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Rasmuson, Johan
Publications (7 of 7) Show all publications
Sironen, T., Sane, J., Lokki, M.-L., Meri, S., Andersson, L. C., Hautala, T., . . . Vaheri, A. (2017). Fatal Puumala Hantavirus Disease: Involvement of Complement Activation and Vascular Leakage in the Pathobiology. Open Forum Infectious Diseases, 4(4), Article ID ofx229.
Open this publication in new window or tab >>Fatal Puumala Hantavirus Disease: Involvement of Complement Activation and Vascular Leakage in the Pathobiology
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2017 (English)In: Open Forum Infectious Diseases, ISSN 2328-8957, Vol. 4, no 4, article id ofx229Article in journal (Refereed) Published
Abstract [en]

The case-fatality rate of hantavirus disease depends strongly on the causative hantavirus, ranging from 0.1% to 40%. However, the pathogenesis is not fully understood, and at present no licensed therapies exist. We describe fatal cases caused by Puumala hantavirus indicating involvement of complement activation and vascular leakage.

Place, publisher, year, edition, pages
Oxford University Press, 2017
Keywords
case-fatality rate, complement, hantavirus, Puumala virus, vascular leakage
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-144431 (URN)10.1093/ofid/ofx229 (DOI)000419560500051 ()29255728 (PubMedID)
Available from: 2018-02-02 Created: 2018-02-02 Last updated: 2018-08-17Bibliographically approved
Rasmuson, J., Pourazar, J., Mohamed, N., Lejon, K., Evander, M., Blomberg, A. & Ahlm, C. (2016). Cytotoxic immune responses in the lungs correlate to disease severity in patients with hantavirus infection. European Journal of Clinical Microbiology and Infectious Diseases, 35(4), 713-721
Open this publication in new window or tab >>Cytotoxic immune responses in the lungs correlate to disease severity in patients with hantavirus infection
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2016 (English)In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 35, no 4, p. 713-721Article in journal (Refereed) Published
Abstract [en]

Hantavirus infections may cause severe and sometime life-threatening lung failure. The pathogenesis is not fully known and there is an urgent need for effective treatment. We aimed to investigate the association between pulmonary viral load and immune responses, and their relation to disease severity. Bronchoscopy with sampling of bronchoalveolar lavage (BAL) fluid was performed in 17 patients with acute Puumala hantavirus infection and 16 healthy volunteers acting as controls. Lymphocyte subsets, granzyme concentrations, and viral load were determined by flow cytometry, enzyme-linked immunosorbent assay (ELISA), and quantitative reverse transcription polymerase chain reaction (RT-PCR), respectively. Analyses of BAL fluid revealed significantly higher numbers of activated CD8+ T cells and natural killer (NK) cells, as well as higher concentrations of the cytotoxins granzymes A and B in hantavirus-infected patients, compared to controls. In patients, Puumala hantavirus RNA was detected in 88 % of BAL cell samples and correlated inversely to the T cell response. The magnitude of the pulmonary cytotoxic lymphocyte response correlated to the severity of disease and systemic organ dysfunction, in terms of need for supplemental oxygen treatment, hypotension, and laboratory data indicating renal failure, cardiac dysfunction, vascular leakage, and cell damage. Regulatory T cell numbers were significantly lower in patients compared to controls, and may reflect inadequate immune regulation during hantavirus infection. Hantavirus infection elicits a pronounced cytotoxic lymphocyte response in the lungs. The magnitude of the immune response was associated with disease severity. These results give insights into the pathogenesis and possibilities for new treatments.

Keywords
hantavirus, hemorrhagic fever with renal syndrome, bronchoalveolar lavage, granzymes, viral load, cytotoxic T-lymphocytes, regulatory T-cells
National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-99100 (URN)10.1007/s10096-016-2592-1 (DOI)000373300000023 ()26873376 (PubMedID)
Note

Originally included in thesis in manuscript form

Available from: 2015-02-04 Created: 2015-02-04 Last updated: 2018-09-17Bibliographically approved
Rasmuson, J. (2015). Cardiopulmonary involvement in Puumala hantavirus infection. (Doctoral dissertation). Umeå: Umeå Universitet
Open this publication in new window or tab >>Cardiopulmonary involvement in Puumala hantavirus infection
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome in Europe. After inhalation of virus shed by bank voles, the virus systemically targets the vascular endothelium leading to vascular dysfunction and leakage. Many patients with PUUV infection experience cardiopulmonary manifestations but the underlying mechanisms have not been determined.

The aims of the studies presented were to describe cardiopulmonary manifestations, investigate pathogenetic mechanisms including presence of virus in the lungs and the local immune response in PUUV infection.

The results showed cardiopulmonary involvement of varying severity in almost all studied patients. High-resolution computed tomography frequently revealed vascular leakage into the lungs or pleural cavities. Pulmonary function tests generally showed reduced gas diffusing capacity, evidenced in patients as dyspnea, poor oxygenation and frequent need of oxygen treatment. Among patients who were not fully recovered at 3 months follow-up, remaining decreased gas diffusing capacity was highly common.

