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  • 1.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Alzrigat, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Párraga, Alba Atienza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Singh, Umashankar
    Ungerstedt, Johanna
    Österborg, Anders
    Brown, Peter J
    Ma, Anqi
    Jin, Jian
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.2016In: Oncotarget, E-ISSN 1949-2553, Vol. 7, no 6, p. 6809-6923Article in journal (Refereed)
    Abstract [en]

    Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

  • 2.
    Edvinsson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Thelin, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Nyström-Rosander, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    No evidence of Chlamydophila spp. or other intracellular bacteria in mitral valves.2013In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 164, no 2, p. 249-250Article in journal (Refereed)
  • 3.
    Edvinsson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Norlander, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Skoog, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Bartonella spp. seroprevalence in tick-exposed Swedish patients with persistent symptoms2021In: Parasites & Vectors, E-ISSN 1756-3305, Vol. 14, article id 530Article in journal (Refereed)
    Abstract [en]

    Background: Bartonella spp. are emerging pathogens transmitted by arthropod vectors, possibly including ticks. We have investigated signs of bartonellosis in Swedish patients with presumed tick-bite exposure and symptom duration of at least 6 months.

    Methods: Serological testing for Bartonella henselae and Bartonella quintana was performed in 224 patients. Symptoms, tick exposure, evidence of co-infection and previous treatments were evaluated. Seropositive patients were compared to a matched group (twofold larger and negative serology) from the same study cohort.

    Results: Seroprevalence was 7% for B. henselae and 1% for B. quintana, with one patient testing positive to both agents. Tick bites were reported by 63% of the patients in the seropositive group and 88% in the seronegative group and presumed tick exposure was more common in the seronegative group. Animal contact was equally common in both groups, along with reported symptoms. The most common symptoms were fatigue, muscular symptoms, arthralgia and cognitive symptoms. Exposure to co-infections was evenly distributed in the seropositive and seronegative groups.

    Conclusions: Antibodies to Bartonella were more common in this cohort of patients than in cohorts of healthy Swedish blood donors in previous studies but lower than those in blood donors from southern Europe. Positive Bartonella serology was not linked to any specific symptom, nor to (suspected) tick-bite exposure.

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    FULLTEXT01
  • 4.
    Elfving, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Lindblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Seroprevalence of Rickettsia spp. infection among tick-bitten patients and blood donors in Sweden2008In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 40, no 1, p. 74-77Article in journal (Refereed)
    Abstract [en]

    Serum samples from 236 Swedish patients with symptoms of infectious disease appearing after a tick bite were analysed for the presence of antibodies to Rickettsia helvetica, the only rickettsial species so far isolated from ticks in Sweden. Of these subjects, 137 had tested seropositive for Borrelia burgdorferi. For control purposes, sera from 161 healthy blood donors were examined. A total of 10/397 samples (2.6%) showed IgG-antibodies to R. helvetica at or above a titre of 1/80 as cut-off. 6/137 (4.4%) belonged to the Borrelia positive group, 3/99 (3.0%) to the tick-bitten but Borrelia negative group and 1/161 (0.6%) to the control group. The difference between the tick-exposed groups and the control group was significant in Pearson's 2-sided chi(2) test. In 1 serum sample the presence of antibodies to R. helvetica was further confirmed by Western immunoblot. The study shows that infection with Rickettsia spp. as well as coinfection with Lyme borreliosis needs to be considered in the diagnosis of tick-transmitted infections in Sweden. Owing to a known occurrence of immunological cross-reactivites, however, the results must be cautiously interpreted with regard to species of Rickettsia involved.

  • 5.
    Elfving, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Lukinius, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Life cycle, growth characteristics and host cell response of Rickettsia helvetica in a Vero cell line2012In: Experimental & applied acarology, ISSN 0168-8162, E-ISSN 1572-9702, Vol. 56, no 2, p. 179-187Article in journal (Refereed)
    Abstract [en]

    Rickettsia helvetica, a spotted fever rickettsia and emerging pathogen with Ixodes ricinus ticks as the main vector, is an agent of human disease and may cause febrile illness as well as meningitis. In three parallel series the isolated standard type of R. helvetica, obtained from a PCR-positive I. ricinus tick, was high-passaged and propagated in a Vero cell line. By using quantitative real-time PCR, the generation time from inoculation to stationary phase of growth was calculated to 20-22 h. In the static cultivation system the stationary phase was observed from the seventh day after inoculation, and there was no observed degradation of R. helvetica DNA during the 14 days studied. Microscopy showed that the organisms invaded the host cells rapidly and were primarily found free in the cytoplasm and only occasionally located in the nucleus. Four days after inoculation some of the host cells were broken and many indifferent stages of cytoplasmic organic decomposition were seen. However the R. helvetica organism did not show any morphologic alterations and the number of organisms was stable after the replication peak which may indicate that R. helvetica is adapted to growth in a Vero cell line and/or that the phase of degradation occurs later than the 14 days studied. The findings differ from what has been reported for other rickettsiae of the spotted fever group and may be of importance for invasiveness and virulence of R. helvetica.

  • 6.
    Elfving, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology. Center of Clinical Research, Dalarna, Falun, Sweden..
    Malmsten, Jonas
    Swedish Univ Agr Sci, Dept Clin Sci, Div Reprod, Uppsala, Sweden.;Natl Vet Inst, Dept Pathol & Wildlife Dis, S-75007 Uppsala, Sweden..
    Dalin, Anne-Marie
    Natl Vet Inst, Dept Pathol & Wildlife Dis, S-75007 Uppsala, Sweden..
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Dalarna, Clin Res Ctr, Falun, Sweden..
    Serologic and Molecular Prevalence of Rickettsia helvetica and Anaplasma phagocytophilum in Wild Cervids and Domestic Mammals in the Central Parts of Sweden2015In: Vector Borne and Zoonotic Diseases, ISSN 1530-3667, E-ISSN 1557-7759, Vol. 15, no 9, p. 529-534Article in journal (Refereed)
    Abstract [en]

    Both Rickettsia helvetica and Anaplasma phagocytophilum are common in Ixodes ricinus ticks in Sweden. Knowledge is limited regarding different animal species' competence to act as reservoirs for these organism. For this reason, blood samples were collected from wild cervids (roe deer, moose) and domestic mammals (horse, cat, dog) in central Sweden, and sera were tested using immunofluorescence assay to detect antibodies against spotted fever rickettsiae using Rickettsia helvetica as antigen. Sera with a titer >= 1:64 were considered as positive, and 23.1% (104/450) of the animals scored positive. The prevalence of seropositivity was 21.5% (23/107) in roe deer, 23.3% (21/90) in moose, 36.5% (23/63) in horses, 22.1% (19/90) in cats, and 17.0% (17/100) in dogs. PCR analysis of 113 spleen samples from moose and sheep from the corresponding areas were all negative for rickettsial DNA. In roe deer, 85% (91/107) also tested seropositive for A. phagocytophilum with a titer cutoff of 1:128. The findings indicate that the surveyed animal species are commonly exposed to rickettsiae and roe deer also to A. phagocytophilum.

  • 7.
    Elfving, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology. Department of Clinical Microbiology, Falu Hospital, Falun, Sweden.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Bergström, Sven
    Department of Molecular Biology, Umeå University.
    Waldenström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lundkvist, Åke
    Swedish Institute for Infectious Disease Control, Solna.
    Sjöstedt, Anders
    Clinical Bacteriology, Department of Clinical Mic0robiology, Umeå University Hospital.
    Mejlon, Hans
    Uppsala University, Music and Museums, Museum of Evolution.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Dissemination of Spotted Fever Rickettsia Agents in Europe by Migrating Birds2010In: PLOS ONE, E-ISSN 1932-6203, Vol. 5, no 1, p. e8572-Article in journal (Refereed)
    Abstract [en]

    Migratory birds are known to play a role as long-distance vectors for many microorganisms. To investigate whether this is true of rickettsial agents as well, we characterized tick infestation and gathered ticks from 13,260 migratory passerine birds in Sweden. A total of 1127 Ixodes spp. ticks were removed from these birds and the extracted DNA from 957 of them was available for analyses. The DNA was assayed for detection of Rickettsia spp. using real-time PCR, followed by DNA sequencing for species identification. Rickettsia spp. organisms were detected in 108 (11.3%) of the ticks. Rickettsia helvetica, a spotted fever rickettsia associated with human infections, was predominant among the PCR-positive samples. In 9 (0.8%) of the ticks, the partial sequences of 17kDa and ompB genes showed the greatest similarity to Rickettsia monacensis, an etiologic agent of Mediterranean spotted fever-like illness, previously described in southern Europe as well as to the Rickettsia sp.IrITA3 strain. For 15 (1.4%) of the ticks, the 17kDa, ompB, gltA and ompA genes showed the greatest similarity to Rickettsia sp. strain Davousti, Rickettsia japonica and Rickettsia heilongjiangensis, all closely phylogenetically related, the former previously found in Amblyomma tholloni ticks in Africa and previously not detected in Ixodes spp. ticks. The infestation prevalence of ticks infected with rickettsial organisms was four times higher among ground foraging birds than among other bird species, but the two groups were equally competent in transmitting Rickettsia species. The birds did not seem to serve as reservoir hosts for Rickettsia spp., but in one case it seems likely that the bird was rickettsiemic and that the ticks had acquired the bacteria from the blood of the bird. In conclusion, migratory passerine birds host epidemiologically important vector ticks and Rickettsia species and contribute to the geographic distribution of spotted fever rickettsial agents and their diseases.

  • 8.
    Feresiadou, Amalia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Press, Rayomand
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden..
    Kmezic, Ivan
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden..
    Nygren, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Svenningsson, Anders
    Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden..
    Niemelä, Valter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease2019In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 332, p. 31-36Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases.

    METHODS: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease.

    RESULTS: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL.

    CONCLUSIONS: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.

  • 9. Gärdlund, B
    et al.
    Hammers, S
    Arneborn, P
    Prag, M
    Dwyer, R
    Krook, A
    Montelius, R
    Tideström, L
    Forsberg, P
    Muller, R
    Lindblom, A
    Nilsson, K
    Vig, I
    Smedjegård, J
    Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. The Heparin Prophylaxis Study Group.1996In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 347, no 9012, p. 1357-61Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Fatal pulmonary embolism and other thromboembolic complications are common in hospital inpatients. However, there is little evidence on the routine use of pharmacological thromboprophylaxis in non-surgical patients. We assessed the efficacy and safety of low-dose heparin in the prevention of hospital-acquired, clinically relevant, fatal pulmonary embolism in patients with infectious diseases.

