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Laboratory Diagnosis of Lyme Borreliosis: Anti-Borrelia Antibodies and the Chemokine CXCL13
Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lyme borreliosis (LB), the most common tick-borne disease in Europe and North America, is caused by spirochetes of the Borrelia burgdorferi sensu lato complex. The spirochetes can invade several different organs, thereby causing many different symptoms and signs. Diagnosis of LB relies on patient history, physical examination, and detection of anti-Borrelia antibodies. However, anti-Borrelia antibodies are not always detectable, and they commonly persist even after LB is successfully treated or spontaneously healed.

The aim of my work was to study diagnostic aspects on clinical cases of LB and control subjects in an area endemic to LB, with a focus on newly developed anti-Borrelia antibody tests. A total of 617 patients with symptoms and/or signs consistent with LB, as well as 255 control subjects, were studied. The diagnostic panel included the following new LB tests: Immunetics Quick ELISA C6 Borrelia assay kit (C6), invariable region 6 peptide antibody assays (IR6), Liaison Borrelia CLIA (Li) and the chemokine CXCL13. Results were compared with the older Virotech Borrelia burgdorferi ELISA (VT) and with a Western blot method, the Virotech Borrelia Ecoline IgG/IgM Line Immunoblot (WB EL), when appropriate.

In general, no significant differences were noted between the C6, VT and Li tests regarding serosensitivity in various LB manifestations. However, the seropositivity rate was lower for the C6 test compared with the VT and Li tests 2–3 and 6 months after diagnosis of erythema migrans (EM), indicating normalization of antibody levels. In addition, EM patients reporting a previous LB episode had a C6 seropositivity rate similar to that of patients without a previous LB episode, and seroprevalence in healthy blood donors was lower in the C6 test than the VT and Li tests. Taken together, these results support the recommendation of the serum C6 test as a Borrelia serological test due to its ability to reflect ongoing or recent infection.

Although the majority of EM patients at presentation showed concordant serological responses to IR6 peptides representing the three main Borrelia species and the C6 peptide, there were also clinical EM cases that were C6-negative and could be detected mainly by a seroresponse to a B. burgdorferi sensu stricto-derived IR6 peptide. Thus, an antibody test combining antigens could be of value in the serodiagnosis of LB in Europe.

The serosensitivity of the C6 test in cases of Lyme neuroborreliosis (LNB) was shown to be associated with symptom duration. A serosensitivity rate of 93% was found in LNB patients ³ 12 years of age with a symptom duration of more than 30 days. Therefore, a negative C6 test in serum in such a patient argues against an LNB diagnosis.

The presence of chemokine CXCL13 in cerebrospinal fluid was confirmed to be a reliable marker of LNB. CXCL13 differentiated LNB from other conditions and also indicated a high probability of LNB in children with short symptom duration where anti-Borrelia antibodies were still lacking in the cerebrospinal fluid.

A two-tiered approach (C6 test in combination with WB EL) showed no significant improvement in specificity over the C6 test alone. However, WB EL may be useful in diagnosing suspected cases of acrodermatitis chronicum atrophicans and Lyme arthritis, usually displaying multiple IgG bands.

