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      Ticking on Pandora’s box: a prospective case-control study into ‘other’ tick-borne diseases

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          Abstract

          Background

          Tick-borne pathogens other than Borrelia burgdorferi sensu lato – the causative agent of Lyme borreliosis – are common in Ixodes ricinus ticks. How often these pathogens cause human disease is unknown. In addition, diagnostic tools to identify such diseases are lacking or reserved to research laboratories. To elucidate their prevalence and disease burden, the study ‘Ticking on Pandora’s Box’ has been initiated, a collaborative effort between Amsterdam University Medical Center and the National Institute for Public Health and the Environment.

          Methods

          The study investigates how often the tick-borne pathogens Anaplasma phagocytophilum, Babesia species, Borrelia miyamotoi, Neoehrlichia mikurensis, spotted fever group Rickettsia species and/or tick-borne encephalitis virus cause an acute febrile illness after tick-bite. We aim to determine the impact and severity of these tick-borne diseases in the Netherlands by measuring their prevalence and describing their clinical picture and course of disease.

          The study is designed as a prospective case-control study. We aim to include 150 cases – individuals clinically suspected of a tick-borne disease – and 3 matched healthy control groups of 200 persons each. The controls consist respectively of a group of individuals with either a tick-bite without complaints, the general population and of healthy blood donors. During a one-year follow-up we will acquire blood, urine and skin biopsy samples and ticks at baseline, 4 and 12 weeks. Additionally, participants answer modified versions of validated questionnaires to assess self-reported symptoms, among which the SF-36, on a 3 monthly basis.

          Discussion

          This article describes the background and design of the study protocol of ‘Ticking on Pandora’s Box’. With our study we hope to provide insight into the prevalence, clinical presentation and disease burden of the tick-borne diseases anaplasmosis, babesiosis, B. miyamotoi disease, neoehrlichiosis, rickettsiosis and tick-borne encephalitis and to assist in test development as well as provide recommendations for national guidelines.

          Trial registration

          NL9258 (retrospectively registered at Netherlands Trial Register, trialregister.nl in in February 2021).

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12879-021-06190-9.

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          Most cited references51

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          Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations.

          The primary objectives of this research were to translate, validate, and generate normative data on the SF-36 Health Survey for use among Dutch-speaking residents of the Netherlands. Translation of the SF-36 into Dutch followed the stepwise, iterative procedures developed by the IQOLA Project. Following extensive pilot testing, the SF-36 was administered to: (1) a random sample of adult residents of Amsterdam (n = 4172); (2) a random, nationwide sample of adults (n = 1742); (3) a sample of migraine sufferers (n = 423); and (4) a sample of cancer patients undergoing active anti-neoplastic treatment (n = 485). Data quality across the four studies was consistently high. The rates of missing data ranged from 1% to 5% at the item level, and from 1.2% to 2.6% at the scale level. Multitrait scaling analysis confirmed the hypothesized scale structure of the SF-36 and associated scale scoring in all four samples. Cronbach's alpha coefficients surpassed the 0.70 criterion for group comparisons in all but one case (the Social Functioning scale in the cancer sample), with a mean alpha coefficient across all scales and samples of 0.84. Known-group comparisons yielded consistent support for the validity of the SF-36. In the two community samples, statistically significant differences in SF-36 mean scale scores were observed as a function of age, gender, and the prevalence of chronic health conditions. In the migraine and cancer samples, mean SF-36 scale scores varied significantly as a function of various indicators of disease severity. The SF-36 profiles for the two community samples were highly similar. The cancer sample yielded the lowest SF-36 scores, with the migraine sample holding an intermediate position. On-going studies will generate data on the responsiveness of the SF-36 to within-group changes in health over time. Efforts are underway to translate and validate the questionnaire for use among ethnic minority groups in the Netherlands.
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            The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America.

            Evidence-based guidelines for the management of patients with Lyme disease, human granulocytic anaplasmosis (formerly known as human granulocytic ehrlichiosis), and babesiosis were prepared by an expert panel of the Infectious Diseases Society of America. These updated guidelines replace the previous treatment guidelines published in 2000 (Clin Infect Dis 2000; 31[Suppl 1]:1-14). The guidelines are intended for use by health care providers who care for patients who either have these infections or may be at risk for them. For each of these Ixodes tickborne infections, information is provided about prevention, epidemiology, clinical manifestations, diagnosis, and treatment. Tables list the doses and durations of antimicrobial therapy recommended for treatment and prevention of Lyme disease and provide a partial list of therapies to be avoided. A definition of post-Lyme disease syndrome is proposed.
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              Coinfection by Ixodes Tick-Borne Pathogens: Ecological, Epidemiological, and Clinical Consequences.

              Ixodes ticks maintain a large and diverse array of human pathogens in the enzootic cycle, including Borrelia burgdorferi and Babesia microti. Despite the poor ecological fitness of B. microti, babesiosis has recently emerged in areas endemic for Lyme disease. Studies in ticks, reservoir hosts, and humans indicate that coinfection with B. burgdorferi and B. microti is common, promotes transmission and emergence of B. microti in the enzootic cycle, and causes greater disease severity and duration in humans. These interdisciplinary studies may serve as a paradigm for the study of other vector-borne coinfections. Identifying ecological drivers of pathogen emergence and host factors that fuel disease severity in coinfected individuals will help guide the design of effective preventative and therapeutic strategies.
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                Author and article information

                Contributors
                pandora@amc.uva.nl
                Journal
                BMC Infect Dis
                BMC Infect Dis
                BMC Infectious Diseases
                BioMed Central (London )
                1471-2334
                29 May 2021
                29 May 2021
                2021
                : 21
                : 501
                Affiliations
                [1 ]GRID grid.7177.6, ISNI 0000000084992262, Amsterdam UMC, Center for Experimental and Molecular Medicine, Amsterdam Institute of Infection and Immunology, , University of Amsterdam, ; P.O. Box 22660 (1100 DD), Amsterdam, The Netherlands
                [2 ]GRID grid.31147.30, ISNI 0000 0001 2208 0118, National Institute for Public Health and the Environment (RIVM), , Center of Infectious Disease Control, ; P.O. Box 1 (3720 BA), Bilthoven, The Netherlands
                Author information
                http://orcid.org/0000-0003-0347-2049
                Article
                6190
                10.1186/s12879-021-06190-9
                8164744
                34051756
                04e6cef9-40b9-47f0-8c26-421b47a49fb2
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 30 March 2021
                : 16 May 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001826, ZonMw;
                Award ID: 50-52200-98-313
                Categories
                Study Protocol
                Custom metadata
                © The Author(s) 2021

                Infectious disease & Microbiology
                prospective case-control study,study protocol,ixodes ricinus ticks,tick-borne pathogens,tick-borne diseases,hard tick-borne fever,fever after tick-bite

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