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Spotted Fever Rickettsioses in Sweden

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Spotted Fever Rickettsioses in Sweden Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1253 Spotted Fever Rickettsioses in Sweden Aspects of Epidemiology, Clinical Manifestations and Co-infections ANDERS LINDBLOM ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-554-9677-7 UPPSALA urn:nbn:se:uu:diva-302137 2016 Dissertation presented at Uppsala University to be publicly examined in Mikrobiologens hörsal, Dag Hammarskjöldsväg 17, Uppsala, Wednesday, 26 October 2016 at 13:15 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in Swedish. Faculty examiner: Professor Clas Ahlm (Institutionen för klinisk mikrobiologi, Umeå universitet). Abstract Lindblom, A. 2016. Spotted Fever Rickettsioses in Sweden. Aspects of Epidemiology, Clinical Manifestations and Co-infections. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1253. 64 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9677-7. The spotted fever group rickettsiae are emerging diseases. They cause damage in their hosts by invading the endothelium in small to medium-sized blood vessels, which results in vasculitis that can cause clinical manifestations from most organs. The present thesis describes the prevalence of Rickettsia helvetica in ticks, the incidence of rickettsial infection based on seroreactivity and seroconversion in humans and their symptoms, from different parts of Sweden and the Åland Islands in Finland. This was accomplished through serological analysis of both retrospective and prospective serum samples from confirmed and suspected tick-bitten individuals compared to individuals with no knowledge of tick exposure (blood donors). We found a comparable seroprevalence to Rickettsia spp. in different geographical areas where ticks are present; it was also comparable to the seroprevalence of Borrelia spp. Seroprevalence was also more common, as suspected, in the tick-exposed group compared to blood donors. In comparison with co-infections with other tick-borne infections (Anaplasma spp. and Borrelia spp.), we could conclude that co-infections do exist and that, based on clinical findings, it is difficult to distinguish which microorganism causes certain clinical manifestations. For reliable conclusions regarding the causative microorganism, the diagnosis should basically rely on diagnostic tests. In comparison with Borrelia spp., seroconversion to Rickettisa spp. was more common in the areas we investigated, indicating that rickettsiosis is a common tick-borne infection in Sweden and most likely underdiagnosed. When investigating patients with meningitis, we found R. felis in cerebrospinal fluid from two patients with subacute meningitis. This was the first report in which R. felis was found and diagnosed in patients in Sweden. The patients recovered without sequelae and without causal treatment. To provide guidelines on when to treat Rickettisa spp. infections, more investigations are needed. The present thesis shows that Rickettsia spp. are common in ticks and do infect humans. Rickettsial infection should be considered in both non-specific or specific symptoms after a tick bite. It was also shown in the thesis that flea-borne rickettsiosis (R. felis) occurs in Sweden and may cause invasive infections Keywords: Rickettsia helvetica, Rickettsia felis, co-infection, erythema migrans, meningitis, serology, PCR, western blot Anders Lindblom, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Akademiska sjukhuset, Uppsala University, SE-75185 Uppsala, Sweden. © Anders Lindblom 2016 ISSN 1651-6206 ISBN 978-91-554-9677-7 urn:nbn:se:uu:diva-302137 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-302137) To Kristin and our children Louise, Sara and Frida List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Elfving, K., Lindblom A., and Nilsson K. (2008) Seroprevalence of Rickettsia spp. infection among tick-bitten patients and blood donors in Sweden. Scandinavian Journal of Infectious Diseases, 40(1): 74-7. II Lindblom, A., Wallménius, K., Nordberg, M., Forsberg, P. Eli- asson, I., Påhlson, C., Nilsson, K. (2013) Seroreactivity for spotted fever rickettsiae and co-infections with other tick-borne agents among habitants in central and southern Sweden. Eur J Clin Microbiol Infect Dis, 32(3): p. 317-323. III Lindblom, A., Wallménius, K., Sjöwall, J., Fryland, L., Wil- helmsson, P., Lindgren, P-E., Forsberg, P., Nilsson, K. Preva- lence of Rickettsia spp. in ticks and serological and clinical out- comes in tick-bitten individuals in Sweden and on the Åland Is- lands. Manuscript. IV Lindblom, A., Severinson, K. and Nilsson, K. (2010) Rickettsia felis infection in Sweden: report of two cases with subacute men- ingitis and review of the literature. Scandinavian Journal of In- fectious Diseases, 42(11-12): 906-909. Reprints were made with permission from the respective publishers. Contents Introduction ................................................................................................... 11 Historical notes ......................................................................................... 11 Rickettsia .................................................................................................. 12 General characteristics ......................................................................... 12 Taxonomy and phylogeny ................................................................... 13 The vectors .......................................................................................... 14 Epidemiology ....................................................................................... 17 Pathogenesis and pathophysiology ...................................................... 19 Clinical manifestations ........................................................................ 21 Prevention ............................................................................................ 25 Treatment ............................................................................................. 26 Laboratory diagnostics ......................................................................... 26 Aim ............................................................................................................... 30 Specific aims ............................................................................................ 30 Material and methods .................................................................................... 31 Materials and subjects .............................................................................. 31 Methods .................................................................................................... 32 Laboratory methods ............................................................................. 32 Tick feeding duration ........................................................................... 36 Statistical methods ............................................................................... 36 Ethics ................................................................................................... 37 Results and discussion .................................................................................. 38 Seroprevalence and incidence in humans ................................................. 38 Prevalence of Rickettsia sp. in ticks and its correlation with serological response in humans .................................................................................. 39 Symptoms of Rickettsia helvetica ............................................................ 41 Co-infection .............................................................................................. 45 Infection caused by Rickettsia felis .......................................................... 46 Conclusions ................................................................................................... 50 Future directions ........................................................................................... 51 Acknowledgements ....................................................................................... 52 Sammanfattning på svenska .......................................................................... 54 References ..................................................................................................... 56 Abbreviations bp Base pair CDC Centers for Disease Control and Pre- vention CRP C-reactive protein CSF Cerebrospinal fluid Ct Cycle threshold ELISA Enzyme-linked immunosorbent assay EM Erythema migrans gltA Citrate synthase HGT Horizontal gene transfer IFA Immunofluorescence assay IHC Immunohistochemistry LFCIA Lateral flow coal immunochromato- graphic assay Mb Mega base pair MIF Microimmunofluorescence assay MSF Mediterranean spotted fever Omp Outer membrane protein PCR Polymerase chain reaction RMSF Rocky Mountain spotted fever rrs 16S rRNA Sca Surface cell antigens SFG Spotted fever group sp. Species, singular spp. Species, plural TBE Tick-borne encephalitis TEM Transmission electron microscopy TG Typhus group Introduction Historical notes Rickettsia species are old bacteria, having been around for approximately 150 million years. A development occurred about 50 million years ago that led to differentiation into most of the species we know today [1]. Some historians believe epidemic typhus caused the Athens plague during the 5th century BC [2]. Recent research has suggested that the Athens plague
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