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  • 1. Andersson, H.
    et al.
    Hartmanová, B.
    Bäck, Erik
    Örebro University, Department of Clinical Medicine.
    Eliasson, H.
    Örebro University, Department of Clinical Medicine.
    Landfors, M.
    Näslund, L.
    Rydén, P.
    Sjöstedt, A.
    Transcriptional profiling of the peripheral blood response during tularemia2006In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 7, no 6, p. 503-513Article in journal (Refereed)
    Abstract [en]

    Tularemia is a febrile disease caused by the highly contagious bacterium Francisella tularensis. We undertook an analysis of the transcriptional response in peripheral blood during the course of ulceroglandular tularemia by use of Affymetrix microarrays comprising 14,500 genes. Samples were obtained from seven individuals at five occasions during 2 weeks after the first hospital visit and convalescent samples 3 months later. In total, 265 genes were differentially expressed, 95 of which at more than one time point. The differential expression was verified with real-time quantitative polymerase chain reaction for 36 genes (R(2)=0.590). The most prominent changes were noted in samples drawn on days 2-3 and a considerable proportion of the upregulated genes appeared to represent an interferon-gamma-induced response and also a proapoptotic response. Genes involved in the generation of innate and acquired immune responses were found to be downregulated, presumably a pathogen-induced event. A logistic regression analysis revealed that seven genes were good predictors of the early phase of tularemia. This is the first description of the transcriptional host response to ulceroglandular tularemia and the study has identified gene subsets relevant to the pathogenesis of the disease and subsets that may serve as early diagnostic biomarkers.

  • 2.
    Cajander, Sara
    et al.
    Örebro University, School of Medical Sciences. Infektionskliniken, Universitetssjukhuset i Örebro, Örebro, Sweden.
    Eliasson, Henrik
    Infektionskliniken, Örebro University Hospital, Region Örebro län, Örebro, Sweden.
    Mb Osler: ökad risk för infektioner och livshotande komplikationer: Fyra fall av invasiv infektionssjukdom under samma tidsperiod beskrivs2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 37, p. 1613-1615Article in journal (Refereed)
    Abstract [sv]

    Mb Osler är internationellt mer känd under namnen heredi-tary hemorrhagic telangiectasia (HHT) eller Osler–Weber–Rendu syndrome. Sjukdomen beror på en nedärvd genetisk defekt, där den muterade genen påverkar TGF-superfamiljens signalering i kärlendotel. Detta leder till telangiektasier och ibland större arteriovenösa missbildningar [1]. Eftersom kärl-missbildningarna kan uppstå i olika organ varierar symtom-bilden mellan olika familjer och individer. En till två tredjede-lar av de drabbade söker någon gång medicinsk hjälp på grund av komplikationer till sjukdomen [2]. De vanligaste kliniska uttrycken är recidiverande näsblöd-ningar och järnbristanemi. Incidensen varierar geografiskt och finns rapporterad från 1/2351 till 1/39216 [3]. Diagnosen ställs med hjälp av de sk Curaçao-kriterierna [4] (Fakta 1). Hos en del patienter leder sjukdomen till svåra organkompli-kationer, och på senare tid har ökad risk för infektioner upp-märksammats. Vi beskriver fyra patienter med diagnosen Mb Osler som vårdades på grund av allvarlig infektionssjukdom under sam-ma tidsperiod.

  • 3.
    Eliasson, Henrik
    Örebro University, School of Health and Medical Sciences.
    Tularemia: epidemiological, clinical and diagnostic aspects2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tularemia is a zoonosis caused by the small, fastidious, gram-negative rod Francisella tularensis that appears over almost the entire Northern Hemisphere. In Sweden, tularemia has appeared mainly in restricted areas in northern parts of central Sweden.

    The disease can be transmitted through several routes: direct contact with infected animals, by vectors, through contaminated food or water or through inhalation of aerosolized bacteria. Distinct clinical forms of the disease are seen, depending on the route of transmission. During the last years, tularemia has emerged in new areas in central Sweden, south of the endemic area. The emergence of tularemia in the County of Örebro prompted the investigations presented in this thesis.

    We performed a case-control study, using a mailed questionnaire, to identify risk factors for acquiring tularemia in Sweden (Paper I). After multivariate analysis, mosquito bites and cat ownership could be associated with tularemia in all studied areas while farming appeared as a risk factor only in endemic areas.

