{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:47:28Z","timestamp":1753890448398,"version":"3.41.2"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,11]],"date-time":"2023-09-11T00:00:00Z","timestamp":1694390400000},"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:p>The tick-borne multisystemic infection caused by <jats:italic>Borrelia burgdorferi sensu lato<\/jats:italic>, Lyme borreliosis, or Lyme disease, occurring in temperate regions of the northern hemisphere, continues to spread geographically with the expanding tick population. Despite the rising perceived risk of infection in the population, the clinical diagnosis of Borrelia infection is not always obvious and the most important laboratory test, antibody detection, has limited accuracy in diagnosing active disease. According to international guidelines, the primary serology test, which has a high sensitivity-low specificity, should, be verified using a high specificity confirmation test to improve the specificity. However, this enhancement in specificity comes at the cost of lower sensitivity. This two-step procedure is often omitted in everyday clinical practice. An optimal primary test would be one where no secondary tests for confirmation would be necessary. In the present study, the performance of a novel assay for quantitating IgG1-subclass antibodies to <jats:italic>Borrelia<\/jats:italic> C6-peptide was compared to a commercial reference assay of total IgG and IgM antibodies to <jats:italic>Borrelia<\/jats:italic> C6-peptide in the setting of a high endemic area for borreliosis. A derivation study on a retrospective clinical material was performed to compare the performance parameters and assess the discriminatory properties of the assays, followed by a prospective validation study. The IgG1-antibody assay achieved comparable summary performance parameters to those of the reference assay. The sensitivity was almost 100% while the specificity was about 50%. In a high-endemic setting, characterized by high background seropositivity of about 50% and disease prevalence of approximately 10%, antibody tests are unable to rule-in active <jats:italic>Borrelia<\/jats:italic> infection. The rule-out assessment of the methods revealed that of 1000 patients, 7 \u2013 54 with negative results based on the reference method could have an active <jats:italic>Borrelia<\/jats:italic> infection. Such uncertainty was not found for the index test and may help improve the risk classification of patients.<\/jats:p>","DOI":"10.3389\/fcimb.2023.1108115","type":"journal-article","created":{"date-parts":[[2023,9,11]],"date-time":"2023-09-11T05:46:10Z","timestamp":1694411170000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Diagnostic probability classification in suspected borreliosis by a novel Borrelia C6-peptide IgG1- subclass antibody test"],"prefix":"10.3389","volume":"13","author":[{"given":"Dag","family":"Nyman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marika","family":"Nordberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara","family":"Nyberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Olausson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nellie","family":"Carlstr\u00f6mer Berthen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sten-Anders","family":"Carlsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,11]]},"reference":[{"key":"B1","first-page":"S49","article-title":"Limit of blank, limit of detection and limit of quantitation","author":"Armbruster","year":"2008","journal-title":"Clin. Biochem. Rev."},{"key":"B2","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1128\/jcm.28.3.637-638.1990","article-title":"Complement fixation test for the diagnosis of Lyme disease","volume":"28","author":"Artsob","year":"1990","journal-title":"J. Clin. Microbiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e00018","DOI":"10.1128\/CMR.00018-19","article-title":"Laboratory diagnosis of Lyme borreliosis","volume":"34","author":"Branda","year":"2021","journal-title":"Clin. Microbiol. Rev."},{"key":"B4","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1128\/CVI.00075-07","article-title":"Dominant epitopes of the C6 diagnostic peptide of Borrelia burgdorferi are largely inaccessible to antibody on the parent VlsE molecule","volume":"14","author":"Embers","year":"2007","journal-title":"Clin. Vacc Immunol."