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Clinical and Immunological Aspects of Lyme borreliosis
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) is a tick-borne infection caused by spirochetes of the Borrelia (B.) burgdorferi sensu lato complex. The infection is associated with several clinical features, of which erythema migrans (EM) and neuroborreliosis (NB) are the most common in Europe. The prognosis after antibiotic therapy is generally good. However, some patients may have residual symptoms post-treatment. The cause of the delayed convalescence is unclear. There are several factors that may affect the clinical outcome of LB, for example, the early interaction between the host’s immune response and B. burgdorferi, the spirochete genotype, antibiotic therapy, as well as the host’s vulnerability.

This thesis aimed to explore the type of early immune response that is generated to B. burgdorferi and its importance for the clinical outcome of LB, and to study the condition of persistent symptoms post-NB from clinical, immunological and diagnostic perspectives. In total, 125 adult patients with different clinical features and outcomes of LB and 23 healthy controls were included.

In a prospective follow-up study of EM, we confirmed that the prognosis of EM is good after antibiotic therapy, and that B. afzelii is the most common B. burgdorferi genotype associated with EM in the Nordic countries. Seven patients (8%) reported persistent symptoms more than six months post-treatment. These patients had also a decreased early expression of inflammatory, Th1-type cytokines in the EM lesions, suggesting an importance of early, local Th1-type immunity to B. burgdorferi for a successful clinical outcome of LB. No correlation between clinical characteristics, allergic predisposition, B. burgdorferi genotype or serology and the development of symptoms post-treatment was found.

Asymptomatic B. burgdorferi-seropositive individuals are interesting from clinical and immunological points of view, since they apparently have encountered B. burgdorferi without developing symptoms of LB. In this thesis, asymptomatic individuals were shown to display an enhanced innate inflammatory immune response to live B. garinii spirochetes, induced by dendritic cells and whole blood cells, in comparison with patients with a history of subacute NB and healthy controls. Whether this is the optimal immune response to B. burgdorferi remains to be determined.

A randomized, placebo-controlled cross-over study showed that three weeks of doxycycline therapy did not significantly improve objective neurological signs, subjective symptoms or quality of life in NB patients with persistent symptoms post-treatment. Nor could any doxycycline-mediated effects on systemic cytokine responses be demonstrated.

Brain magnetic resonance imaging (MRI) findings in NB patients with persistent symptoms post-treatment were shown to be nonspecific and to correlate with age, but not with the duration of symptoms.

In conclusion, this thesis shows that there is an association between the early immune response to B. burgdorferi sensu lato and the clinical outcome of LB. The cause of prolonged convalescence post-treatment remains unknown and needs further investigation. However, repeated treatment with doxycycline does not lead to improvement of the persistent symptoms; nor does brain MRI facilitate diagnosis of, or provide an explanation for the post-treatment symptoms.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2011. , 134 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1225
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-68745ISBN: 978-91-7393-237-0OAI: oai:DiVA.org:liu-68745DiVA: diva2:420438
Public defence
2011-05-06, Elsa Brändströms sal, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2011-06-01 Created: 2011-06-01 Last updated: 2013-08-29Bibliographically approved
List of papers
1. Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans
Open this publication in new window or tab >>Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans
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2011 (English)In: PLOS ONE, ISSN 1932-6203, Vol. 6, no 3, 0018220- p.Article in journal (Refereed) Published
Abstract [en]

Background: Despite the good prognosis of erythema migrans (EM), some patients have persisting symptoms of various character and duration post-treatment. Several factors may affect the clinical outcome of EM, e. g. the early interaction between Borrelia (B.) burgdorferi and the host immune response, the B. burgdorferi genotype, antibiotic treatment as well as other clinical circumstances. Our study was designed to determine whether early cytokine expression in the skin and in peripheral blood in patients with EM is associated with the clinical outcome. Methods: A prospective follow-up study of 109 patients with EM was conducted at the A land Islands, Finland. Symptoms were evaluated at 3, 6, 12 and 24 months post-treatment. Skin biopsies from the EM and healthy skin were immunohistochemically analysed for expression of interleukin (IL)-4, IL-10, IL-12p70 and interferon (IFN)-gamma, as well as for B. burgdorferi DNA. Blood samples were analysed for B. burgdorferi antibodies, allergic predisposition and levels of systemic cytokines. Findings: None of the patients developed late manifestations of Lyme borreliosis. However, at the 6-month follow-up, 7 of 88 patients reported persisting symptoms of diverse character. Compared to asymptomatic patients, these 7 patients showed decreased expression of the Th1-associated cytokine IFN-gamma in the EM biopsies (p = 0.003). B. afzelii DNA was found in 48%, B. garinii in 15% and B. burgdorferi sensu stricto in 1% of the EM biopsies, and species distribution was the same in patients with and without post-treatment symptoms. The two groups did not differ regarding baseline patient characteristics, B. burgdorferi antibodies, allergic predisposition or systemic cytokine levels. Conclusion: Patients with persisting symptoms following an EM show a decreased Th1-type inflammatory response in infected skin early during the infection, which might reflect a dysregulation of the early immune response. This finding supports the importance of an early, local Th1-type response for optimal resolution of LB.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67829 (URN)10.1371/journal.pone.0018220 (DOI)000289057200045 ()
Note
Original Publication: Johanna Sjöwall, Linda Fryland, Marika Nordberg, Florence Sjögren, Ulf Garpmo, Christian Jansson, Sten-Anders Carlsson, Sven Bergstrom, Jan Ernerudh, Dag Nyman, Pia Forsberg and Christina Ekerfelt, Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans, 2011, PLOS ONE, (6), 3, 0018220. http://dx.doi.org/10.1371/journal.pone.0018220 Copyright: Public Library of Science (PLoS) http://www.plos.org/Available from: 2011-04-29 Created: 2011-04-29 Last updated: 2013-08-29
2. Innate immune responses in Lyme borreliosis: Enhanced tumour necrosis factor-a and interleukin-12 in asymptomatic individuals in response to live spirochetes
Open this publication in new window or tab >>Innate immune responses in Lyme borreliosis: Enhanced tumour necrosis factor-a and interleukin-12 in asymptomatic individuals in response to live spirochetes
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2005 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 141, no 1, 89-98 p.Article in journal (Refereed) Published
Abstract [en]

