Doxycycline-mediated effects on persistent symptoms and systemic cytokine responses post-neuroborreliosis: a randomized, prospective, cross-over study

Johanna Sjöwall, Anna Ledel, Jan Ernerudh, Christina Ekerfelt, Pia Forsberg, Johanna Sjöwall, Anna Ledel, Jan Ernerudh, Christina Ekerfelt, Pia Forsberg

Abstract

Background: Persistent symptoms after treatment of neuroborreliosis (NB) are well-documented, 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/design: 15 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 changes in systemic cytokine responses.

Results: All 15 patients finished the study. No doxycycline-mediated improvement of post-treatment symptoms or quality of life was observed. Nor could any doxycycline-mediated changes in systemic cytokine responses be detected. The study was completed without any serious adverse events.

Discussion: No doxycycline-mediated improvement of post-treatment symptoms or quality of life was observed. Nor could any doxycycline-mediated changes in systemic cytokine responses be detected. The study was completed without any serious adverse events. To conclude, in this pilot study, doxycycline-treatment did not lead to any improvement of either the persistent symptoms or quality of life in post-NB patients. Accordingly, doxycycline does not seem to be the optimal treatment of diverse persistent symptoms post-NB. However, the results need to be confirmed in larger studies.

Trial registration: NCT01205464 (clinicaltrials.gov).

Figures

Figure 1
Figure 1
Overview of the study interventions. The four boxes illustrate the visits to the doctor, and the content in the boxes include the different outcome measures. At visit 1, the patients were randomly and double-blindly assigned to receive either doxycycline or a placebo treatment during 3 weeks. At the third visit, the patients received the opposite study drug, in a cross-over manner. The vertical black arrows indicate time points of blood sampling for analysis of cytokine responses in blood (at the start of, after 5 days, and at the end of treatment, respectively). During the six-week wash-out period, no assessments or examinations were carried out. Abbreviations: SSS, symptom severity score; SF-36, Short Form-36.
Figure 2
Figure 2
The study flow chart. Abbreviations: n, number.
Figure 3
Figure 3
The number of OF-specific IFN-γ secreting mononuclear cells/100 000 lymphocytes, detected with the ELISPOT assay, before and after treatment with Doxycycline and Placebo. The graph illustrates cytokine data from the first nine included patients. The OF-specific cytokine secretion was obtained by subtracting the number of spots in unstimulated (spontaneous) wells from the number of spots in OF-stimulated wells, illustrating the Borrelia-specific memory immune response. Values, which represent medians of triplicates, are given as number of cytokine secreting cells/100 000 lymphocytes. The dotted horizontal line indicates the cut-off (= 15 cells/100 000) for OF-specific IFN-γ secretion. No significant differences in change of the number of cytokine secreting cells were found either within or between the two treatment groups. Horizontal lines denote the median. Abbreviations: OF, outer surface protein–enriched fraction of B. garinii strain Ip90; IFN, interferon; ELISPOT; enzyme-linked immunospot assay.

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