    In Paper II, we evaluated a PCR analysis, targeting the tul4 gene, used on samples from primary lesions in patients with ulceroglandular tularemia. The method performed well, with a sensitivity of 78% and a specifi city of 96%. The clinical characteristics of tularemia in an emergent area in Sweden were studied Paper III), using case fi les and a questionnaire. Of 278 cases of tularemia reported during the years 2000 to 2004, 234 had been in contact with a doctor from the Department of Infectious Diseases at Örebro University Hospital, and were thus included. The ulceroglandular form of the disease was seen in 89% of the cases, with the primary lesion, in most cases, on the lower leg. An overwhelming majority of cases occurred during late summer and early autumn, further supporting transmission by mosquitoes. Erythemas overlying the affected lymph node areas were seen in 19% of patients with forms of tularemia affecting peripheral lymph nodes. Late skin manifestations, of various appearances, were seen in 30% of the cases, predominantly in women. A raised awareness of tularemia among physicians in the county during the course of the outbreak was found, as documented by the development of shorter doctor’s delay and less prescription of antibiotics inappropriate in tularemia.

    Finally, we developed a simplifi ed whole-blood lymphocyte stimulation test, as a diagnostic tool in tularemia (Paper IV). The level of IFN-γ, as a proxy for lymphocyte proliferation, was measured after 24-h stimulation. Additionally, a tularemia ELISA with ultra-purifi ed LPS as the antigen was evaluated, showing a high sensitivity. The lymphocyte stimulation test, when performed on consecutive samples from subjects with ongoing tularemia was able to detect the disease earlier in the course of the disease than both the new ELISA and the tube agglutination test. Furthermore, all tularemia cases became positive in the lymphocyte stimulation test within 12 days of disease. In conclusion, this thesis describes risk factors for acquiring tularemia as well as the clinical characteristics of the disease in Sweden. Additionally, a Francisella PCR analysis and a tularemia ELISA based on highly purifi ed LPS is evaluated, and a simplified lymphocyte stimulation test, for early confirmation of the disease, is developed.

    List of papers
    1. The 2000 tularemia outbreak: a case-control study of risk factors in disease-endemic and emergent areas, Sweden
    Open this publication in new window or tab >>The 2000 tularemia outbreak: a case-control study of risk factors in disease-endemic and emergent areas, Sweden
    Show others...
    2002 (English)In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 8, no 9, p. 956-960Article in journal (Refereed) Published
    Abstract [en]

    A widespread outbreak of tularemia in Sweden in 2000 was investigated in a case-control study in which 270 reported cases of tularemia were compared with 438 controls. The outbreak affected parts of Sweden where tularemia had hitherto been rare, and these "emergent" areas were compared with the disease-endemic areas. Multivariate regression analysis showed mosquito bites to be the main risk factor, with an odds ratio (OR) of 8.8. Other risk factors were owning a cat (OR 2.5) and farm work (OR 3.2). Farming was a risk factor only in the disease-endemic area. Swollen lymph nodes and wound infections were more common in the emergent area, while pneumonia was more common in the disease-endemic area. Mosquito bites appear to be important in transmission of tularemia. The association between cat ownership and disease merits further investigation.

    National Category
    Medical and Health Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-2913 (URN)12194773 (PubMedID)
    Available from: 2008-02-20 Created: 2008-02-20 Last updated: 2017-12-14Bibliographically approved
    2. Clinical use of a diagnostic PCR for Francisella tularensis in patients with suspected ulceroglandular tularaemia
    Open this publication in new window or tab >>Clinical use of a diagnostic PCR for Francisella tularensis in patients with suspected ulceroglandular tularaemia
    2005 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 37, no 11, p. 833-837Article in journal (Refereed) Published
    Abstract [en]

    A retrospective analysis to evaluate the clinical use of a diagnostic PCR for Francisella tularensis in patients with suspected ulceroglandular tularaemia was performed. 154 samples, 129 from patients with definitive tularaemia and 25 from patients where tularaemia could be ruled out, were analysed. The diagnostic PCR had a specificity of 96%, a sensitivity of 78.3%, and a Positive Predictive Value of 99%. Especially samples from encrusted lesions, even up to 4 weeks old, in patients with tularaemia, were PCR positive to a high degree when taken properly. The diagnostic PCR is useful in suspected ulceroglandular tularaemia, giving a fast and accurate diagnosis.

