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Improved Laboratory Diagnostics of Lyme Neuroborreliosis in Children
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
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2008 (English)In: The Pediatric Infectious Disease Journal, ISSN 0891-3668, E-ISSN 1532-0987, Vol. 27, no 7, 605-612 p.Article in journal (Refereed) Published
Abstract [en]

Background: Laboratory diagnostics in Lyme neuroborreliosis need improvement. We hereby investigate 4 new recombinant or peptide Borrelia antigens in cerebrospinal fluid in children with neuroborreliosis to evaluate their performance as diagnostic antigens.

Methods: An enzyme-linked immunosorbent assay was used to detect IgG antibodies to recombinant decorin binding protein A (DbpA), BBK32, outer surface protein C (OspC), and the invariable region 6 peptide (IR6). The recombinant antigens originated from 3 pathogenic subspecies; Borrelia afzelii, Borrelia garinii, and Borrelia burgdorferi sensu stricto. Cerebrospinal fluid and serum from children with clinical features indicative for neuroborreliosis (n = 57) were analyzed. Classification of patients was based on clinical symptoms and laboratory findings. Controls were children with other neurologic diseases (n = 20) and adult patients with no proven infection (n = 16).

Results: Sensitivity for DbpA was 82%, for BBK32 70%, for OspC 58% and for IR6 70%. Specificities were 94%, 100%, 97%, and 97%, respectively. No single antigen was superior. When new antigens were combined in a panel, sensitivity was 80% and specificity 100%. The reference flagella antigen showed a sensitivity of 60% and a specificity of 100%. Over all, the B. garinii related antigens dominated.

Conclusions: Recombinant DbpA and BBK32 as well as the peptide antigen IR6 perform well in laboratory diagnostics of neuroborreliosis in children. New antigens seem to improve diagnostic performance when compared with the routine flagella antigen. If different antigens are combined in a panel to cover the antigenic diversity, sensitivity improves further and a specificity of 100% can be achieve.

Place, publisher, year, edition, pages
2008. Vol. 27, no 7, 605-612 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-13162DOI: 10.1097/INF.0b013e31816a1e29OAI: diva2:17949
Available from: 2008-05-07 Created: 2008-05-07 Last updated: 2010-05-17
In thesis
1. Neuroborreliosis in childhood: Clinical, immunological and diagnostic aspects
Open this publication in new window or tab >>Neuroborreliosis in childhood: Clinical, immunological and diagnostic aspects
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lyme Borreliosisis is a multi-organ infectious disease caused by the spirochete Borrelia burgdorferi. The spirochete is transmitted to humans by tick bites. Neuroborreliosis (NB) is a disseminated form of the disease, in which the spirochetes invade the nervous system. In children, subacute meningitis and facial nerve palsy are typical clinical manifestations of NB.

The aim of this thesis was to study clinical, immunological and laboratory characteristics in children being evaluated for NB in a Lyme endemic area of Sweden, in order to identify factors of importance for prognosis and clinical recovery. A total of 250 patients and 220 controls were included during 1998-2005, with a prospective and a retrospective part.

Less than half (41%) of children with signs and symptoms indicative of NB get the diagnosis confirmed by detection of Borrelia specific flagella antibodies in CSF (clinical routine method). Surprisingly few patients were diagnosed as having other infectious or neurologic diseases and consequently, many patients ended up with an uncertain diagnosis. However, four new Borrelia antigens (DbpA, BBK32, OspC, IR6) were evaluated and performed well in laboratory diagnostics. If they were combined in a panel, together with the flagella antigen, the sensitivity was 82% and the specificity 100%, leading to improved diagnostic accuracy in children with NB, as compared to using the routine flagella antibody test alone.

Clinical recovery at the 6-month follow-up (n=177) was generally good and nonspecific symptoms, such as headache and fatigue, were not more frequently reported in patients than in controls. No patient was found to have recurrent or progressive neurologic symptoms.

However, permanent facial nerve palsy was found in 22% of patients at the 2-year follow-up, with consequences such as eye-closing problems, excessive tear secretion, pronunciation difficulties and cosmetic complaints.

When cellular immune responses were investigated, the number of Borrelia-specific IL-4 and IFN-γ secreting cells in CSF was found to be more prominent in children with NB than in controls. Furthermore, a much stronger IL-4 response in CSF was seen in children as compared to adults with NB. This cytokine profile of children with NB is believed to represent an effective and balanced type1/type2 response in a relevant compartment, and could contribute to the less severe course of the disease seen in children as compared to adults with NB.

No prognostic factors were found to influence the outcome in patients with “Confirmed NB” or facial nerve palsy. Nor was any specific cytokine profile, or antibody response to new Borrelia antigens in CSF, correlated to a less favorable clinical outcome.

