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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 \u2018Ticking on Pandora\u2019s Box\u2019 has been initiated, a collaborative effort between Amsterdam University Medical Center and the National Institute for Public Health and the Environment.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The study investigates how often the tick-borne pathogens <jats:italic>Anaplasma phagocytophilum<\/jats:italic>, <jats:italic>Babesia<\/jats:italic> species, <jats:italic>Borrelia miyamotoi<\/jats:italic>, <jats:italic>Neoehrlichia mikurensis<\/jats:italic>, spotted fever group <jats:italic>Rickettsia<\/jats:italic> 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.<\/jats:p>\n                <jats:p>The study is designed as a prospective case-control study. We aim to include 150 cases \u2013 individuals clinically suspected of a tick-borne disease \u2013 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\u2009weeks. Additionally, participants answer modified versions of validated questionnaires to assess self-reported symptoms, among which the SF-36, on a 3 monthly basis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>This article describes the background and design of the study protocol of \u2018Ticking on Pandora\u2019s Box\u2019. With our study we hope to provide insight into the prevalence, clinical presentation and disease burden of the tick-borne diseases anaplasmosis, babesiosis, <jats:italic>B. miyamotoi<\/jats:italic> disease, neoehrlichiosis, rickettsiosis and tick-borne encephalitis and to assist in test development as well as provide recommendations for national guidelines.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.trialregister.nl\/trial\/9258\">NL9258<\/jats:ext-link> (retrospectively registered at Netherlands Trial Register, trialregister.nl in in February 2021).<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12879-021-06190-9","type":"journal-article","created":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T09:03:11Z","timestamp":1625562191000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Ticking on Pandora\u2019s box: a prospective case-control study into \u2018other\u2019 tick-borne diseases"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0347-2049","authenticated-orcid":false,"given":"D.","family":"Hoornstra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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