    METHODS: Our study used the postrandomisation consent design. 19,751 consecutive patients, aged 55 years or older, admitted to departments of infectious diseases in six Swedish hospitals, were screened for inclusion in the randomised, controlled, unblinded, multicentre trial. Of the eligible patients, 5776 were assigned subcutaneous standard heparin (5000 IU every 12 h) until hospital discharge or for a maximum of 3 weeks; 5917 were assigned no prophylactic treatment (control group). We sought consent only from the heparin group. Follow-up was for 3 weeks after discharge from hospital or for a maximum of 60 days from randomisation. The primary endpoint was necropsy-verified pulmonary embolism of predefined clinical relevance.

    FINDINGS: By intention-to-treat analysis mortality was similar in the heparin and control groups (5.3 vs 5.6%, p = 0.39) and the median time from admission to death was 16 days in both groups (IQR 8-31 vs 6-28 days). Necropsy-verified pulmonary embolism occurred in 15 heparin-treated and 16 control-group patients. There was a significant difference between heparin and control groups in median time from randomisation to fatal pulmonary embolism (28 [24-36] vs 12.5 [10-20] days, p = 0.007). This difference corresponds to the duration of heparin prophylaxis. Non-fatal thromboembolic complications occurred in more of the control than of the heparin group (116 vs 70, p = 0.0012).

    INTERPRETATION: Our findings do not support the routine use of heparin prophylaxis for 3 weeks or less in large groups of non-surgical patients. Further studies are needed to investigate whether heparin prophylaxis of longer duration may prevent fatal pulmonary embolism.

  • 10.
    Henningsson, Anna J.
    et al.
    Lab Med, Div Clin Microbiol, Jönköping, Region Jonkopin, Sweden.;Div Clin Microbiol, Linköping, Region Ostergot, Sweden.;Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect, Linköping, Sweden..
    Aase, Audun
    Norwegian Inst Publ Hlth, Div Infect Control & Environm Hlth, Oslo, Norway..
    Bavelaar, Herjan
    Lab Med, Div Clin Microbiol, Jönköping, Region Jonkopin, Sweden..
    Flottorp, Signe
    Norwegian Inst Publ Hlth, Div Hlth Serv, Oslo, Norway..
    Forsberg, Pia
    Linköping Univ, Dept Biomed & Clin Sci, Div Infect Med, Linköping, Sweden..
    Kirkehei, Ingvild
    Norwegian Coll Policing, Oslo, Norway..
    Lövmar, Matilda
    Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect, Linköping, Sweden..
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Nyman, Dag
    Aland Grp Borrelia Res, Mariehamn, Finland..
    Ornstein, Katharina
    Skane Univ Hlth Care, Ystad Hosp, Kristianstad, Sweden..
    Sjöwall, Johanna
    Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect, Linköping, Sweden.;Dept Infect Dis, Norrköping, Region Ostergot, Sweden..
    Skogman, Barbro H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Center for Clinical Research Dalarna. Dalarna Univ, Dept Pediat, Falun, Sweden; Örebro Univ, Fac Med & Hlth Sci, Örebro, Sweden.
    Tjernberg, Ivar
    Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect, Linköping, Sweden.;Dept Clin Chem & Transfus Med, Kalmar, Region Kalmar C, Sweden..
    Aaberge, Ingeborg
    Norwegian Inst Publ Hlth, Div Infect Control & Environm Hlth, Oslo, Norway..
    Laboratory Methods for Detection of Infectious Agents and Serological Response in Humans With Tick-Borne Infections: A Systematic Review of Evaluations Based on Clinical Patient Samples2021In: Frontiers In Public Health, ISSN 2296-2565, Vol. 9, article id 580102Article, review/survey (Refereed)
    Abstract [en]

    Background: For the most important and well-known infections spread by Ixodes ticks, Lyme borreliosis (LB) and tick-borne encephalitis (TBE), there are recommendations for diagnosis and management available from several health authorities and professional medical networks. However, other tick-borne microorganisms with potential to cause human disease are less known and clear recommendations on diagnosis and management are scarce. Therefore, we performed a systematic review of published studies and reviews focusing on evaluation of laboratory methods for clinical diagnosis of human tick-borne diseases (TBDs), other than acute LB and TBE. The specific aim was to evaluate the scientific support for laboratory diagnosis of human granulocytic anaplasmosis, rickettsiosis, neoehrlichiosis, babesiosis, hard tick relapsing fever, tularemia and bartonellosis, as well as tick-borne co-infections and persistent LB in spite of recommended standard antibiotic treatment.

    Methods: We performed a systematic literature search in 11 databases for research published from 2007 through 2017, and categorized potentially relevant references according to the predefined infections and study design. An expert group assessed the relevance and eligibility and reviewed the articles according to the QUADAS (diagnostic studies) or AMSTAR (systematic reviews) protocols, respectively. Clinical evaluations of one or several diagnostic tests and systematic reviews were included. Case reports, non-human studies and articles published in other languages than English were excluded.

    Results: A total of 48 studies fulfilled the inclusion criteria for evaluation. The majority of these studies were based on small sample sizes. There were no eligible studies for evaluation of tick-borne co-infections or for persistent LB after antibiotic treatment.

    Conclusions: Our findings highlight the need for larger evaluations of laboratory tests using clinical samples from well-defined cases taken at different time-points during the course of the diseases. Since the diseases occur at a relatively low frequency, single-center cross-sectional studies are practically not feasible, but multi-center case control studies could be a way forward.

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    FULLTEXT01
  • 11. Hesstvedt, Liv
    et al.
    Arendrup, Maiken C
    Poikonen, Eira
    Klingpor, Lena
    Friman, Vanda
    Nordøy, Ingvild
    Differences in epidemiology of candidaemia in the Nordic countries - what is to blame?2017In: Mycoses, ISSN 0933-7407, E-ISSN 1439-0507, Vol. 60, no 1, p. 11-19Article in journal (Refereed)
    Abstract [en]

    National data from Denmark, Finland, Norway and Sweden demonstrate remarkable differences in candidaemia epidemiology. Only Denmark has reported a high incidence of 10 per 100 000 inhabitants and a species shift towards increased C. glabrata candidaemias. The reasons for this development remain unclear. The aim of this study was to explore possible contributing factors for the differences in Candida epidemiology in the Nordic countries. We used public data from 2011 from Denmark, Finland, Norway and Sweden on epidemiology, demographics, health facilities, predisposing risk factors, consumption of antimicrobial drugs and fungicides in agricultural industry. Only the prevalence of haematological malignancies (P < 0.001) was significantly higher in Denmark compared to the other Nordic countries. The antibacterial drug use of metronidazole, piperacillin-tazobactam, ciprofloxacin, colistin and carbapenems, and antifungal use of fluconazole in humans (P < 0.001), were significantly higher in Denmark compared to the other Nordic countries (all P < 0.001). Our findings suggest haematological malignancy, the use of certain antibacterial drugs and azoles in humans as possible contributing factors for the differences in Candida epidemiology. However, our results should be interpreted with caution due to the lack of long-term, case-specific data. Further studies are needed.

  • 12.
    Hoffman, Tove
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Carra, Laura G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Öhagen, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR).
    Fransson, Thord
    Department of Environmental Research and Monitoring, Swedish Museum of Natural History, Stockholm, Sweden.
    Barboutis, Christos
    Antikythira Bird Observatory, Hellenic Ornithological Society/BirdLife Greece, Athens, Greece.
    Piacentini, Dario
    Via Cesare Lippi 35, 400 26, Imola, BO, Italy.
    Figuerola, Jordi
    Estación Biológica de Doñana, CSIC, Avda. Américo Vespucio s/n, 410 92 Sevilla, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), 280 29 Madrid, Spain.
    Kiat, Yosef
    Israeli Bird Ringing Center (IBRC), Israel Ornithological Center (IOC), Society for the Protection of Nature in Israel (SPNI), Tel-Aviv, Israel.
    Onrubia, Alejandro
    Migres Foundation, P.O. Box 152, 11380 Tarifa, Cadiz, Spain.
    Jaenson, Thomas G.T.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Association between guilds of birds in the African-Western Palaearctic region and the tick species Hyalomma rufipes, one of the main vectors of Crimean-Congo hemorrhagic fever virus2021In: One Health, ISSN 2352-7714, Vol. 13, article id 100349Article in journal (Refereed)
    Abstract [en]

    Introduction

    The ecology of the vertebrate host contributes to the geographical range expansion of ticks. In this study, we investigated which tick taxa that infest and are dispersed by birds along African-Western Palaearctic flyways during northward migration, and whether bird ecology was associated with tick taxa.

    Materials and methods

    Ticks were collected from birds trapped at bird observatories in Spain, Italy, Greece, and Israel during the spring migration of 2014 and 2015, using mist nets. The tick-infested bird species were classified into guilds, using different combinations of the variables: migration distance, wintering region, foraging behaviour, and winter habitat. Ticks were molecularly determined to genus and species level by sequencing fragments of the 12S ribosomal DNA (rDNA) gene and by phylogenetic inference, using the Maximum Likelihood algorithm. Data were analysed using descriptive measures, graphs, Chi2 tests, the Tukey-Kramer test, and a parametric linear model (generalized linear model) in order to analyse and adjust for characteristics in the bird guilds and their relationship to collected tick taxa.

    Results

    Most (84.2%) of the 10,209 trapped birds were long-distance migrants, of which 2.4% were infested by ticks. The most common tick species was Hyalomma rufipes (77.7%; 447/575), a known vector and reservoir of Crimean-Congo hemorrhagic fever virus. Bird guilds containing only long-distance migrants with wintering areas in Africa were associated with the tick species H. rufipes (p < 0.0001). Furthermore, bird winter habitat was associated with H. rufipes (p = 0.003); with bird species overwintering in open habitat (p = 0.014) and wetlands (p = 0.046) having significantly more H. rufipes as compared to birds with a winter habitat comprising forest and shrubs (p = 0.82).

    Conclusions

    With climate change, the likelihood of establishment of permanent Hyalomma populations in central and northern Europe is increasing. Thus, surveillance programs for monitoring the risk of introduction and establishment of H. rufipes in the Western-Palaearctic should be established. Our study suggests that migratory bird species wintering in African open habitats and wetlands are good candidates for monitoring potential introduction.