    National Category
    Medical and Health Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-2914 (URN)10.1080/00365540500400951 (DOI)16308216 (PubMedID)
    Available from: 2008-02-20 Created: 2008-02-20 Last updated: 2017-12-14Bibliographically approved
    3. Tularaemia in an emergent area in Sweden: An analysis of 234 cases in five years
    Open this publication in new window or tab >>Tularaemia in an emergent area in Sweden: An analysis of 234 cases in five years
    2007 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 39, no 10, p. 880-889Article in journal (Refereed) Published
    Abstract [en]

    A retrospective study of clinical tularaemia in an emergent area in Sweden is presented. 234 patients seen during the y 2000-2004 were studied, using case files and a questionnaire. There was a predominance of ulceroglandular tularaemia (89%), occurring in late summer and early autumn, reflecting the dominance of mosquito-borne transmission. The incubation period varied from a few hours to 11 d, with a median of 3 d. Cutaneous manifestations of tularaemia, apart from primary lesions, were noted in 43% of the cases. Coughing was common, even in patients with ulceroglandular tularaemia, supporting the view that haematogenous spread to the respiratory system occurs. Regular laboratory tests, such as WBC, ESR and C-reactive protein, were in general only moderately elevated. In the earlier y studied, the Doctor's Delay was substantial as was the misdiagnosis and prescription of inadequate antibiotics. In the later y, however, the delay and misdiagnosis were significantly lower, reflecting the increased recognition of the disease by the physicians in the area. A few relapses occurred, all in patients treated with doxycycline. No lethality was seen, reflecting the benign course of tularaemia type B infection.

    Place, publisher, year, edition, pages
    London: Taylor & Francis, 2007
    National Category
    Medical and Health Sciences Infectious Medicine
    Research subject
    Infectious Diseases
    Identifiers
    urn:nbn:se:oru:diva-2915 (URN)10.1080/00365540701402970 (DOI)
    Available from: 2008-02-20 Created: 2008-02-20 Last updated: 2017-12-14Bibliographically approved
    4. Kinetics of immune response in tularemia: comparison between ELISA, tube agglutination and a novel whole blood lymphocyte stimulation test
    Open this publication in new window or tab >>Kinetics of immune response in tularemia: comparison between ELISA, tube agglutination and a novel whole blood lymphocyte stimulation test
    Show others...
    (English)Manuscript (Other academic)
    National Category
    Medical and Health Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-2916 (URN)
    Available from: 2008-02-20 Created: 2008-02-20 Last updated: 2017-10-18Bibliographically approved
  • 4.
    Eliasson, Henrik
    et al.
    Örebro University, School of Health and Medical Sciences.
    Broman, Tina
    Forsman, Mats
    Bäck, Erik
    Örebro University, School of Health and Medical Sciences.
    Tularemia: current epidemiology and disease management2006In: Infectious Disease Clinics of North America, ISSN 0891-5520, E-ISSN 1557-9824, Vol. 20, no 2, p. 289-311, ixArticle in journal (Refereed)
  • 5.
    Eliasson, Henrik
    et al.
    Örebro University, School of Health and Medical Sciences.
    Bäck, Erik
    Örebro University, School of Health and Medical Sciences.
    Tularaemia in an emergent area in Sweden: An analysis of 234 cases in five years2007In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 39, no 10, p. 880-889Article in journal (Refereed)
    Abstract [en]

    A retrospective study of clinical tularaemia in an emergent area in Sweden is presented. 234 patients seen during the y 2000-2004 were studied, using case files and a questionnaire. There was a predominance of ulceroglandular tularaemia (89%), occurring in late summer and early autumn, reflecting the dominance of mosquito-borne transmission. The incubation period varied from a few hours to 11 d, with a median of 3 d. Cutaneous manifestations of tularaemia, apart from primary lesions, were noted in 43% of the cases. Coughing was common, even in patients with ulceroglandular tularaemia, supporting the view that haematogenous spread to the respiratory system occurs. Regular laboratory tests, such as WBC, ESR and C-reactive protein, were in general only moderately elevated. In the earlier y studied, the Doctor's Delay was substantial as was the misdiagnosis and prescription of inadequate antibiotics. In the later y, however, the delay and misdiagnosis were significantly lower, reflecting the increased recognition of the disease by the physicians in the area. A few relapses occurred, all in patients treated with doxycycline. No lethality was seen, reflecting the benign course of tularaemia type B infection.

  • 6.
    Eliasson, Henrik
    et al.
    Örebro University, School of Health and Medical Sciences.
    Lindbäck, Johan
    Nuorti, Pekka
    Arneborn, Malin
    Giesecke, Johan
    Tegnell, Anders
    The 2000 tularemia outbreak: a case-control study of risk factors in disease-endemic and emergent areas, Sweden2002In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 8, no 9, p. 956-960Article in journal (Refereed)
    Abstract [en]

    A widespread outbreak of tularemia in Sweden in 2000 was investigated in a case-control study in which 270 reported cases of tularemia were compared with 438 controls. The outbreak affected parts of Sweden where tularemia had hitherto been rare, and these "emergent" areas were compared with the disease-endemic areas. Multivariate regression analysis showed mosquito bites to be the main risk factor, with an odds ratio (OR) of 8.8. Other risk factors were owning a cat (OR 2.5) and farm work (OR 3.2). Farming was a risk factor only in the disease-endemic area. Swollen lymph nodes and wound infections were more common in the emergent area, while pneumonia was more common in the disease-endemic area. Mosquito bites appear to be important in transmission of tularemia. The association between cat ownership and disease merits further investigation.