Echocardiography revealed mainly right heart dysfunction which was related to manifestations within the lungs, in terms of increased estimated pulmonary vascular resistance, mild to moderate pulmonary hypertension, and reduced right ventricular systolic function in patients with more pronounced lung involvement, as indicated by need of oxygen treatment.

Analyses on bronchoalveolar lavage (BAL) and bronchial biopsies revealed a highly activated cytotoxic T cell (CTL) response in the lungs. The CTL response was not balanced by the expansion of regulatory T cells and high numbers of CTLs were associated with more severe disease. PUUV RNA was detected in almost all patients’ BAL samples and the viral load was inversely correlated to the number of CTLs.

Three patients presenting with severe and fatal cardiopulmonary distress were also described. Autopsies revealed PUUV protein in vascular endothelium in all investigated organs, including the heart and lungs, along with a massive CTL response mainly in the lungs.

In conclusion, cardiopulmonary involvement of varying severity was present in almost all patients with PUUV infection. Cytotoxic immune responses could contribute to disease development but also help in clearing the infection. Long lasting fatigue after hantavirus infection may be explained by remaining manifestations within the lungs. 

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2015. p. 69
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1698
Keywords
Hemorrhagic fever with renal syndrome, hantavirus, echocardiography, respiratory function tests, computed tomography, bronchoalveolar lavage, biopsy, cytotoxic T cells, disease severity
National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-99103 (URN)978-91-7601-215-4 (ISBN)
Public defence
2015-02-27, E04, byggnad 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2015-02-06 Created: 2015-02-04 Last updated: 2018-06-07Bibliographically approved
Rasmuson, J., Lindqvist, P., Sörensen, K., Hedström, M., Blomberg, A. & Ahlm, C. (2013). Cardiopulmonary involvement in Puumala hantavirus infection. BMC Infectious Diseases, 13(1), 501
Open this publication in new window or tab >>Cardiopulmonary involvement in Puumala hantavirus infection
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2013 (English)In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 13, no 1, p. 501-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Hantavirus infections cause potentially life-threatening disease in humans world-wide. Infections with American hantaviruses may lead to hantavirus pulmonary syndrome characterised by severe cardiopulmonary distress with high mortality. Pulmonary involvement in European Puumala hantavirus (PUUV) infection has been reported, whereas knowledge of potential cardiac manifestations is limited. We aimed to comprehensively investigate cardiopulmonary involvement in patients with PUUV-infection.

METHODS: Twenty-seven hospitalised patients with PUUV-infection were examined with lung function tests, chest high-resolution CT (HRCT), echocardiography including speckle tracking strain rate analysis, ECG and measurements of cardiac biomarkers N-terminal pro-B-type natriuretic peptide (NT-ProBNP) and troponin T. Patients were re-evaluated after 3 months. Twenty-five age and sex-matched volunteers acted as controls for echocardiography data.

RESULTS: Two-thirds of the patients experienced respiratory symptoms as dry cough or dyspnoea. Gas diffusing capacity was impaired in most patients, significantly improving at follow-up but still subnormal in 38%. HRCT showed thoracic effusions or pulmonary oedema in 46% of the patients. Compared to controls, the main echocardiographic findings in patients during the acute phase were significantly higher pulmonary vascular resistance, higher systolic pulmonary artery pressure, lower left ventricular ejection fraction and impaired left atrial myocardial motion. Pathological ECG, atrial fibrillation or T-wave changes, was demonstrated in 26% of patients. NT-ProBNP concentrations were markedly increased and were inversely associated with gas diffusing capacity but positively correlated to pulmonary vascular resistance. Furthermore, patients experiencing impaired general condition at follow-up had significantly lower gas diffusing capacity and higher pulmonary vascular resistance, compared to those feeling fully recovered.

CONCLUSIONS: In a majority of patients with PUUV-infection, both cardiac and pulmonary involvement was demonstrated with implications on patients' recovery. The results demonstrate vascular leakage in the lungs that most likely is responsible for impaired gas diffusing capacity and increased pulmonary vascular resistance with secondary pulmonary hypertension and right heart distress. Interestingly, NT-ProBNP was markedly elevated even in the absence of overt ventricular heart failure. The method of simultaneous investigations of important cardiac and respiratory measurements improves the interpretation of the underlying pathophysiologic mechanisms.

Place, publisher, year, edition, pages
BioMed Central, 2013
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-83698 (URN)10.1186/1471-2334-13-501 (DOI)000328902800001 ()24160911 (PubMedID)
Available from: 2013-12-04 Created: 2013-12-04 Last updated: 2018-06-08Bibliographically approved
Pettersson, L., Rasmuson, J., Andersson, C., Ahlm, C. & Evander, M. (2011). Hantavirus-specific IgA in saliva and viral antigen in the parotid gland in patients with hemorrhagic fever with renal syndrome. Journal of Medical Virology, 83(5), 864-870
Open this publication in new window or tab >>Hantavirus-specific IgA in saliva and viral antigen in the parotid gland in patients with hemorrhagic fever with renal syndrome
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2011 (English)In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 83, no 5, p. 864-870Article in journal (Refereed) Published
Abstract [en]