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  • 13.
    Hoffman, Tove
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sjödin, Andreas
    CBRN Defence and Security, Swedish Defence Research Agency, Cementvägen 20, 90621 Umeå, Sweden.
    Öhrman, Caroline
    CBRN Defence and Security, Swedish Defence Research Agency, Cementvägen 20, 90621 Umeå, Sweden.
    Karlsson, Linda
    CBRN Defence and Security, Swedish Defence Research Agency, Cementvägen 20, 90621 Umeå, Sweden.
    McDonough, Ryelan Francis
    Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011, USA.
    Sahl, Jason W.
    Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011, USA.
    Birdsell, Dawn
    Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011, USA.
    Wagner, David M.
    Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011, USA.
    Carra, Laura G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wilhelmsson, Peter
    Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection, Linköping University, 581 83 Linköping, Sweden; Department of Clinical Microbiology, Region Jönköping County, 553 05 Jönköping, Sweden .
    Pettersson, John
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Marie Bashir Institute for Infectious Diseases and Biosecurity, School of Life and Environmental Sciences and School of Medical Sciences, the University of Sydney, Sydney, New South Wales 2006, Australia.
    Barboutis, Christos
    Antikythira Bird Observatory, Hellenic Ornithological Society/BirdLife Greece, Athens, Greece.
    Figuerola, Jordi
    Estación Biológica de Doñana, CSIC, Avda. Américo Vespucio 26, 410 92 Sevilla, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), 280 29 Madrid, Spain.
    Onrubia, Alejandro
    Migres Foundation, P.O. Box 152, 11380, Tarifa (Cadiz), Spain.
    Kiat, Yosef
    Israeli Bird Ringing Center (IBRC), Israel Ornithological Center (IOC), Society for the Protection of Nature in Israel (SPNI), Tel-Aviv, Israel.
    Piacentini, Dario
    Via Cesare Lippi 35, 400 26, Imola, BO, Italy.
    Jaenson, Thomas G.T.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Lindgren, Per-Eric
    Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection, Linköping University, 581 83 Linköping, Sweden; Department of Clinical Microbiology, Region Jönköping County, 553 05 Jönköping, Sweden.
    Moutailler, Sara
    ANSES, INRAE, Ecole Nationale Vétérinaire d'Alfort, UMR BIPAR, Laboratoire de Santé Animale, Maisons-Alfort, F-94700, France.
    Fransson, Thord
    Department of Environmental Research and Monitoring, Swedish Museum of Natural History, Stockholm, Sweden.
    Forsman, Mats
    CBRN Defence and Security, Swedish Defence Research Agency, Cementvägen 20, 90621 Umeå, Sweden.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Co-occurrence of Francisella and spotted fever group Rickettsia in avian-associated Hyalomma rufipes2022In: Microorganisms, E-ISSN 2076-2607, Vol. 10, no 7Article in journal (Refereed)
    Abstract [en]

    Introduction: The migratory behaviour of wild birds aids in the geographical spread of ticks and their microorganisms. Ticks are known to harbor both pathogenic and symbiotic bacteria - such as species of the genera Francisella, Rickettsia,and Midichloria - and multiple bacterial species may occur within them. Francisella occurs in different tick taxa andconsists of closely related pathogenic and non-pathogenic species. Spotted fever group Rickettsia are transmitted to humans by different tick genera and are emerging human pathogens in Europe. The aims of this study were to investigate dispersal of Francisella as well as co-occurrence of Francisella and spotted fever group Rickettsia in ticks infesting northward migrating birds in the African-Western Palaearctic region.

    Materials and methods: Birds were trapped using mist nets at bird observatories in Spain, Italy, Greece, and Israel during their spring migration of 2014 and 2015. Ticks were screened for the genus Francisella, the species Francisella tularensis, and spotted fever group Rickettsia by microfluidic qPCR. Ticks with putative positive results for F. tularensiswere subjected to confirmation analyses, metagenomics analysis, enrichment, and whole genome sequencing.

    Results: There was a high prevalence of Francisella species (76.7%) and co-occurrence of Francisella species and spotted fever group Rickettsia (50.6%) in the tick species Hyalomma rufipes. Two H. rufipes yielded putative positive test results for the human pathogen F. tularensis during initial screening. Metagenomics analysis revealed presence of Francisella sp., Rickettsia sp., and Midichloria sp. DNA in the two H. rufipes ticks. The levels of Rickettsia and Midichloria DNA were relatively high while the level of Francisella DNA was low and required enrichment for the construction of metagenome-assembled genomes. Phylogenetic inference and calculations of the average nucleotide identity (ANI) indicated that: i) the Francisella genomes belonged to the Francisella-like endosymbiont (FLE) group in Clade 1 of Francisella and had highest sequence identity to an FLE found in Ornithodoros moubata (ANI: 96.7/97.0%), ii) the Rickettsia genomes had highest resemblance to Rickettsia aeschlimannii (ANI: 98.8 - 99.9%), and iii) the Midichloria genomes resembled Midichloria mitochondrii (ANI: 91.5 - 92.3%).

    Conclusions: The results of this study suggest ticks containing Francisella species, FLEs, and spotted fever groupRickettsia are dispersed by northbound migratory birds in the African-Western Palaearctic and suggest H. rufipes may not be involved in the transmission of F. tularensis in the study region. Future studies should aim at confirming the prevalence of Francisella spp. and spotted fever group Rickettsia in H. rufipes, in addition to focusing on the influence of FLEs on H. rufipes and their interaction with pathogenic and symbiotic bacteria of the genera Rickettsia and Midichloria. 

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  • 14. Höper, Linnea
    et al.
    Skoog, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Stenson, Martin
    Grankvist, Anna
    Wass, Linda
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Child Health and Nutrition.
    Söderlind, Jacob
    Sakinis, Augustinas
    Wennerås, Christine
    Vasculitis due to Candidatus Neoehrlichia mikurensis: a cohort study of 40 Swedish patients2021In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 73, no 7, p. e2372-e2378Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Candidatus (Ca.) Neoehrlichia (N.) mikurensis is an emerging tick-borne pathogen of humans that is closely related to Ehrlichia and Anaplasma species. This strict intracellular bacterium escapes detection by routine microbiologic diagnostic methods such as blood culture leading to considerable under-diagnosis of the infectious disease it causes, neoehrlichiosis.

    METHODS: Here, we describe the vascular and thromboembolic events afflicting a series of 40 patients diagnosed with neoehrlichiosis in Sweden during a 10-year period (2009-2019).

    RESULTS: The majority of the patients (60%) developed vascular events ranging from repeated thrombophlebitis, deep vein thrombosis, pulmonary embolism, transitory ischemic attacks to arteritis. Younger age was a risk factor for vascular complications. In contrast, there was no difference in the incidence of vascular events between immunosuppressed and immunocompetent patients. However, there were qualitative differences such that deep vein thrombosis exclusively afflicted the immunosuppressed patients whereas arteritis was restricted to the immunocompetent ones. We also present the case histories of two patients who developed vasculitis mimicking polyarteritis nodosa and giant cell arteritis. Both were cured by doxycycline treatment.

    CONCLUSIONS: Ca. N. mikurensis infection should be considered in patients living in tick-endemic areas of Europe and northern Asia who present with atypical vascular and/or thromboembolic events. Early diagnosis and antibiotics targeting this emerging infectious agent can eradicate the infection and prevent the development of new vascular events.

  • 15.
    Kask, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Påhlson, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Staxäng, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Signatures in in vitro infection of NSC-34 mouse neurons and their cell nucleus with Rickettsia helvetica2023In: BMC Microbiology, E-ISSN 1471-2180, Vol. 23, article id 113Article in journal (Refereed)
    Abstract [en]

    Background: Rickettsia helvetica, a spotted fever rickettsia, is transmitted to humans via ticks in Europe, North Africa, and Asia. The central nervous system is a crucial target for rickettsial diseases, which has been reported for 12 of the 31 species, of which R. helvetica is one. This study aimed, in an experimental model, to identify characteristics of R. helvetica infection in a mouse neuronal cell line, NSC-34.

    Results: NSC-34, a fusion cell line of mouse motor spinal cord neurons and neuroblastoma cells, was used as a model. Propagation of R. helvetica in neurons was confirmed. Short actin tails were shown at the polar end of the bacteria, which makes it likely that they can move intracellularly, and even spread between cells. Another protein, Sca4, which with the cell adhesion protein vinculin enables the passage of the cell membrane, was expressed during infection. No significant increase in TNF alpha levels was seen in the infected neurons, which is of interest because TNF alpha protects the host cell from infection-induced apoptotic death which is crucial for host cell survival. The bacteria were also shown to invade and grow in the cell nucleus of the neuron.

    Conclusions: The findings suggest that a R. helvetica infection may be harmful to NSC-34 neurons under these in vitro conditions, but the full effects of the infection on the cell need to be studied further, also on human neurons, to also understand the possible significance of this infection in relation to pathogenetic mechanisms.

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  • 16.
    Klingspor, Lena
    et al.
    Karolinska Inst, Div Clin Microbiol, Dept Lab Med, Stockholm, Sweden.
    Ullberg, Mans
    Karolinska Inst, Div Clin Microbiol, Dept Lab Med, Stockholm, Sweden;Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden.
    Rydberg, Johan
    Dept Clin Microbiol, Div Lab Med, Lund, Sweden.
    Kondori, Nahid
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Gothenburg, Sweden.
    Serrander, Lena
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Swanberg, Jonas
    Ryhov Hosp, Dept Clin Microbiol, Jonkoping, Sweden.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Bengten, Cecilia Jendle
    Karlstad Cent Hosp, Dept Clin Microbiol, Karlstad, Sweden.
    Johansson, Marcus
    Kalmar Cty Hosp, Dept Clin Microbiol, Kalmar, Sweden.
    Granlund, Margareta
    Umea Univ, Dept Clin Microbiol, Umea, Sweden.
    Tornqvist, Eva
    Orebro Univ Hosp, Dept Lab Med Clin Microbiol, Orebro, Sweden.
    Nyberg, Anders
    Cty Hosp Sundsvall Harnosand, Lab Med Clin Microbiol, Sundsvall Harnosand, Sweden.
    Kindlund, Karin
    Hallands Hosp, Dept Clin Microbiol, Halmstad, Sweden.
    Ygge, Minna
    Sunderby Hosp, Lulea, Sweden.
    Kartout-Boukdir, Dalila
    Unilabs AB, Malarsjukhuset Hosp, Clin Microbiol, Eskilstuna, Sweden.
    Toepfer, Michael
    Unilabs AB, Skaraborg Hosp, Clin Microbiol, Eskilstuna, Sweden.
    Halldin, Eva
    Vasteras Hosp, Clin Microbiol, Vasteras, Sweden.
    Kahlmeter, Gunnar
    Cent Hosp Vaxjo, Dept Clin Microbiol, Vaxjo, Sweden.
    Ozenci, Volkan
    Karolinska Inst, Div Clin Microbiol, Dept Lab Med, Stockholm, Sweden;Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden.
    Epidemiology of fungaemia in Sweden: A nationwide retrospective observational survey2018In: Mycoses, ISSN 0933-7407, E-ISSN 1439-0507, Vol. 61, no 10, p. 777-785Article in journal (Refereed)
    Abstract [en]

    ObjectivesTo identify the epidemiology and antifungal susceptibilities of Candida spp. among blood culture isolates to identify the epidemiology and antifungal susceptibilities of Candida spp. among blood culture isolates in Sweden. MethodsThe study was a retrospective, observational nationwide laboratory-based surveillance for fungaemia and fungal meningitis and was conducted from September 2015 to August 2016. ResultsIn total, 488 Candida blood culture isolates were obtained from 471 patients (58% males). Compared to our previous study, the incidence of candidaemia has increased from 4.2/100000 (2005-2006) to 4.7/100000 population/year (2015-2016). The three most common Candida spp. isolated from blood cultures were Candida albicans (54.7%), Candida glabrata (19.7%) and species in the Candida parapsilosis complex (9.4%). Candida resistance to fluconazole was 2% in C.albicans and between 0% and 100%, in non-albicans species other than C.glabrata and C.krusei. Resistance to voriconazole was rare, except for C.glabrata, C.krusei and C.tropicalis. Resistance to anidulafungin was 3.8% while no Candida isolate was resistant to amphotericin B. ConclusionsWe report an overall increase in candidaemia but a minor decrease of C.albicans while C.glabrata and C.parapsilosis remain constant over this 10-year period.