An NB prediction score test, based on clinical variables at admission, is suggested to help physicians to determine whether to start early antibiotic treatment, before results from Borrelia antibody tests are available.

Results in this thesis support the notion that mononuclear pleocytosis in CSF, in patients being evaluated for NB, indicates that they are true NB cases despite the fact that an antibody response cannot yet be visualized. with the routine flagella test. Consequently, early antibiotic treatment in NB seems to be the correct course of action and over-treatment is not a substantial problem.

Abstract [sv]

Borrelia-infektion hos barn och vuxna är den vanligaste fästingburna infektionen i Sverige och orsakas av en bakterie som heter Borrelia burgdorferi. Den sprids till människa via fästingbett och kan orsaka besvär från hud, leder, hjärtmuskel och nervsystem. När nervsystemet är infekterat kallas det Neuroborrelios.

Denna avhandling handlar om Neuroborrelios hos barn i syd-östra Sverige, ett område med hög Borrelia-förekomst. Jag har studerat symtom, laborativa provsvar och tillfrisknande hos 250 barn med misstänkt Neuroborrelios under åren 1998-2005 och jämfört med friska barn. Dessutom har jag tittat närmare på vissa signalsubstanser inom immunförsvaret i blod och ryggvätska och vilken roll signalsubstanserna spelar för förlopp och utläkning av infektionen. Avhandlingen innehåller också en utvärdering av fyra nya diagnostiska test vid misstänkt Neuroborrelios hos barn.

Det visar sig att mindre än hälften (41%) av barnen med misstänkt Neuroborrelios får diagnosen säkerställd med det befintliga Borrelia-testet (baserat på ett protein som kallas flagellin) som används rutinmässigt. Dock förblir diagnosen oklar för många barn (59%). De fyra nya Borrelia-testen (baserade på protein som kallas DbpA, BBK32, OspC och IR6) visar sig fungera bra och om man kombinerar dem med befintligt Borrelia-test, kan man säkerställa Neuroborrelios hos 82% av barnen med misstänkt infektion. Jag hoppas att dessa nya Borrelia-test i framtiden kan leda till förbättrad diagnostik hos barn som utreds för misstänkt Neuroborrelios.

Immunförsvarets signalsubstanser, som analyserades i ryggvätska och blod, visade sig ha en viss profil hos barn med Neuroborrelios jämfört med barn utan Borrelia-infektion, men även jämfört med vuxna med Neuroborrelios. De immunologiska T cellerna producerade två olika sorters signalsubstanser, som kallas ”Interferon-γ” och ”Interleukin-4”. Denna immunologiska profil verkar fördelaktig och kan möjligen bidra till den i allmänhet goda utläkning av Neuroborrelios som man ser hos barn jämfört med vuxna.

De vanligaste symtomen vid en Borrelia-infektion i nervsystemet är huvudvärk, trötthet, dålig aptit, feber och ont i nacken. Ansiktsförlamning är det vanligaste specifika neurologiska symtomet. Antibiotikabehandling ges till 69% av barnen och vid en 6 månaders uppföljning rapporterar patienterna god utläkning av de olika symtomen. Inget barn hade återkommande eller allvarliga neurologiska symtom vid uppföljningen. Däremot, barn med ansiktsförlamning visade sig få kvarstående besvär i viss utsträckning. När de undersöktes 2 år efter sin ansiktsförlamning förekom mild till måttlig kvarstående förlamning i 22% av fallen. Patienterna uppgav besvär av ökat tårflöde, sluddrigt tal, svårigheter med att stänga ögat och dessutom rapporterade många patienter att snedheten i ansiktet var kosmetiskt störande.

Inga specifika symtom, laborativa prov, immunologiska signalsubstanser eller diagnostiska test visade sig vara kopplade till ökad risk för kvarstående besvär efter Neuroborrelios i allmänhet och inte eller hos patienter med ansiktsförlamning.

En checklista har utarbetats med olika symtom som är typiska för barn med Neuroborrelios. Den föreslås kunna användas som beslutsunderlag för start av tidig antibiotikabehandling, redan innan svar på Borrelia-testen finns tillgängliga.

Place, publisher, year, edition, pages
Linköping University Electronic Press, 2008
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1048
Neuroborreliosis, Immune response, Diagnostics, Children, Lyme Borreliosis
National Category
urn:nbn:se:liu:diva-11520 (URN)978-91-7393-961-4 (ISBN)
Public defence
2008-05-23, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Available from: 2008-05-07 Created: 2008-05-07 Last updated: 2015-11-19

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Hedin-Skogman, BarbroCroner, StefanForsberg, PiaErnerudh, Jan
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