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Tularemia: epidemiological, clinical and diagnostic aspects
Örebro University, School of Health and Medical Sciences.
2008 (English)Doctoral 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.

Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2008. , 76 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 13
Keyword [en]
Francisella, tularemia, epidemiology, case-control, diagnosis, PCR, clinical characteristics, immunology, ELISA, lymphocyte stimulation
National Category
Clinical Science
Research subject
Infectious Diseases
Identifiers
URN: urn:nbn:se:oru:diva-1806ISBN: 978-91-7668-581-5 (print)OAI: oai:DiVA.org:oru-1806DiVA: diva2:135507
Public defence
2008-03-14, Wilandersalen, M-huset, Universitetssjukhuset, Örebro, 12:30
Opponent
Supervisors
Available from: 2008-02-20 Created: 2008-02-20 Last updated: 2017-10-18Bibliographically approved
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
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2002 (English)In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 8, no 9, 956-960 p.Article 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, 833-837 p.Article 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, 880-889 p.Article 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

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