  • 17.
    Klingspor, Lena
    et al.
    Karolinska Inst, Stockholm, Sweden.
    Özenci, Volkan
    Karolinska Inst, Stockholm, Sweden.
    Ullberg, Måns
    Karolinska Inst, Stockholm, Sweden.
    Rydberg, Johan
    Univ Skåne, Malmö, Sweden.
    Kondori, Nahid
    Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden.
    Serrander, Lena
    Linköping Univ Hosp, Linköping, Sweden.
    Swanberg, Jonas
    Ryhov Hosp, Jönköping, Sweden.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Bengten, Cecilia Jendle
    Karlstad Hosp, Karlstad, Sweden.
    Johansson, Marcus
    Kalmar Cty Hosp, Kalmar, Sweden.
    Sjöberg, B.
    Örebro Univ Hosp, Örebro, Sweden.
    Granlund, Margareta
    Umeå Univ Hosp, Umeå, Sweden.
    Törnqvist, E.
    Örebro Univ Hosp, Örebro, Sweden.
    Sjögren, Sjögren
    Örebro Univ Hosp, Örebro, Sweden.
    Sundqvist-Persson, Anna-Lena
    Sundsvall Härnösand Hosp, Sundsvall Härnösand, Sweden.
    Kindlund, Karin
    Halmstad Cty Hosp, Halmstad, Sweden.
    Ygge, Minna
    Sunderby Hosp, Luleå, Sweden.
    Kartoutboukir, Dalila
    Unilabs, Eskilstuna, Sweden.
    Toepfer, Michael
    Unilabs, Eskilstuna, Sweden.
    Halldin, Eva
    Västerås Hosp, Västerås, Sweden.
    Nyberg, Anders
    Sundsvall Härnösand Hosp, Sundsvall Härnösand, Sweden.
    Kahlmeter, Gunnar
    Växjö Hosp, Växjö, Sweden.
    Epidemiology of fungaemia and fungal meningitis in Sweden: a nationwide retrospective observational survey from sept 2015-aug 20162018In: Medical Mycology, ISSN 1369-3786, E-ISSN 1460-2709, Vol. 56, no Supplement: 2, p. S61-S61Article in journal (Other academic)
  • 18.
    Lindblom, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Severinson, Kristoffer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Rickettsia felis infection in Sweden: report of two cases with subacute meningitis and review of the literature2010In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 42, no 11-12, p. 906-909Article, review/survey (Refereed)
    Abstract [en]

    Two patients with headache and pleocytosis were diagnosed with Rickettsia felis infection using a polymerase chain reaction of cerebrospinal fluid and serological testing. Sequencing of the amplified products showed that they were 99-100% homologous to R. felis. These cases add to our knowledge of the clinical manifestations, as well as the geographical distribution, of this spotted fever agent.

  • 19.
    Lindblom, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Wallménius, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Nordberg, M
    Forsberg, P
    Eliasson, I
    Påhlson, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Seroreactivity for spotted fever rickettsiae and co-infections with other tick-borne agents among habitants in central and southern Sweden2013In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 32, no 3, p. 317-323Article in journal (Refereed)
    Abstract [en]

    Patients seeking medical care with erythema migrans or flu-like symptoms after suspected or observed tick bite in the southeast of Sweden and previously investigated for Borrelia spp. and/or Anaplasma sp. were retrospectively examined for serological evidence of rickettsial infection (Study 1). Twenty of 206 patients had IgG and/or IgM antibodies to Rickettsia spp. equal to or higher than the cut-off titre of 1:64. Seven of these 20 patients showed seroconversion indicative of recent or current infection and 13 patients had titres compatible with past infection, of which five patients were judged as probable infection. Of 19 patients with medical records, 11 were positive for Borrelia spp. as well, and for Anaplasma sp., one was judged as positive. Five of the 19 patients had antibodies against all three pathogens. Erythema migrans or rash was observed at all combinations of seroreactivity, with symptoms including fever, muscle pain, headache and respiratory problems. The results were compared by screening an additional 159 patients (Study 2) primarily sampled for the analysis of Borrelia spp. or Mycoplasma pneumoniae. Sixteen of these patients were seroreactive for Rickettsia spp., of which five were judged as recent or current infection. Symptoms of arthritis, fever, cough and rash were predominant. In 80 blood donors without clinical symptoms, approximately 1 % were seroreactive for Rickettsia spp., interpreted as past infection. The study shows that both single and co-infections do occur, which illustrate the complexity in the clinical picture and a need for further studies to fully understand how these patients should best be treated.

  • 20.
    Lindblom, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Wallménius, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Sjöwall, Johanna
    Fryland, Linda
    Wilhelmsson, Peter
    Lindgren, Per-Eric
    Forsberg, Pia
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Prevalence of Rickettsia spp. in Ticks and Serological and Clinical Outcomes in Tick-Bitten Individuals in Sweden and on the Åland Islands2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 11, article id e0166653Article in journal (Refereed)
    Abstract [en]

    Tick-transmitted diseases are an emerging health problem, and the hard tick Ixodes ricinus is the main vector for Borrelia spp., tick-borne encephalitis virus and most of the spotted fever Rickettsiae in Europe. The aim of the present study was to examine the incidence of rickettsial infection in the southernmost and south central parts of Sweden and the Aland Islands in Finland the risk of infection in humans and its correlation with a bite of a Rickettsia-infected tick, the self-reported symptoms of rickettsial disease, and the prevalence of co-infection between Rickettsia spp. and Borrelia spp. Persons with a recent tick bite were enrolled through public media and asked to answer a questionnaire, provide a blood sample and bring detached ticks at enlistment and at follow-up three months later. Blood samples were previously analysed for Borrelia spp. antibodies and, for this report, analysed for antibodies to Rickettsia spp. by immunofluorescence and in 16 cases also using Western Blot. Ninety-six (44.0%) of the 218 participants were seropositive for IgG antibodies to Rickettsia spp. Forty (18.3%) of the seropositive participants had increased titres at the follow-up, indicating recent/current infection, while four (1.8%) had titres indicating probable recent/current infection (>= 1: 256). Of 472 ticks, 39 (8.3%) were Rickettsia sp. positive. Five (31.3%) of 16 participants bitten by a Rickettsia-infected tick seroconverted. Experience of the selfreported symptoms nausea (p = 0.006) and radiating pain (p = 0.041) was more common among those with recent, current or probable infection compared to those who did not seroconvert. Participants who showed seroreactivity or seroconversion to Rickettsia spp. had more symptoms than those who were seronegative. Seven (3.2%) participants showed seroconversion to Borrelia spp., and three (1.4%) of these showed seroconversion to both Rickettsia spp. and Borrelia spp., in accordance with previous studies in Sweden. Symptoms of rickettsial disease were in most of the cases vague and general that were difficult to differentiate from other tick-borne diseases.

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  • 21.
    Lindström, Björn E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Center for Clinical Research Dalarna. Falun Cent Hosp, Dept Ophthalmol, Falun, Sweden..
    Skogman, Barbro H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Center for Clinical Research Dalarna. Örebro Univ, Fac Med & Hlth Sci, Örebro, Sweden..
    Lindström, Annika K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Reproductive biology.
    Tallstedt, Leif
    St Eriks Eye Hosp, Dept Ophthalmol, Stockholm, Sweden..
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Borrelia Ocular Infection: A Case Report and a Systematic Review of Published Cases2022In: Ophthalmic Research, ISSN 0030-3747, E-ISSN 1423-0259, Vol. 65, no 2, p. 121-130Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Lyme borreliosis can cause many diverse manifestations, also ocular disease where the diagnosis of ocular borreliosis is challenging. The primary aim was to report on the evidence of Borrelia spirochetes in the ocular tissue in presumed ocular borreliosis.

    Methods: A systematic review of pathological eye conditions was performed where Borrelia has been suspected in relevant ocular tissue, together with a case report of diagnosed uveitis with polymerase chain reaction (PCR)-confirmed Borrelia afzelii in the vitreous. The evidence for clinical and laboratory diagnosis was evaluated systematically. As a secondary aim, the treatment of ocular Borrelia infection was also evaluated for confirmed cases.

    Results: Thirteen includable studies were found, and after the removal of case duplicates, eleven unique cases were extracted. Apart from the present case report, 4 other cases reported strong evidence for the detection of B. spirochetes in ocular tissue. Four cases presented reasonable evidence for assumed detected Borrelia, while three additional cases showed only weak diagnostic credibility that Borrelia was detected.

    Conclusion: This systematic review, including all reported cases and our case report, supports evidence of ocular infection of Borrelia species. Furthermore, in case of suspicion of infection and seronegativity, it is justified to look for Borrelia in eye tissue samples. In addition, microscopy without using PCR is not sufficient to confirm the diagnosis of borreliosis on ocular tissue. In the articles studied, there was no unambiguous recommendation of treatment.