In conclusion, although the serodiagnosis of LB remains to be settled, this thesis provides some practical tools regarding the use and interpretation of Borrelia serology including proposed diagnostic routines.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2011. , 103 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1222
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:liu:diva-65728ISBN: 978-91-7393-256-1 (print)OAI: oai:DiVA.org:liu-65728DiVA: diva2:398541
Public defence
2011-03-18, Epidemin, Länssjukhuset i Kalmar, Kalmar, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2011-02-18 Created: 2011-02-18 Last updated: 2013-11-08Bibliographically approved
List of papers
1. C6 peptide ELISA test in the serodiagnosis of Lyme borreliosis in Sweden.
Open this publication in new window or tab >>C6 peptide ELISA test in the serodiagnosis of Lyme borreliosis in Sweden.
2007 (English)In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 26, no 1, 37-42 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to evaluate the synthetic C6 peptide test as a first-line test in a two-tiered scheme for Borrelia serology in a clinically well-characterized population of patients with Lyme borreliosis in Kalmar County, Sweden. The study population consisted of a prospective group (n = 200), a control group (n = 255), and a retrospective group (n = 29). The test panel consisted of the Immunetics Quick ELISA C6 Borrelia assay kit (Immunetics, Cambridge, MA, USA), the Virotech Borrelia burgdorferi ELISA (Genzyme Virotech, Rüsselsheim, Germany), and the Liaison Borrelia CLIA (DiaSorin, Saluggia, Vercelli, Italy). Seroprevalence among 200 healthy blood donors was significantly lower in the C6 test (8%) compared to the Virotech ELISA (14%) and the Liaison CLIA (12%). In convalescent sera (2-3 months and 6 months post infection) from 158 patients with erythema migrans, the seropositivity in the C6 test was also significantly lower compared to both the Virotech ELISA and the Liaison CLIA. Serosensitivity in the acute phase of erythema migrans and other clinical manifestations of borreliosis did not differ significantly between the C6 test and the Virotech ELISA or the Liaison CLIA. Overall, a positive C6 test seems to correlate well with acute borreliosis. Cross-reactivity was lower in the C6 test in sera positive for Epstein-Barr virus infection as compared to the Virotech ELISA. This study supports the use of the C6 test as a screening test for borreliosis, in endemic areas.

National Category
Infectious Medicine
Identifiers
urn:nbn:se:liu:diva-64731 (URN)10.1007/s10096-006-0239-3 (DOI)17180348 (PubMedID)
Available from: 2011-02-03 Created: 2011-02-03 Last updated: 2017-12-11
2. C6-peptide serology as diagnostic tool in neuroborreliosis
Open this publication in new window or tab >>C6-peptide serology as diagnostic tool in neuroborreliosis
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2008 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 116, no 5, 393-399 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to evaluate the usefulness of borrelia serology (Quick ELISA C6 Borrelia assay kit) as a diagnostic tool in cases of suspected neuroborreliosis. A retrospective patient material consisting of 124 paired serum and cerebrospinal fluid samples with a positive anti-borrelia antibody index (AI) using the IDEIA Lyme Neuroborreliosis test was compared with 124 AI-negative matched control subjects. The patients were divided into four groups based on presence of pleocytosis and age above or below 12 years. The presence of positive C6 serology in AI-positive patients with pleocytosis was 89% (83/93), significantly different (p<0.01) from in patients without pleocytosis (58%, 18/31). In AI-positive patients aged ≥12 years with pleocytosis, 94% (51/54) had a positive C6 serology. Of AI-positive patients with a symptom duration of more than 30 days, 93% (27/29) were positive by the C6 test. We conclude that the C6 serum test, together with clinical evaluation, is a powerful diagnostic tool in adult (≥12 years) European patients with suspected neuroborreliosis with a symptom duration of more than 30 days. Patients with suspected neuroborreliosis and positive C6 results should be further investigated by lumbar puncture for definite diagnosis. © The Authors 2008.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-43521 (URN)10.1111/j.1600-0463.2008.00842.x (DOI)74047 (Local ID)74047 (Archive number)74047 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
3. Antibody responses to borrelia IR6 peptide variants and the C6 peptide in Swedish patients with erythema migrans
Open this publication in new window or tab >>Antibody responses to borrelia IR6 peptide variants and the C6 peptide in Swedish patients with erythema migrans
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2009 (English)In: International Journal of Medical Microbiology, ISSN 1438-4221, Vol. 299, no 6, 439-446 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to evaluate the antibody responses to different VlsE protein IR6 peptide variants and the synthetic C6 peptide in acute and convalescent (2-3 and 6 months) serum samples from Swedish patients with clinical erythema migrans (EM). Serum samples were prospectively collected from 148 patients with EM and compared to serum samples obtained from 200 healthy blood donors. The IgG responses to 3 IR6 peptide variants originating from Borrelia burgdorferi (B. burgdorferi) sensu stricto, B. garinii, and B. afzelii were measured by enzyme-linked immunosorbent assays (ELISAs) and compared to a commercial C6 peptide ELISA. Seropositivity rate in the IR6 or C6 peptide ELISAs ranged from 32% to 58% at presentation, 30-52% after 2-3 months, and 20-36% after 6 months. At presentation, positive antibodies in any of the 4 ELISAs were found in 66%. In 7/52 (13%), C6-negative EM cases, serological reaction was found to the B. burgdorferi sensu stricto-derived IR6 peptide. In patients reporting previous LB compared to those without previous LB, significantly higher seropositivity rates were noted for all IR6 peptides, but not for the C6 peptide. In the serology of EM in Europe, C6 ELISA does not seem to cover all cases. An ELISA using a mixture of B. burgdorferi sensu stricto IR6 peptide and the C6 peptide could be of value in the serodiagnosis of LB in Europe. Further studies on combinations of variant IR6 peptides and the C6 peptide in other manifestations of LB are needed to address this issue.

