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Lack of doxycycline-mediated effects on systemic cytokine responses and persistent symptoms post-neuroborreliosis: A double-blind, randomized, cross-over study
Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, General Practice. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-3993-9985
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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 [en]
Persistent symptoms, neuroborreliosis, doxycycline, immunomodulation, randomized, cross-over
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-68744OAI: oai:DiVA.org:liu-68744DiVA: diva2:420434
Available from: 2011-06-01 Created: 2011-06-01 Last updated: 2013-08-29Bibliographically approved
In thesis
1. Clinical and Immunological Aspects of Lyme borreliosis
Open this publication in new window or tab >>Clinical and Immunological Aspects of Lyme borreliosis
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:nbn:se:liu:diva-68745 (URN)978-91-7393-237-0 (ISBN)
Public defence
2011-05-06, Elsa Brändströms sal, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
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Available from: 2011-06-01 Created: 2011-06-01 Last updated: 2013-08-29Bibliographically approved

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Sjöwall, JohannaErnerudh, JanEkerfelt, ChristinaForsberg, Pia

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Infectious DiseasesFaculty of Health SciencesGeneral PracticeClinical ImmunologyDepartment of Clinical Immunology and Transfusion MedicineDepartment of Infectious Diseases in Östergötland
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