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  • 22.
    Madsen, Kim B.
    et al.
    Falu Hospital, Section of Opthalmology.
    Wallménius, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Fridman, Åke
    Falu Hospital, Section of Opthalmology.
    Påhlson, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Falu Hospital, Centre of Clinical Research.
    Seroprevalence against Rickettsia and Borrelia Species in Patients with Uveiti: A Prospective Survey2017In: Journal of Ophthalmology, ISSN 2090-004X, E-ISSN 2090-0058, article id 9247465Article in journal (Refereed)
    Abstract [en]

    Vector-borne diseases such as Lyme borreliosis and rickettsioses have been associated with ocular inflammation. Our aim was to study patients with diagnosed uveitis to evaluate serological signs of infection or exposure to these tick-borne agents. Forty-eight patients were prospectively examined with serology together with medical records and a questionnaire concerning previous exposure, diseases, and treatments. Seven patients (14.6%) showed seroconversion to Rickettsia spp. between acute and convalescent phase sera, which provides support for a positive Rickettsia diagnosis according to guidelines. The specificity was confirmed by Western blot. Additional 28 patients had stationary titres of which eight (16.6%) had 1 : 256 or higher titre in the first serum, and another 13 patients were seronegative. No epidemiological risk factor or marker could be identified. For Borrelia, only three patients showed moderate IgG titres. A control group of 100 blood donors, 60 patients with rheumatic disease, and 56 patients seeking medical care were tested of which 2.0–7.1% showed low anti-Rickettsia titres and 3.0–8.3% anti-Borrelia titres. The findings are indicative for an association between infection or exposure to Rickettsia spp. and uveitis with a seropositivity among patients with recurrent uveitis in concordance with the spread of rickettsial exposure in a tick-exposed population.

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  • 23.
    Neumüller, Magnus
    et al.
    Department of Biology and Chemical Engineering.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Påhlson, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Trypanosoma spp. in Swedish game animals2012In: Parasitology Research, ISSN 0932-0113, E-ISSN 1432-1955, Vol. 110, no 1, p. 135-139Article in journal (Refereed)
    Abstract [en]

    Serum and blood samples from 36 game animals, shot during the hunting seasons 2007-2009, were collected and analyzed for the presence of Trypanosoma spp. by three methods: isolation, polymerase chain reaction (PCR), and serology. Only fissiped animals were included, four different ruminants and wild boar. Trypanosomes could be isolated from two of the animals, and eight had detectable parasite DNA. Seven animals had high titers of anti-trypanosoma IgG antibodies. The two isolated strains, one from roe dear and one from European elk, were determined to Trypanosoma theileri by partial DNA sequencing of the 18S ribosomal gene. In the seven boars, no Trypanosoma were detected, but four out of seven strongly positive serological samples came from this group. This is the first study in Scandinavia on the presence of Trypanosoma in game animals. The results indicate that trypanosomiasis is frequently occurring among Swedish game animals.

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  • 24.
    Nilsson, K
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Liu, A
    Påhlson, C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lindquist, O
    Demonstration of intracellular microorganisms (Rickettsia spp., Chlamydia pneumoniae, Bartonella spp.) in pathological human aortic valves by PCR.2005In: J Infect, ISSN 0163-4453, Vol. 50, no 1, p. 46-52Article in journal (Other scientific)
  • 25.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rickettsia helvetica; Detection in arthropods and human tissues and its relation to clinical disease2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A relation between R. helvetica and perimyocarditis was, in two young men who died of sudden cardiac death during exercise in 1997, suggested by a seminested PCR, for three different genes, sequencing of the amplified products, documentation of a seroresponse and histopathologic changes in accordance with rickettsioses. One of the young men also had a sarcoidosis. When investigating him and another autopsy case with sarcoidosis further, genetic material from R.helvetica was detected by PCR and histological

    and immunohistochemical (IHC) examination with three antibodies of the PCR positive tissues showed presence of rickettsia-like organisms (r.l.o.), which were predominantly located in the endothelium and the macrophages. TEM clearly identified and demonstrated r.l.o. within the granuloma with findings suggestive of ongoing infection. Immuno-gold labeling of the Proteus OX-19 antiserum showed that the gold markers were localized to the r.l.o. These findings, together with histologic and IHC examination of paraffin-embedded biopsy specimens from 30 patients with confirmed sarcoidosis, where 26 specimens were judged to be positive for r.l.o., support the hypothesis that R. helvetica may cause a chronic vasculitis, as in sarcoidosis. An evaluation of three patients with febrile illness, myalgia and eschar, their significant seroconversion together with substantial data including those from IHC and TEM examination, indicate current rickettsial disease. In a prospective study, 35 Swedish recruits, deployed to Gotland, were examined for seroconversion. Of the 35, eight showed a four-fold increase in IgG titer, reflecting a high rate of exposure. The findings supports the hypothesis that Rickettsia helvetica is a human pathogen that has to be taken into consideration in the diagnosis of tick-transmitted infections in Europe.

    Two collections of Ixodes ricinus ticks were subjected to DNA isolation. By sequencing of the 16SrDNA- and citrate synthase genes it was shown that the detected rickettsia had amplified sequences showing 100% homology with the deposited sequences of Rickettsia helvetica. In the first collection with PCR of the citrate synthase gene the prevalence of rickettsial DNA was 1.7%; in the second collection with a seminested PCR of the 16SrDNA gene the prevalence of rickettsial DNA was found to be in the range from 16% to 36.8%.

  • 26.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Septicaemia with Rickettsia helvetica in a patient with acute febrile illness, rash and myasthenia2009In: Journal of Infection, ISSN 0163-4453, E-ISSN 1532-2742, Vol. 58, no 1, p. 79-82Article in journal (Refereed)
    Abstract [en]

    The spotted fever rickettsia, Rickettsia helvetica, is mostly reported to present a flu-like self-limiting disease. In the present case, however, where the presence of R. helvetica in the blood was verified by PCR together with serologic evidence of infection, the patient presented a different clinical picture with acute febrile illness, rash and long-lasting myasthenia.

  • 27.
    Nilsson, Kenneth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Bauer, Annette
    Pathology & Cytology Dalarna, Region Dalarna, Falun, Sweden.
    Hofmeyer, Syster
    Pathology & Cytology Dalarna, Region Dalarna, Falun, Sweden.
    Gere, Maria
    Pathology & Cytology Dalarna, Region Dalarna, Falun, Sweden.
    Tot, Tibor
    Pathology & Cytology Dalarna, Region Dalarna, Falun, Sweden.
    Granulomatous mastitis caused by Rickettsia species2021In: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 479, no 6, p. 1091-1094Article in journal (Refereed)
    Abstract [en]

    Granulomatous mastitis is a rare inflammatory disease of varying etiology. Tuberculosis and cystic neutrophilic granulomatous mastitis caused by Corynebacterium are the best-established infectious examples. Despite the increasing incidence of Rickettsia-related diseases worldwide, granulomatous inflammation of breast parenchyma caused by Rickettsia has not yet been reported. We present a unique case of bilateral granulomatous mastitis documented with mammography, magnetic resonance imaging and core-needle biopsy. The rickettsial etiology of the disease was proved with specific immunohistochemistry and confirmed with DNA extraction, PCR and serology. The lesions completely resolved after a full-course tetracycline treatment. This case report widens the knowledge about the possible clinical manifestations of Rickettsia infection and adds a new bacterium to the list of etiological factors causing granulomatous mastitis.

  • 28.
    Nilsson, Kenneth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Elfving, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Påhlson, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Rickettsia helvetica in patient with meningitis, Sweden, 20062010In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 16, no 3, p. 490-492Article in journal (Refereed)
    Abstract [en]

    Pathogenicity of Rickettsia helvetica is relatively unknown. We isolated a spotted fever group rickettsial organism from a patient with subacute meningitis. Nucleotide sequences of the 16S rRNA, ompB, and 17kDa genes identified the isolate as R. helvetica. This organism may be associated with serious infections such as central nervous system disorders.

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  • 29.
    Nilsson, Kenneth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Friberg, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Rollman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Tano, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Impact of prolonged storage of clinical samples at 4 degrees C on the recovery of dermatophytes by culture or PCR analysis2019In: Journal de Mycologie Médicale, ISSN 1156-5233, E-ISSN 1773-0449, Vol. 29, no 1, p. 1-6Article in journal (Refereed)
    Abstract [en]

    Dermatophytes are common pathogens in superficial mycoses that are routinely identified by culture or PCR analysis of freshly collected skin, nail or hair specimens. Although clinical samples are normally processed without delay, practical or research issues may necessitate sample storage until later analysis. However, the influence of extended sample storage on the ability to recover fungi by culture vs. PCR analysis has not been specifically studied. Here, a total of 172 dermatological samples collected from 2013-2015 were examined before and after refrigerated storage at 4 degrees C for 10.2-32.3 (mean 25.6) months. By culture, 35% of the dermatophyte-containing fresh samples remained positive at reexamination. At species level, only 19% of initially Trichophyton rubrum-positive samples yielded a positive result after refrigeration, whereas few samples containing Trichophyton violaceum, Microsporum canis or Microsporum audouinii remained culture-positive. Using PCR, 76% of dermatophyte DNA-positive fresh samples were still positive at re-analysis. Notably, 92% of the samples targeted by the T. rubrum DNA primer remained positive after storage. Hence, PCR analysis is more favourable than cultivation with regard to the detectability of dermatophytes in long-term refrigerated clinical samples.

  • 30.
    Nilsson, Kenneth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jaenson, Thomas G. T.
    Uhnoo, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindquist, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Pettersson, Bertil
    Uhlén, Mathias
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Påhlson, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Characterization of a spotted fever group Rickettsia from Ixodes ricinus ticks in Sweden1997In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 35, no 1, p. 243-247Article in journal (Refereed)
    Abstract [en]

    A spotted fever group rickettsia isolated from the common tick, Ixodes ricinus, was genetically characterized by PCR and genomic sequencing. This study was performed with nymphal and adult ticks collected in southern and central Sweden. I. ricinus is the only North European tick species of medical importance which is regularly collected from humans. No species of the genus Rickettsia has previously been found in Scandinavian ticks, nor has any case of domestic rickettsial infection in humans or animals been reported. According to the nucleotide sequencing, the present Rickettsia sp. belongs to the spotted fever group of rickettsiae. Ticks are the most common arthropod reservoirs and vectors of the rickettsiae of this group. Among 748 ticks investigated, 13 (1.7%) were positive for a Rickettsia sp. Borrelia burgdorferi was detected in 52 (7%) of the ticks, a prevalence similar to or somewhat lower than that previously been recorded in other Swedish studies. There was no evidence of ehrlichial or chlamydial DNA in these ticks. The Rickettsia sp. was further characterized by 16S ribosomal DNA (rDNA) sequencing and restriction fragment length polymorphism (RFLP). The 16S rDNA sequencing resulted in a sequence identical to that described for Rickettsia helvetica, but the pattern obtained with RFLP of the citrate synthetase gene diverged from previously known patterns. The rickettsial agent of one tick which was positive by PCR was confirmed by transmission electron microscopy. The morphology of this rickettsia was similar to that of the spotted fever and typhus group rickettsiae. This represents the first documented isolate of a Rickettsia sp. from Swedish ticks.

