirmed <jats:italic>S. aureus<\/jats:italic> bone infections (AO Trauma Clinical Priority Program [CPP] Bone Infection Registry). A staggering 20.6% of the enrolled patients experienced adverse clinical outcomes (arthrodesis, reinfection, amputation, and septic death) after 1\u2010year. At enrollment, anti\u2010<jats:italic>S. aureus<\/jats:italic>\u00a0immunoglobulin G (IgG) levels in patients with adverse outcomes were 1.35\u2010fold lower than those in patients whose infections were successfully controlled (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Overall, there was a 51%\u201369% reduction in adverse outcome risk for every 10\u2010fold increase in initial IgG concentration against Gmd, Amd, IsdH, CHIPS, SCIN, and Hla (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Notably, anti\u2010IsdB antibodies remained elevated in patients with adverse outcomes; for every 10\u2010fold change in the ratio of circulating anti\u2010Isd to anti\u2010Atl\u00a0IgG at enrollment, there was a trending 2.6\u2010fold increased risk (odds ratio\u2009=\u20092.555) of an adverse event (<jats:italic>p<\/jats:italic>\u2009=\u20090.105). Moreover, antibody increases over time correlated with adverse outcomes and decreases with positive outcomes. These studies demonstrate the potential of the humoral immune response against <jats:italic>S. aureus<\/jats:italic> as a prognostic indicator for assessing treatment success and identifying patients requiring additional interventions.<\/jats:p>","DOI":"10.1002\/jor.24955","type":"journal-article","created":{"date-parts":[[2020,12,16]],"date-time":"2020-12-16T07:34:42Z","timestamp":1608104082000},"page":"2169-2176","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Serum antibodies against <i>Staphylococcus aureus<\/i> can prognose treatment success in patients with bone infections"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7521-6154","authenticated-orcid":false,"given":"Gowrishankar","family":"Muthukrishnan","sequence":"first","affiliation":[{"name":"Center for Musculoskeletal Research University of Rochester Medical Center  Rochester New York USA"},{"name":"Department of Orthopaedics and Rehabilitation University of Rochester Medical Center  Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Beck","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Research University of Rochester Medical Center  Rochester New York USA"},{"name":"Department of Orthopaedics and Rehabilitation University of Rochester Medical Center  Rochester New York USA"},{"name":"Department of Biostatistics and Computational Biology University of Rochester Medical Center  Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Owen","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6197-2506","authenticated-orcid":false,"given":"Chao","family":"Xie","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Research University of Rochester Medical Center  Rochester New York USA"},{"name":"Department of Orthopaedics and Rehabilitation University of Rochester Medical Center  Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L.","family":"Kates","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9690-7701","authenticated-orcid":false,"given":"John L.","family":"Daiss","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Research University of Rochester Medical Center  Rochester New York USA"},{"name":"Department of Orthopaedics and Rehabilitation University of Rochester Medical Center  Rochester New York 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