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Presence of activated airway T lymphocytes in human puumala hantavirus disease
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. (Clas Ahlm)
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
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2011 (English)In: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 140, no 3, 715-722 p.Article 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.

Place, publisher, year, edition, pages
2011. Vol. 140, no 3, 715-722 p.
National Category
Infectious Medicine
URN: urn:nbn:se:umu:diva-42630DOI: 10.1378/chest.10-2791PubMedID: 21436245OAI: diva2:409857
Available from: 2011-04-11 Created: 2011-04-11 Last updated: 2016-05-24Bibliographically approved
In thesis
1. Cardiopulmonary involvement in Puumala hantavirus infection
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. 69 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1698
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
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)
Available from: 2015-02-06 Created: 2015-02-04 Last updated: 2015-02-04Bibliographically approved

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