  • 31.
    Nilsson, Kenneth L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Ouppmärksammad fästingöverförd infection2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 43Article in journal (Refereed)
  • 32.
    Nilsson, Kenneth
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lindquist, Olle
    Department of Surgical Sciences.
    Liu, Ai Jie
    Jaenson, Thomas
    Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology. Systematisk zoologi.
    Friman, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Påhlson, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Rickettsia helvetica in Ixodes ricinus ticks in Sweden1999In: J Clin Microbiol, Vol. 37, p. 400-403Article in journal (Refereed)
  • 33.
    Nilsson, Kenneth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Center for Clinical Research Dalarna. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lukinius, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Påhlson, Carl
    Moron, Cecilia
    Hajem, Nedaá
    Olsson, Britt
    Lindquist, Olle
    Evidence of Rickettsia spp. infection in Sweden: a clinical, ultrastructural and serological study2005In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 113, no 2, p. 126-134Article in journal (Refereed)
    Abstract [en]

    Sweden is an area potentially endemic for spotted fever rickettsioses. Rickettsia helvetica has been isolated from its tick vector Ixodes Ricinus, and in a handful of cases linked to human disease. This study demonstrates for the first time in Sweden the transmission of rickettsial infection after a tick bite and the attack rate in an endemic area. We present three cases of documented rickettsial infection and a prospective serological study of Swedish recruits who were trained in the area where the patients lived and showed seroconversion to spotted fever rickettsiae. All patients showed a four-fold increas in antibody titer to the spotted fever rickettsia, R. helvetica, and immunohistochemical examination revealed rickettsia-like organisms in the walls of skin capillaries and veins. Electron microscopy showed organisms resembling R. helvetica and immunogold labeling with two anti-rickettsial antibodies demonstrated specific labeling of the rickettsial organisms in the skin biopsy specimens. Eight of the thirty-five recruits showed a four-fold increase in IgG titer reflecting a high rate of exposure. The results of this study demonstrate that spotted fever rickettsioses should be taken into consideration in the diagnosis of tick-transmitted infections in Sweden.

  • 34.
    Nilsson, Kenneth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Skoog, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Edvinsson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Child Health and Nutrition.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine. Department of Medical Sciences, Zoonosis Science Centre, Uppsala University, Uppsala, Sweden.
    Protein biomarker profiles in serum and CSF in 158 patients with PTLDS or persistent symptoms after presumed tick-bite exposure compared to those in patients with confirmed acute neuroborreliosis2022In: PLOS ONE, E-ISSN 1932-6203, Vol. 17, no 11, article id e0276407Article in journal (Refereed)
    Abstract [en]

    Background Current diagnostics for patients with lingering symptoms categorized as post-treatment Lyme disease syndrome (PTLDS) have their limitations and may be difficult to interpret. The aim of this exploratory study was to evaluate the feasibility of protein biomarker profiling as a diagnostic platform for this category of patients and to compare these results with similarly obtained results from a group of patients with acute neuroborreliosis.

    Methods and findings Two groups of patient cohorts (Cohort 1 and 2) were analyzed for biomarkers in serum and cerebrospinal fluid (CSF); the results were used for group-level comparison. Cohort 1 comprised 158 adult patients selected from 224 previously diagnosed patients, who between October 2015 and December 2018, after referral, were enrolled and structurally investigated based on defined inclusion criteria. They displayed similar lingering symptoms, with a duration of at least 6 months, after presumed previous tick-borne infection (TBI) and are fully described in a previously published study originating from the Center for Vector-borne Infections (CVI), Uppsala University Hospital, Sweden. Cohort 2, comprised 30 patients diagnosed at Uppsala University Hospital between 2016 and 2019 with laboratory-confirmed acute neuroborreliosis. Their proteomic results, based on serum and CSF analyses, were compared with the 158 patients in Cohort 1. The expression and the concentration of potential biomarkers in each patient's serum and CSF samples were measured based on two multiplex protein panels enabling simultaneous analysis of 92 inflammatory and neurology biomarkers. The PTLDS patient subgroup showed no nominally significant proteins compared to the other CVI patients in Cohort 1. However, CVI patients with signs of inflammation, which were evenly distributed in Cohort 1, showed 16 significantly (p <0.05) different proteins in both CSF and serum, but no association was seen with laboratory-confirmed exposure to Borrelia spp or other TBIs. When comparing the two cohorts, different protein profiles were observed, with 125/148 significantly different proteins in CSF and 93/174 in serum, in patients with laboratory confirmed acute neuroborreliosis, of which 6 in CSF and 6 in serum were significant at the p <0.001 level.

    Conclusions In this first comprehensive inflammatory and neurological biomarker profile study no differences in biomarker profiles were detected between patients with PTLDS and patients with similar persisting symptoms but who did not meet the PTLDS criteria, regardless of whether laboratory verified previous exposure to Borrelia or other TBI's were present. However, the expressed markers differed from those found in patients with confirmed acute neuroborreliosis, which does not support the view that PTLDS reflects an ongoing Borrelia infection. Further studies are needed to understand and assess the usefulness of biosignatures of patients with PTLDS before they can be applied in a clinical setting.

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  • 35.
    Nilsson, Kenneth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Skoog, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Jones, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Labbé Sandelin, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine. Kalmar Cty Hosp, Dept Communicable Dis & Dis Control, Kalmar, Sweden..
    Björling, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Fridenström, Ester
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Edvinsson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    A comprehensive clinical and laboratory evaluation of 224 patients with persistent symptoms attributed to presumed tick-bite exposure2021In: PLOS ONE, E-ISSN 1932-6203, Vol. 16, no 3, article id e0247384Article in journal (Refereed)
    Abstract [en]

    Background Persistent symptoms attributed to presumed tick-bite exposure constitute an unresolved medical controversy. We evaluated whether Swedish adults who met the criteria for post-treatment Lyme disease syndrome (PTLDS) exhibited characteristics distinguishable from adults who did not, but who displayed similar symptoms and disease course after suspected previous tick-bite infection (TBI). Methods and findings During 2015-2018, 255 patients-referred to the Centre for Vector-borne Infections, Uppsala University Hospital, Sweden with symptoms lasting longer than six months-were recruited. Of this group, 224 completed the study. Each patient was examined by an infectious disease specialist and, besides a full medical history, underwent a panel of blood and cerebrospinal fluid laboratory tests including hematological, biochemical, microbiological and immunological analyses, and the RAND-36 scale to measure quality of life. For analysis purposes, patients were divided into five subgroups, of which one represented PTLDS. According to serological results indicating TBI and documented/ reported objective signs of Lyme disease, 85 (38%) patients fulfilled the criteria for PTLDS and were compared with the other 139 (62%) serologically classified patients. In the PTLDS group, erythema chronicum migrans (ECM) was documented/reported in 86% of patients, previous neuroborreliosis in 15%, and acrodermatitis chronica atroficans (ACA) in 3.5%. However, there were no significant differences regarding symptoms, laboratory results or disease course between patients with PTLDS and those without laboratory evidence of Borrelia exposition. Most reported symptoms were fatigue-related (70%), musculoskeletal (79%), neurological (82%) and neurocognitive (57%). Tick bites were recalled by 74%. The RAND-36 score was significantly below that of the general Swedish population. Signs of immunological/inflammatory reactivity with myositis antibodies were detected in 20% of patients, fibrinogen levels were moderately increased in 21% and elevated rheumatoid factor in 6%. Conclusions The PTLDS group did not differ exclusively in any respect from the other subgroups, which either lacked previously documented/reported evidence of borreliosis or even lacked detectable serological signs of exposure to Lyme disease. The results suggest that symptoms often categorized as Chronic-Lyme-Disease (CLD) in the general debate, cannot be uniquely linked to Lyme disease. However, approximately 20% of the total group of patients showed signs of autoimmunity. Further studies are needed to elucidate the underlying causes and mechanisms of PTLDS and there is reason to consider a multifactorial approach.

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  • 36.
    Nilsson, Kenneth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Wallmenius, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Hartwig, Styrbjörn
    Department of Otorhinolaryngology, Falu hospital, Sweden.
    Norlander, Tomas
    Department of Otorhinolaryngology, Falu hospital, Sweden.
    Påhlson, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Bell’s palsy and sudden deafness associated with Rickettsia spp . infection in Sweden: A retrospective and prospective serological survey including PCR findings2014In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 21, no 2, p. 206-214Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE:

    Sixty patients with facial palsy and 67 with sudden deafness were retrospectively or prospectively examined for serological evidence of rickettsial infection; in six cases where cerebrospinal fluid was available, patients were also examined for presence of rickettsial DNA.

    METHODS:

    Rickettsial antibodies were detected in single or paired serum samples using immunofluorescence with Rickettsia helvetica as the antigen and in four cases also using western blot. Using PCR and subsequent direct cycle sequencing, the nucleotide sequences of the amplicons (17 kDa protein gene) in cerebrospinal fluid were analysed.

    RESULTS:

    Five out of 60 (8.3%) patients with facial palsy and eight of 67 (11.9%) with hearing loss showed confirmative serological evidence of infection with Rickettsia spp. An additional three and four patients in the facial palsy and hearing loss groups, respectively, showed evidence of having a recent or current infection or serological findings suggestive of infection. In four cases, the specificity of the reaction was confirmed by western blot. An additional 70 patients were seroreactive with IgG or IgM antibodies higher than or equal to the cut-off of 1:64, whereas 37 patients were seronegative. Only two of 127 patients had detectable antibodies to Borrelia spp. In three of six patients, rickettsial DNA was detected in the cerebrospinal fluid, where the obtained sequences (17 kDa) shared 100% similarity with the corresponding gene sequence of Rickettsia felis.

    CONCLUSIONS:

    These results highlight the importance of considering Rickettsia spp. as a cause of neuritis, and perhaps as a primary cause of neuritis unrelated to neuroborreliosis.

  • 37.
    Nilsson, Kenneth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Wallménius, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Påhlson, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Coinfection with Rickettsia helvetica and Herpes simplex virus 2 in a Young Woman with Meningoencephalitis2011In: Case Reports in Infectious Diseases, ISSN 2090-6625, p. 469194-Article in journal (Refereed)
    Abstract [en]

    Herpes virus type 2 DNA was detected by PCR in the cerebrospinal fluid in a young woman presenting with headache, stiff neck and pleocytosis and serological findings consistent with reactivation. Since she was exposed to ticks, Lyme disease and tick-borne-encephalitis were excluded. Further investigation in an ongoing project, using PCR and sequencing of the amplified products, showed the presence of Rickettsia helvetica in the cerebrospinal fluid. The bacteria were also isolated in Vero cell culture and microimmunofluorescence confirmed the development of antibodies against Rickettsia spp. with predominance of IgM reactivity consistent with recent infection. She was treated with antibiotics and improved rapidly. The patient could easily have been judged to have isolated herpes meningitis. Because Sweden and other European countries are endemic areas for rickettsioses, the paper reaffirms the importance of investigating for the presence of rickettsial infections in endemic areas in cases of meningitis of uncertain aetiology.