Innate immunity is important for early defence against borrelia spirochetes and should play a role in the clinical outcome of the infection. In order to study early cytokine responses, in vitro differentiated dendritic cells (DCs) and whole blood cells from 21 patients with different clinical outcomes of Lyme neuroborreliosis were stimulated with live borrelia spirochetes. The borrelia-induced secretion of interleukin (IL)-4, IL-10, IL-12p70, Interferon (INF)-? and tumour necrosis factor (TNF)-a in DCs and IL-1ß, IL-6, IL-8, IL-10, IL-12p70, TNF-a, regulated upon activation normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1a, MIP-1ß and eotaxin in whole blood cells was measured by enzyme-linked immunospot (ELISPOT) and multiplex arrays, respectively. We found increased numbers of TNF-a-secreting DCs (P = 0.018) in asymptomatic seropositive individuals compared to patients with subacute neuroborreliosis and seronegative controls. Asymptomatic individuals were also found to have elevated levels of IL-12p70 (P = 0.031) in whole blood cell supernatants compared to seronegative controls. These results are in line with previous experiments using cells of the adaptive immune response, indicating that strong T helper type 1 (Th1) proinflammatory responses might be associated with a successful resolution of Lyme disease. © 2005 British Society for Immunology.

Keyword
Borrelia, Clinical outcome, Dendritic cell, IL-12p70, TNF-a
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-50469 (URN)10.1111/j.1365-2249.2005.02820.x (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2013-11-07
3. Lack of doxycycline-mediated effects on systemic cytokine responses and persistent symptoms post-neuroborreliosis: A double-blind, randomized, cross-over study
Open this publication in new window or tab >>Lack of doxycycline-mediated effects on systemic cytokine responses and persistent symptoms post-neuroborreliosis: A double-blind, randomized, cross-over study
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Persistent symptoms after treatment of neuroborreliosis (NB) are welldocumented, although the causative mechanisms are mainly unknown. The effect of repeated antibiotic treatment has not been studied in detail. The aim of this study was to determine whether: (1) persistent symptoms improve with doxycycline treatment; (2) doxycycline has an influence on systemic cytokine responses, and; (3) improvement of symptoms could be due to doxycycline-mediated immunomodulation.

Methods: Fifteen NB patients with persistent symptoms ≥6 months post-treatment were double-blindly randomized to receive 200 mg of doxycycline or a placebo for three weeks. After a six-week wash-out period, a cross-over with a three-week course of a placebo or doxycycline was conducted. The primary outcome measures were improvement of persistent symptoms assessed by neurological examinations, a symptom severity score and estimation of the quality of life. The secondary outcome measure was change in systemic cytokine responses.

Results: No serious adverse effects were registered. No doxycycline-mediated improvement of symptoms or quality of life was observed. Nor could any doxycycline-mediated changes in systemic cytokine responses be detected.

Conclusions In this pilot study, no doxycycline-mediated improvement of persistent symptoms or quality of life was observed. Consequently, use of doxycycline for treatment of persistent symptoms post-NB cannot be recommended.

Keyword
Persistent symptoms, neuroborreliosis, doxycycline, immunomodulation, randomized, cross-over
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68744 (URN)
Available from: 2011-06-01 Created: 2011-06-01 Last updated: 2013-08-29Bibliographically approved
4. Brain magnetic resonance imaging does not contribute to the diagnosis of chronic neuroborreliosis
Open this publication in new window or tab >>Brain magnetic resonance imaging does not contribute to the diagnosis of chronic neuroborreliosis
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2007 (English)In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 48, no 7, 755-762 p.Article in journal (Refereed) Published
Abstract [en]

Background: Borrelia infections, especially chronic neuroborreliosis ( NB), may cause considerable diagnostic problems. This diagnosis is based on symptoms and findings in the cerebrospinal fluid but is not always conclusive. Purpose: To evaluate brain magnetic resonance imaging ( MRI) in chronic NB, to compare the findings with healthy controls, and to correlate MRI findings with disease duration. Material and Methods: Sixteen well- characterized patients with chronic NB and 16 matched controls were examined in a 1.5T scanner with a standard head coil. T1- ( with and without gadolinium), T2-, and diffusion- weighted imaging plus fluid- attenuated inversion recovery ( FLAIR) imaging were used. Results: White matter lesions and lesions in the basal ganglia were seen in 12 patients and 10 controls ( no significant difference). Subependymal lesions were detected in patients down to the age of 25 and in the controls down to the age of 43. The number of lesions was correlated to age both in patients ( rho=0.83, P < 0.01) and in controls ( rho=0.61, P < 0.05), but not to the duration of disease. Most lesions were detected with FLAIR, but many also with T2- weighted imaging. Conclusion: A number of MRI findings were detected in patients with chronic NB, although the findings were unspecific when compared with matched controls and did not correlate with disease duration. However, subependymal lesions may constitute a potential finding in chronic NB.

Keyword
adults, Borrelia, brain, brain stem, CNS, Lyme, meninges, MR imaging, neuroborreliosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-45936 (URN)10.1080/02841850701367903 (DOI)000249137200010 ()
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2015-10-08

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