},{"key":"B5","unstructured":"registry website, in finnish or Swedish only"},{"key":"B6","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1186\/s12879-022-07686-8","article-title":"Non-specific symptoms and post-treatment Lyme disease syndrome in patients with Lyme borreliosis: a prospective cohort study in Belgium, (2016-2020)","volume":"22","author":"Geebelen","year":"2022","journal-title":"BMC Infect. Dis."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.1212\/WNL.41.10.1571","article-title":"Central nervous system abnorMalities in Lyme neuroborreliosis","volume":"41","author":"Halperin","year":"1991","journal-title":"Neurology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1111\/j.1469-0691.2004.01041.x","article-title":"Analysis of Borrelia burgdorferi IgG antibodies with a combination of IgG ELISA and VlsE C6 peptide ELISA","volume":"11","author":"Jansson","year":"2005","journal-title":"Clin. Microbiol. Inf"},{"key":"B9","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1086\/322669","article-title":"Persistence of immunoglobulin M or immunoglobulin G antibody response to Borrelia burgdorferi 10-20 years after active Lyme disease","volume":"33","author":"Kalish","year":"2001","journal-title":"Clin. Infect. Dis."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1933","DOI":"10.1007\/s10096-019-03631-x","article-title":"Serological diagnostics of Lyme borreliosis: comparison of assays in twelve clinical laboratories in Northern Europe","volume":"38","author":"Lager","year":"2019","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"B11","first-page":"16:140","article-title":"The diagnostic accuracy of serological tests for Lyme borreliosis in Europe: a systematic review and meta-analysis","volume":"25","author":"Leeflang","year":"2016","journal-title":"BMC Infect. Dis."},{"key":"B12","doi-asserted-by":"publisher","first-page":"6702","DOI":"10.1128\/IAI.67.12.6702-6706.1999","article-title":"Analysis of antibody response to invariable regions of VlsE, the invariable regions of the variable surface antigen of Borrelia burgdorferi","volume":"67","author":"Liang","year":"1999","journal-title":"Infect. Immun."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2349","DOI":"10.1128\/IAI.68.4.2349-2352.2000","article-title":"Epitope mapping of the immunodominant invariable region of Borrelia burgdorferi VlsE in three host species","volume":"68","author":"Liang","year":"2000","journal-title":"Infect. Immun."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3990","DOI":"10.1128\/JCM.37.12.3990-3996.1999","article-title":"Sensitive and specific serodiagnosis of Lyme disease by enzyme-linked immunosorbent assay with a peptide based on an immunodominant conserved region of Borrelia burgdorferi VlsE","volume":"37","author":"Liang","year":"1999","journal-title":"J. Clin. Microbiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1111\/j.1469-0691.2006.01374.x","article-title":"VlsE C6 peptide and IgG ELISA antibody analysis for clinical diagnosis of Lyme borreliosis in an endemic area","volume":"12","author":"Nyman","year":"2006","journal-title":"Clin. Microbiol. Infect."},{"key":"B16","first-page":"618","article-title":"\u00c5sbrin E: IgG subclasses of specific antibodies in Ixodes ricinus-borne borreliosis","volume":"69","author":"Olsson","year":"1987","journal-title":"Clin. Exp. Immunol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1007\/s100960050362","article-title":"Evaluation of treatment responses in late Lyme borreliosis on the basis of antibody decrease during the follow-up period","volume":"18","author":"Panelius","year":"1999","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"B18","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1136\/eb-2012-100645","article-title":"Principles for high-quality, high-value testing","volume":"18","author":"Power","year":"2013","journal-title":"BMJ Evidence-Based Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"607","DOI":"10.3390\/microorganisms10030607","article-title":"Madec Y Multidisciplinary management of suspected Lyme borreliosis: Clinical features of 569 patients and factors associated with recovery at 3 and 12 months, a prospective cohort study","volume":"10","author":"Raffetin","year":"2022","journal-title":"Microorganisms"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1093\/clinchem\/37.7.1153","article-title":"Quantification of virus-specific antibodies in cerebrospinal fluid and serum: sensitive and specific detection of antibody synthesis in brain","volume":"37","author":"Reiber","year":"1991","journal-title":"Clin. Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.1016\/j.cmi.2018.04.007","article-title":"Diagnostic value of cerebrospinal fluid CXCL13 for acute Lyme neuroborreliosis. A systematic review and meta-analysis","volume":"24","author":"Rupprecht","year":"2018","journal-title":"Clin. Microbiol. Infect."},{"key":"B22","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1099\/00222615-40-4-293","article-title":"Diagnosis of Lyme borreliosis: non-specific serological reactions with Borrelia burgdorferi sonicate antigen caused by IgG2 antibodies","volume":"40","author":"Sepp\u00e4l\u00e4","year":"1994","journal-title":"J. Med. Microbiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1639","DOI":"10.1016\/S0140-6736(03)14798-8","article-title":"Lyme borreliosis","volume":"362","author":"Stanek","year":"2003","journal-title":"Lancet"},{"key":"B24","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1093\/femsre\/fux047","article-title":"Lyme borreliosis-from tick bite to diagnosis and treatment","volume":"42","author":"Stanek","year":"2018","journal-title":"FEMS Microbiol. Rev."},{"key":"B25","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1056\/NEJM198908313210906","article-title":"Lyme disease","volume":"321","author":"Steere","year":"1989","journal-title":"N Engl. J. Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2147","DOI":"10.1172\/JCI138062","article-title":"Posttreatment Lyme disease syndromes: distinct pathogenesis caused by maladaptive host responses","volume":"130","author":"Steere","year":"2020","journal-title":"J. Clin. Invest."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1172\/JCI21681","article-title":"The emergence of Lyme disease","volume":"113","author":"Steere","year":"2004","journal-title":"J. Clin. Invest."},{"key":"B28","doi-asserted-by":"publisher","first-page":"16090","DOI":"10.1038\/nrdp.2016.90","article-title":"Lyme borreliosis","volume":"2","author":"Steere","year":"2016","journal-title":"Nat. Rev."},{"key":"B29","doi-asserted-by":"publisher","first-page":"3125","DOI":"10.1093\/cid\/ciz1218","article-title":"Posttreatment symptoms in Lyme borreliosis","volume":"71","author":"Strle","year":"2020","journal-title":"CID"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.7326\/0003-4819-127-12-199712150-00011","article-title":"Laboratory evaluation in the diagnosis of Lyme disease","volume":"127","author":"Tugwell","year":"1997","journal-title":"Ann. Int. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"100142","DOI":"10.1016\/j.lanepe.2021.100142","article-title":"Prevalence of persistent symptoms after treatment for lyme borreliosis: A prospective observational cohort study","volume":"6","author":"Ursinus","year":"2021","journal-title":"Lancet Regional Health-Europe"},{"key":"B32","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.ttbdis.2015.08.009","article-title":"A prospective study on the incidence of Borrelia burgdorferi sensu lato infection after a tick bite in Sweden and on the \u00c5land Islands, Finland, (2008 \u2013 2009)","volume":"7","author":"Wilhelmsson","year":"2016","journal-title":"Ticks Tick Borne Dis."},{"key":"B33","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1089\/153036603322662200","article-title":"Diagnosis of lyme borreliosis in Europe","volume":"3","author":"Wilske","year":"2003","journal-title":"Vector-Borne Zoonotic Dis."},{"key":"B34","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1111\/j.1574-695X.2006.00139.x","article-title":"Microbiological and serological diagnosis of Lyme borreliosis","volume":"49","author":"Wilske","year":"2007","journal-title":"FEMS Immunol. Med. Mikrobiol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"3118","DOI":"10.1093\/cid\/ciz1215","article-title":"Prospective evaluation of the frequency and severity of symptoms in Lyme disease patients with erythema migrans compared with matched controls at baseline, 6 months and 12 months","volume":"71","author":"Wormser","year":"2020","journal-title":"CID"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2023.1108115\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,11]],"date-time":"2023-09-11T05:46:12Z","timestamp":1694411172000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2023.1108115\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,11]]},"references-count":35,"alternative-id":["10.3389\/fcimb.2023.1108115"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2023.1108115","relation":{},"ISSN":["2235-2988"],"issn-type":[{"type":"electronic","value":"2235-2988"}],"subject":[],"published":{"date-parts":[[2023,9,11]]},"article-number":"1108115"}}