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  • 38.
    Nilsson, Kenneth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Wallménius, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Rundlöf-Nygren, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Strömdahl, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Påhlson, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    African tick bite fever in returning Swedish travellers: Report of two cases and aspects of diagnostics2017In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 7, no 1, article id 1343081Article in journal (Refereed)
    Abstract [en]

    Introduction: African tick-bite fever, caused by Rickettsia africae, is endemic in rural areas of sub-Saharan Africa and a possible cause of fever in returning Swedish travellers. Two patients are presented, and the advantages and disadvantages of different diagnostic methods are discussed.

    Patients and methods: Two middle-aged men fell ill with fever after returning home from South Africa. Both had single eschars and one also presented with a lymph node swelling. Samples were taken for serology, general bacterial culture from the wound (Patient 1) using a swab and additionally for Patient 2 PCR of a skin biopsy from the eschar.

    Results and discussion: Both patients seroconverted one month after onset. Real-time PCR of the biopsy was positive, where sequencing of the gltA gene was 99–100% consistent with R. africae. A drop of fluid from the biopsy contained a sufficient number of bacteria to also allow for isolation of rickettsiae in Vero cell culture. Direct molecular detection by PCR from a swab used for bacteria culture from the eschar from Patient 1 also yielded a positive result. In conclusion, the findings highlight the usefulness of swabs for early non-invasive diagnosis of African tick-bite fever in febrile travellers.

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  • 39.
    Nordberg, Marika
    et al.
    Linköping universitet, Kliinisk och experimentell medicin.
    Forsberg, Pia
    Linköping universitet, Klinisk och experimentell medicin.
    Berglund, Johan
    Bjöersdorff, Anneli
    Djursjukhusgruppen, Danderyd.
    Ernerudh, Jan
    Linköping universitet, Klinisk immunologi.
    Garpmo, Ulf
    Kalmar länslasarett, Klinisk Mikrobiologi.
    Haglund, Mats
    Kalmar länslasarett, Infektionssjukdomar.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eliasson, Ingvar
    Norra Älvsborgs sjukhus, .
    Aetiology of tick-borne infections in an adult swedish population-are co-infections with multiple agents common2014In: Open Journal of Clinical Diagnostics, ISSN 2162-5816, E-ISSN 2162-5824, Vol. 4, no 1, p. 31-40Article in journal (Refereed)
    Abstract [en]

    In Scandinavia, tick-borne infections affecting humans include Lyme borreliosis (LB), tick-borne encephalitis (TBE) and human granulocytic anaplasmosis (HGA). Each of these infections can present with unspecific symptoms. In this prospective clinical study, we recruited patients based on two independent inclusion criteria; 1) patients with unspecific symptoms, i.e. fever (≥38.0˚C) or a history of feverishness and/or any combination of headache, myalgia or arthralgia and 2) patients with erythema migrans (EM), following an observed tick bite or tick exposure within one month  prior to onset of symptoms. A total of 206 patients fulfilled the study. Among these, we could identify 186 cases of LB (174 with EM), 18 confirmed and two probable cases of HGA and two cases of TBE. Thirteen of the HGA cases presented without fever. Furthermore, 22 of the EM patients had a sub-clinical co-infection with Anaplasma phagocytophilum, based on serology. Both TBE cases had co-infections, one with Borrelia burgdorferi and one with Anaplasma phagocytophilum. We conclude that it is important to consider several causative agents and possible co-infections in the clinical management of infectious diseases where ticks may be suspected as vectors.

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  • 40.
    Påhlson, Carl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Lu, Xi
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Applied Material Science.
    Ott, Marjam
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Applied Material Science.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Characteristics of in vitro infection of human monocytes, by Rickettsia helvetica2021In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 23, no 2-3, article id 104776Article in journal (Refereed)
    Abstract [en]

    Eighteen species of rickettsiae are reported to cause infections in humans. One of these is Rickettsia helvetica, which is endemic in European and Asian countries and transmitted by the tick Ixodes ricinus. Besides fever, it has been demonstrated to cause meningitis and is also associated with perimyocarditis. One of the initial targets for rickettsiae after inoculation by ticks is the macrophage/monocyte. How rickettsiae remain in the macrophages/monocytes before establishing their infection in vascular endothelial cells remains poorly understood. The main aim of the present study was to investigate the impact on and survival of R. helvetica in a human leukemic monocytic cell line, THP-1. Our results show that R. helvetica survives and propagates in the THP-1 cells. The infection in monocytes was followed for seven days by qPCR and for 30 days by TEM, where invasion of the nucleus was also observed as well as double membrane vacuoles containing rickettsiae, a finding suggesting that R. helvetica might induce autophagy at the early stage of infection. Infected monocytes induced TNF-α which may be important in host defence against rickettsial infections and promote cell survival and inhibiting cell death by apoptosis. The present findings illustrate the importance of monocytes to the pathogenesis of rickettsial disease.

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  • 41.
    Severinsson, Kristofer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Jaenson, Thomas G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Pettersson, John
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Falk, Kerstin
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Detection and prevalence of Anaplasma phagocytophilum and Rickettsia helvetica in Ixodes ricinus ticks in seven study areas in Sweden2010In: Parasites & Vectors, E-ISSN 1756-3305, Vol. 3, no 1, p. 66-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Tick-borne Anaplasma phagocytophilum and Rickettsia spp. are considered to be emerging human pathogens, but only limited data are available on their occurrence in Sweden. Two real-time PCR assays followed by nested PCR and sequence analysis were carried out to investigate the prevalence of A. phagocytophilum and spotted fever rickettsiae in ticks from seven areas in Sweden.

    RESULTS: In 139 pooled samples, representing a total of 1245 Ixodes ricinus ticks (204 larvae, 963 nymphs, 38 males, 40 females), the overall positive mean infection prevalence was 1.3-15.0% for A. phagocytophilum and 1.5-17.3% for R. helvetica. A. phagocytophilum was only detected in nymphs (1.7-19.4%), whereas R. helvetica was detected in all three tick stages. Support for vertical and transstadial transmission was only obtained for R. helvetica. Both agents showed similar infection rates across study areas, although infection rates were greater in coastal areas.

    CONCLUSIONS: The results show that both pathogens occurred in all seven locations, indicating that they are prevalent in Sweden and should be considered etiological agents in patients recently bitten by ticks.

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  • 42.
    Wallmenius, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Barboutis, Christos
    Fransson, Thord
    Jaenson, Thomas G. T.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Lindgren, Per-Eric
    Nyström, Fredrik
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Salaneck, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Spotted fever Rickettsia species in Hyalomma and Ixodes ticks infesting migratory birds in the European Mediterranean area2014In: Parasites & Vectors, E-ISSN 1756-3305, Vol. 7, article id 318Article in journal (Refereed)
    Abstract [en]

    Background: A few billion birds migrate annually between their breeding grounds in Europe and their wintering grounds in Africa. Many bird species are tick-infested, and as a result of their innate migratory behavior, they contribute significantly to the geographic distribution of pathogens, including spotted fever rickettsiae. The aim of the present study was to characterize, in samples from two consecutive years, the potential role of migrant birds captured in Europe as disseminators of Rickettsia-infected ticks. Methods: Ticks were collected from a total of 14,789 birds during their seasonal migration northwards in spring 2009 and 2010 at bird observatories on two Mediterranean islands: Capri and Antikythira. All ticks were subjected to RNA extraction followed by cDNA synthesis and individually assayed with a real-time PCR targeting the citrate synthase (gltA) gene. For species identification of Rickettsia, multiple genes were sequenced. Results: Three hundred and ninety-eight (2.7%) of all captured birds were tick-infested; some birds carried more than one tick. A total number of 734 ticks were analysed of which 353 +/- 1 (48%) were Rickettsia-positive; 96% were infected with Rickettsia aeschlimannii and 4% with Rickettsia africae or unidentified Rickettsia species. The predominant tick taxon, Hyalomma marginatum sensu lato constituted 90% (n = 658) of the ticks collected. The remaining ticks were Ixodes frontalis, Amblyomma sp., Haemaphysalis sp., Rhipicephalus sp. and unidentified ixodids. Most ticks were nymphs (66%) followed by larvae (27%) and adult female ticks (0.5%). The majority (65%) of ticks was engorged and nearly all ticks contained visible blood. Conclusions: Migratory birds appear to have a great impact on the dissemination of Rickettsia-infected ticks, some of which may originate from distant locations. The potential ecological, medical and veterinary implications of such Rickettsia infections need further examination.

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  • 43.
    Wallménius, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Pettersson, John H-O
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Jaenson, Thomas G.T.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Prevalence of Rickettsia spp., Anaplasma phagocytophilum and Coxiella burnetii in adult Ixodes ricinus ticks from 29 study areas in central and southern Sweden2012In: Ticks and Tick-borne Diseases, ISSN 1877-959X, E-ISSN 1877-9603, Vol. 3, no 2, p. 100-106Article in journal (Refereed)
    Abstract [en]

    A total of 887 adult Ixodes ricinus ticks (469 females and 418 males) from 29 different localities in Sweden were screened for Rickettsia, Anaplasma, and Coxiella DNA using PCR and then subjected to gene sequencing. Rickettsial DNA was detected in 9.5–9.6% of the ticks. Most of the positive ticks were infected with Rickettsia helvetica. One tick harbored another spotted fever rickettsia, closely related to or identical with R. sibirica not previously found in I. ricinus nor in Sweden. Six of the ticks (0.7%) were infected with an Anaplasma sp., presumably A. phagocytophilum. Coxiella burnetii DNA was not detected in any of the ticks. The detection of R. helvetica and A. phagocytophilum in several of the localities sampled suggests that these potentially human-pathogenic agents are common in Sweden.