Keyword
C6; ELISA; Erythema migrans; IR6 peptide; Lyme borreliosis; Serology
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-21262 (URN)10.1016/j.ijmm.2008.10.006 (DOI)
Note
Original Publication: Ivar Tjernberg, H. Sillanpaa, I. Seppala, I. Eliasson, Pia Forsberg and P. Lahdenne, Antibody responses to borrelia IR6 peptide variants and the C6 peptide in Swedish patients with erythema migrans, 2009, International Journal of Medical Microbiology, (299), 6, 439-446. http://dx.doi.org/10.1016/j.ijmm.2008.10.006 Copyright: Elsevier Science B. V. Amsterdam http://www.elsevier.com/ Available from: 2009-09-30 Created: 2009-09-30 Last updated: 2011-02-18
4. Diagnostic performance of cerebrospinal fluid chemokine CXCL13 and antibodies to the C6-peptide in Lyme neuroborreliosis.
Open this publication in new window or tab >>Diagnostic performance of cerebrospinal fluid chemokine CXCL13 and antibodies to the C6-peptide in Lyme neuroborreliosis.
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2011 (English)In: Journal of Infection, ISSN 0163-4453, E-ISSN 1532-2742, Vol. 62, no 2, 149-158 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: The aim of this study was to evaluate the chemokine CXCL13 and C6 antibodies separately and in combination in paired serum/cerebrospinal fluid (CSF) samples in the laboratory diagnosis of Lyme neuroborreliosis (LNB).

METHODS: A large retrospective material with paired serum/CSF samples from 261 patients with clinically suspected LNB was investigated. Patients were divided into three main diagnostic groups based on original results of CSF pleocytosis and intrathecal anti-borrelia antibodies (purified flagellum). Levels of CXCL13, albumin, total IgM and IgG in paired samples and C6 antibodies in CSF were compared across diagnostic groups.

RESULTS: A sensitivity of 99% and a specificity of 96% were achieved for CSF-Serum CXCL13 ratio. CSF-C6 antibodies performed with a sensitivity of 99% and a specificity of 88.0%. A combination of CSF-Serum CXCL13 ratio and CSF-C6 antibodies, evaluated in parallel, revealed a sensitivity of 99% and specificity of 98%.

CONCLUSIONS: This study confirms CSF-CXCL13 as a reliable marker of LNB and suggests improved diagnostic performance especially in children with possible LNB.

Place, publisher, year, edition, pages
Elsevier, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-65725 (URN)10.1016/j.jinf.2010.11.005 (DOI)000286981200006 ()21087629 (PubMedID)
Note
Original Publication: Ivar Tjernberg, Anna J Henningsson, Ingvar Eliasson, Pia Forsberg and Jan Ernerudh, Diagnostic performance of cerebrospinal fluid chemokine CXCL13 and antibodies to the C6-peptide in Lyme neuroborreliosis., 2011, Journal of Infection, (62), 2, 149-158. http://dx.doi.org/10.1016/j.jinf.2010.11.005 Copyright: Elsevier Science B.V., Amsterdam http://www.elsevier.com/ Available from: 2011-02-18 Created: 2011-02-18 Last updated: 2017-12-11

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