The Hantavirus genus comprises rodent borne, zoonotic viruses of the Bunyaviridae family that cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. Rodent saliva contains infectious hantavirus and evidence suggests that hantavirus is also shed in human saliva, but person-to-person transmission is rare. In saliva, immunoglobulin (Ig) A is the predominant immunoglobulin class. Secretory IgA serves as an important first line of defence on epithelial surfaces and the binding of secretory IgA to pathogens can inhibit adherence of microorganisms to mucosal cells and neutralize viruses. This study investigated the presence and importance of salivary IgA in relation to viral antigen in the saliva by testing Puumala hantavirus (PUUV) specific IgA, and RNA in saliva in acutely ill patients with HFRS. In saliva samples, PUUV specific IgA was detected in 12 of 33 (36%) patients with HFRS and 20 (61%) were PUUV RNA positive. There was a statistically significant inverse association between the presence of salivary IgA antibodies and PUUV RNA in the saliva. PUUV-specific IgA in saliva was not found in a long-term follow-up, while PUUV IgA in serum was detected in three patients, 28-32 months after the initial study. Notably, both PUUV RNA and PUUV nucleocapsid antigen were detected in endothelial cells within the parotid gland of a deceased patient with HFRS. J. Med. Virol. 83:864-870, 2011. © 2011 Wiley-Liss, Inc.

Keywords
puumalavirus;HFRS;HCPS;antibody;zoonosis;transmission
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-41725 (URN)10.1002/jmv.22040 (DOI)21360546 (PubMedID)
Available from: 2011-03-31 Created: 2011-03-31 Last updated: 2018-06-08Bibliographically approved
Rasmuson, J., Pourazar, J., Linderholm, M., Sandström, T., Blomberg, A. & Ahlm, C. (2011). Presence of activated airway T lymphocytes in human puumala hantavirus disease. Chest, 140(3), 715-722
Open this publication in new window or tab >>Presence of activated airway T lymphocytes in human puumala hantavirus disease
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2011 (English)In: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 140, no 3, p. 715-722Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Hantaviruses cause two clinical syndromes; hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). The clinical spectrum in HFRS also often involves respiratory symptoms. As information of the pulmonary pathogenesis in HFRS is limited, we aimed to further study the local airway immune response in the lower airways.

METHODS: In 15 hospitalized HFRS patients, bronchoscopy was performed with sampling of endobronchial mucosal biopsies and bronchoalveolar lavage (BAL) fluid. Biopsies were stained for leukocytes, lymphocyte subsets and vascular endothelial adhesion molecules. BAL fluid and blood lymphocyte subsets were determined using flow cytometry. Fourteen healthy volunteers acted as control group.

RESULTS: Compared to controls, endobronchial mucosal biopsies from HFRS patients revealed increased numbers of CD8(+) T cells in both epithelium and submucosa (p≤0.001), along with an increase in submucosal CD4(+) T cells (p=0.001). In contrast, patients' submucosal neutrophil and eosinophil numbers were reduced (p<0.001). The expression of vascular cell adhesion molecule-1 (VCAM-1) was enhanced in HFRS patients (p<0.001). In HFRS patients, analyses of T cell subsets in BAL fluid showed higher proportions of CD3(+) and CD8(+) T cells (p=0.011 and p=0.025), NK cells (p<0.001) together with an increased expression of activation markers HLA-DR and CD25 on T cells (p<0.001 and p<0.001).

CONCLUSIONS: The present findings indicate a local immune response in terms of activated T lymphocytes in the lungs of patients with HFRS. The elevated expression of activation markers and VCAM-1 further implies the importance of cytotoxic lymphocytes in the pathogenesis of pulmonary involvement in HFRS.

National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-42630 (URN)10.1378/chest.10-2791 (DOI)21436245 (PubMedID)
Available from: 2011-04-11 Created: 2011-04-11 Last updated: 2018-06-08Bibliographically approved
Rasmuson, J., Andersson, C., Norrman, E., Haney, M., Evander, M. & Ahlm, C. (2011). Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus. European Journal of Clinical Microbiology and Infectious Diseases, 30(5), 685-690
Open this publication in new window or tab >>Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus
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2011 (English)In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 30, no 5, p. 685-690Article in journal (Refereed) Published
Abstract [en]

Hantaviruses have previously been recognised to cause two separate syndromes: hemorrhagic fever with renal syndrome in Eurasia, and hantavirus pulmonary syndrome (HPS) in the Americas. However, increasing evidence suggests that this dichotomy is no longer fruitful when recognising human hantavirus disease and understanding the pathogenesis. Herein are presented three cases of severe European Puumala hantavirus infection that meet the HPS case definition. The clinical and pathological findings were similar to those found in American hantavirus patients. Consequently, hantavirus infection should be considered as a cause of acute respiratory distress in all endemic areas worldwide.

National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-41726 (URN)10.1007/s10096-010-1141-6 (DOI)21234633 (PubMedID)
Available from: 2011-03-31 Created: 2011-03-31 Last updated: 2018-06-08Bibliographically approved
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