  • 44.
    Wang, Mengqi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lu, Xi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Sinha, Tanay Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Center for Clinical Research Dalarna. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Wu, Di
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics.
    Kamali-Moghaddam, Masood
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics.
    Surface protein profiles of extracellular vesicles reveal SARS-CoV-2 infectionManuscript (preprint) (Other academic)
  • 45.
    Wass, Linda
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Gothenburg, Sweden.
    Grankvist, Anna
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Gothenburg, Sweden.
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Gustafsson, Helena
    Gavle Cent Hosp, Dept Hematol, Gavle, Sweden.
    Krogfelt, Karen
    Statens Serum Inst, Dept Bacteria Parasites & Fungi, Copenhagen, Denmark.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Quarsten, Hanne
    Sorlandet Hosp Hlth Enterprise, Dept Med Microbiol, Kristiansand, Norway.
    Henningsson, Anna J.
    Cty Hosp Ryhov, Dept Clin Microbiol, Jonkoping, Sweden.
    Wennerås, Christine
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Gothenburg, Sweden;Sahlgrens Univ Hosp, Dept Clin Microbiol, Guldhedsgatan 10, S-41346 Gothenburg, Sweden.
    Serological reactivity to Anaplasma phagocytophilum in neoehrlichiosis patients2018In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 37, no 9, p. 1673-1678Article in journal (Refereed)
    Abstract [en]

    The tick-borne bacterium Candidatus (Ca.) Neoehrlichia (N.) mikurensis is a cause of "fever of unknown origin" because this strict intracellular pathogen escapes detection by routine blood cultures. Case reports suggest that neoehrlichiosis patients may display serological reactivity to Anaplasma (A.) phagocytophilum. Since Anaplasma serology is part of the diagnostic work-up of undetermined fever in European tick-exposed patients, we wanted to investigate (1) the prevalence of A. phagocytophilum seropositivity among neoehrlichiosis patients, (2) the frequency of misdiagnosed neoehrlichiosis patients among A. phagocytophilum seropositive patients, and (3) the frequency of A. phagocytophilum and Ca. N. mikurensis co-infections. Neoehrlichiosis patients (n = 18) were analyzed for A. phagocytophilum IgM and IgG serum antibodies by indirect immunofluorescence assay. Serum samples from suspected anaplasmosis patients (n = 101) were analyzed for bacterial DNA contents by singleplex PCR specific for A. phagocytophilum and Ca. N. mikurensis, respectively. One fifth of the neoehrlichiosis patients (4/18) were seropositive for IgM and/or IgG to A. phagocytophilum at the time of diagnosis. Among the patients with suspected anaplasmosis, 2% (2/101) were positive for Ca. N. mikurensis by PCR whereas none (0/101) had detectable A. phagocytophilum DNA in the serum. To conclude, patients with suspected anaplasmosis may in fact have neoehrlichiosis. We found no evidence of A. phagocytophilum and Ca. N. mikurensis co-infections in humans with suspected anaplasmosis or confirmed neoehrlichiosis.

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  • 46.
    Wass, Linda
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Infect Dis, Guldhedsgatan 10A, S-41346 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Clin Microbiol, Gothenburg, Region Vastra G, Sweden.
    Quarsten, Hanne
    Sorlandet Hosp Hlth Enterprise, Dept Med Microbiol, Kristiansand, Norway.
    Lindgren, Per-Eric
    Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect 2, Linköping, Sweden.;Cty Hosp Ryhov, Div Clin Microbiol, Lab Med, Jönköping, Sweden.
    Forsberg, Pia
    Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect 2, Linköping, Sweden.
    Skoog, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Lingblom, Christine
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Infect Dis, Guldhedsgatan 10A, S-41346 Gothenburg, Sweden.
    Wenneras, Christine
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Infect Dis, Guldhedsgatan 10A, S-41346 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Clin Microbiol, Gothenburg, Region Vastra G, Sweden.
    Cytokine responses of immunosuppressed and immunocompetent patients with Neoehrlichia mikurensis infection2022In: Medical Microbiology and Immmunology, ISSN 0300-8584, E-ISSN 1432-1831, Vol. 211, no 2-3, p. 133-141Article in journal (Refereed)
    Abstract [en]

    Purpose The tick-borne bacterium Neoehrlichia mikurensis causes the infectious disease neoehrlichiosis in humans. Vascular endothelium is one of the target cells of the infection. Neoehrlichiosis patients with compromised B cell immunity present with more severe inflammation than immunocompetent patients. The aim of this study was to compare the cytokine profiles of immunocompetent and immunosuppressed patients with neoehrlichiosis.

    Methods Blood samples from Swedish and Norwegian immunosuppressed (N = 30) and immunocompetent (N = 16) patients with neoehrlichiosis were analyzed for the levels of 30 cytokines, using a multiplex cytokine assay and ELISA. A gender-matched healthy control group (N = 14) was analyzed in parallel. Data were analyzed using the multivariate method OPLS-DA.

    Results The multiplex cytokine analyses generated more cytokine results than did the uniplex ELISA analyses. Multivariate analysis of the multiplex cytokine results established that increased levels of FGF2, GM-CSF, CXCL10, and IFN-gamma were associated with immunosuppressed patients, whereas increased levels of IL-15 and VEGF were associated with immunocompetent neoehrlichiosis patients. When multivariate analysis findings were confirmed with uniplex ELISA, it was found that both groups of patients had similarly elevated levels of VEGF, FGF2 and IFN-gamma. In contrast, the immunosuppressed patients had clearly elevated levels of CXCL10, CXCL13 and BAFF, whereas the immunocompetent patients had the same levels as healthy controls.

    Conclusion Pro-angiogenic and type 1 cytokines were produced as part of the host response of neoehrlichiosis independent of immune status, whereas immunosuppressed neoehrlichiosis patients produced cytokines required for B cell-mediated defense.

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  • 47.
    Wilhelmsson, Peter
    et al.
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden;Department of Clinical Microbiology, Laboratory Medicine, Region Jönköping County Hospital, Jönköping, Sweden..
    Lindgren, Per-Eric
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden;Department of Clinical Microbiology, Laboratory Medicine, Region Jönköping County Hospital, Jönköping, Sweden;National Reference Laboratory for Borrelia and Other Tick-Borne Bacteria, Division of Clinical Microbiology, Laboratory Medicine, Region Jönköping County Hospital, Jönköping, Sweden..
    Fransson, Thord
    Department of Environmental Research and Monitoring, Swedish Museum of Natural History, Stockholm, Sweden..
    Grandi, Giulio
    Section for Parasitology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden;Department of Microbiology, National Veterinary Institute (SVA), Uppsala, Sweden..
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Candidatus Rickettsia Vini DNA in Ticks Collected from Nest Burrows of the European Sand Martin (Riparia riparia) in Sweden2023In: Vector Borne and Zoonotic Diseases, ISSN 1530-3667, E-ISSN 1557-7759, Vol. 23, no 7, p. 378-383Article in journal (Refereed)
    Abstract [en]

    Background: Birds can cross geographical and environmental barriers and thereby facilitate dispersal of tick-borne pathogens both as carriers of infected ticks and as reservoirs of pathogenic microorganisms. Ixodes lividus (Ixodida: Ixodidae) is an endophilic tick in the Palearctic region that is highly specialized on its host, the European sand martin Riparia riparia. The purpose of this study was to determine whether I. lividus ticks sampled from sand martin nests in Sweden carry vector-borne pathogens.Materials and Methods: Fed ticks were collected in the autumns of 2017 and 2019 from the nests of a European sand martin colony in southern Sweden. Ticks were identified morphologically to developmental stage and species and were tested for tick-borne pathogens using PCR-based methods.Results: None of the 41 ticks tested positive for five tick-borne pathogens including Borrelia spp., tick-borne encephalitis virus (TBEV), Neoehrlichia mikurensis, Anaplasma phagocytophilum, and Babesia spp. Thirty-seven (13 females, 23 nymphs and 1 larva) of the 41 ticks tested positive for the gltA gene of Rickettsia spp. The sequences of the 17 kDa and gltA genes were most closely related to Candidatus Rickettsia vini.Conclusion: Our study confirms other reports that I. lividus ticks associated with the European sand martin have high infection prevalence of Ca. R. vini.

  • 48.
    Zhao, Hongxing
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics. Unit Affin Prote Uppsala, Sci Life Lab, Stockholm, Sweden.
    Wang, Mengqi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Muthelo, Phathutshedzo
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics.
    Löf, Liza
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics. Unit Affin Prote Uppsala, Sci Life Lab, Stockholm, Sweden.
    Sterky, Fredrik
    Univ Gothenburg, Dept Lab Med, Gothenburg, Sweden.;Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Clin Chem, Gothenburg, Sweden..
    Gallini, Radiosa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Unit Affin Prote Uppsala, Sci Life Lab, Stockholm, Sweden.
    Kumar, Nallani Vijay
    Univ Gothenburg, Mammalian Prot Express core facil, Gothenburg, Sweden..
    Monsen, Tor
    Umeå Univ, Dept Clin Microbiol, Umeå, Sweden..
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Åberg, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Unit Affin Prote Uppsala, Sci Life Lab, Stockholm, Sweden.
    Kamali-Moghaddam, Masood
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics.
    Mei, Ya-Fang
    Umeå Univ, Dept Clin Microbiol, Umeå, Sweden..
    Landegren, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics.
    Detection of SARS-CoV-2 antibodies in serum and dried blood spot samples of vaccinated individuals using a sensitive homogeneous proximity extension assay2022In: New Biotechnology, ISSN 1871-6784, E-ISSN 1876-4347, Vol. 72, p. 139-148Article in journal (Refereed)
    Abstract [en]

    A homogeneous PCR-based assay for sensitive and specific detection of antibodies in serum or dried blood spots (DBS) is presented and the method is used to monitor individuals infected with or vaccinated against SARS-CoV-2. Detection probes were prepared by conjugating the recombinant spike protein subunit 1 (S1), containing the receptor binding domain (RBD) of SARS-CoV-2, to each of a pair of specific oligonucleotides. The same was done for the nucleocapsid protein (NP). Upon incubation with serum or DBS samples, the bi- or multivalency of the antibodies (IgG, IgA or IgM) brings pairs of viral proteins with their conjugated oligonucleotides in proximity, allowing the antibodies to be detected by a modified proximity extension assay (PEA). Anti-S1 and anti-NP antibodies could be detected simultaneously from one incubation reaction. This Antibody PEA (AbPEA) test uses only 1 µl of neat or up to 100,000-fold diluted serum or one ø1.2 mm disc cut from a DBS. All 100 investigated sera and 21 DBS collected prior to the COVID-19 outbreak were negative, demonstrating a 100% specificity. The area under the curve, as evaluated by Receiver Operating Characteristic (ROC) analysis reached 0.998 (95%CI: 0.993–1) for samples taken from 11 days after symptoms onset. The kinetics of antibody responses were monitored after a first and second vaccination using serially collected DBS from 14 individuals. AbPEA offers highly specific and sensitive solution-phase antibody detection without requirement for secondary antibodies, no elution step when using DBS sample in a simple procedure that lends itself to multiplex survey of antibody responses.

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