  • 7.
    Eliasson, Henrik
    et al.
    Örebro University, School of Health and Medical Sciences.
    Olcén, Per
    Sjöstedt, Anders
    Jurstrand, Margareta
    Bäck, Erik
    Andersson, Sören
    Kinetics of immune response in tularemia: comparison between ELISA, tube agglutination and a novel whole blood lymphocyte stimulation testManuscript (Other academic)
  • 8. Eliasson, Henrik
    et al.
    Olcén, Per
    Sjöstedt, Anders
    Jurstrand, Margareta
    Bäck, Erik
    Örebro University, School of Health and Medical Sciences.
    Andersson, Sören
    Örebro University, School of Health and Medical Sciences.
    Kinetics of the immune response associated with tularemia: comparison of an enzyme-linked immunosorbent assay, a tube agglutination test, and a novel whole-blood lymphocyte stimulation test2008In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 15, no 8, p. 1238-1243Article in journal (Refereed)
    Abstract [en]

    We have developed and evaluated a novel and simplified whole-blood lymphocyte stimulation assay that focuses on the measurement of gamma interferon after 24 h of stimulation with whole-cell tularemia antigen and a tularemia enzyme-linked immunosorbent assay (ELISA) based on highly purified lipopolysaccharide antigen. Comparison of the kinetics of the two assays and those of the traditional tube agglutination test shows that the cellular immune response can be detected earlier by the lymphocyte stimulation assay. This test already shows a high proportion of positive results during the first week after the onset of the disease, may be applicable in everyday laboratory practice, and has the potential of changing routine diagnostics for tularemia. The new ELISA has a high sensitivity and becomes positive to a high degree during the second week of disease. 

  • 9.
    Eliasson, Henrik
    et al.
    Örebro University, School of Health and Medical Sciences.
    Sjöstedt, Anders
    Bäck, Erik
    Clinical use of a diagnostic PCR for Francisella tularensis in patients with suspected ulceroglandular tularaemia2005In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 37, no 11, p. 833-837Article in journal (Refereed)
    Abstract [en]

    A retrospective analysis to evaluate the clinical use of a diagnostic PCR for Francisella tularensis in patients with suspected ulceroglandular tularaemia was performed. 154 samples, 129 from patients with definitive tularaemia and 25 from patients where tularaemia could be ruled out, were analysed. The diagnostic PCR had a specificity of 96%, a sensitivity of 78.3%, and a Positive Predictive Value of 99%. Especially samples from encrusted lesions, even up to 4 weeks old, in patients with tularaemia, were PCR positive to a high degree when taken properly. The diagnostic PCR is useful in suspected ulceroglandular tularaemia, giving a fast and accurate diagnosis.

  • 10. Svensson, Kerstin
    et al.
    Bäck, Erik
    Örebro University, School of Health and Medical Sciences.
    Eliasson, Henrik
    Berglund, Lennart
    Granberg, Malin
    Karlsson, Linda
    Larsson, Pär
    Forsman, Mats
    Johansson, Anders
    Landscape epidemiology of tularemia outbreaks in Sweden2009In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 15, no 12, p. 1937-1947Article in journal (Refereed)
    Abstract [en]

    Summer outbreaks of tularemia that occurred from 1995 through 2005 in 2 locations in Sweden affected 441 persons. We performed an epidemiologic investigation of these outbreaks using a novel strategy, involving high-resolution genotyping of Francisella tularensis isolates obtained from 136 patients (using 18 genetic markers developed from 6 F. tularensis genome sequences) and interviews with the patients. Strong spatial associations were found between F. tularensis subpopulations and the places of disease transmission; infection by some subpopulations occurred within areas as small as 2 km(2), indicating unidentified environmental point sources of tularemia. In both locations, disease clusters were associated with recreational areas beside water, and genetic subpopulations were present throughout the tularemia season and persisted over years. High-resolution genotyping in combination with patients' statements about geographic places of disease transmission provided valuable indications of likely sources of infection and the causal genotypes during these tularemia outbreaks.

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