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Cardiopulmonary involvement in Puumala hantavirus infection
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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. 

Ort, förlag, år, upplaga, sidor
Umeå: Umeå Universitet , 2015. , s. 69
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1698
Nyckelord [en]
Hemorrhagic fever with renal syndrome, hantavirus, echocardiography, respiratory function tests, computed tomography, bronchoalveolar lavage, biopsy, cytotoxic T cells, disease severity
Nationell ämneskategori
Infektionsmedicin
Forskningsämne
infektionssjukdomar
Identifikatorer
URN: urn:nbn:se:umu:diva-99103ISBN: 978-91-7601-215-4 (tryckt)OAI: oai:DiVA.org:umu-99103DiVA, id: diva2:785875
Disputation
2015-02-27, E04, byggnad 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2015-02-06 Skapad: 2015-02-04 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Delarbeten
1. Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus
Öppna denna publikation i ny flik eller fönster >>Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus
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2011 (Engelska)Ingår i: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 30, nr 5, s. 685-690Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Infektionsmedicin
Identifikatorer
urn:nbn:se:umu:diva-41726 (URN)10.1007/s10096-010-1141-6 (DOI)21234633 (PubMedID)
Tillgänglig från: 2011-03-31 Skapad: 2011-03-31 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
2. Presence of activated airway T lymphocytes in human puumala hantavirus disease
Öppna denna publikation i ny flik eller fönster >>Presence of activated airway T lymphocytes in human puumala hantavirus disease
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2011 (Engelska)Ingår i: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 140, nr 3, s. 715-722Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Infektionsmedicin
Identifikatorer
urn:nbn:se:umu:diva-42630 (URN)10.1378/chest.10-2791 (DOI)21436245 (PubMedID)
Tillgänglig från: 2011-04-11 Skapad: 2011-04-11 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
3. Cardiopulmonary involvement in Puumala hantavirus infection
Öppna denna publikation i ny flik eller fönster >>Cardiopulmonary involvement in Puumala hantavirus infection
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2013 (Engelska)Ingår i: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 13, nr 1, s. 501-Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
BioMed Central, 2013
Nationell ämneskategori
Infektionsmedicin
Identifikatorer
urn:nbn:se:umu:diva-83698 (URN)10.1186/1471-2334-13-501 (DOI)000328902800001 ()24160911 (PubMedID)
Tillgänglig från: 2013-12-04 Skapad: 2013-12-04 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
4. Cytotoxic immune responses in the lungs correlate to disease severity in patients with hantavirus infection
Öppna denna publikation i ny flik eller fönster >>Cytotoxic immune responses in the lungs correlate to disease severity in patients with hantavirus infection
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2016 (Engelska)Ingår i: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 35, nr 4, s. 713-721Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
hantavirus, hemorrhagic fever with renal syndrome, bronchoalveolar lavage, granzymes, viral load, cytotoxic T-lymphocytes, regulatory T-cells
Nationell ämneskategori
Infektionsmedicin
Forskningsämne
infektionssjukdomar
Identifikatorer
urn:nbn:se:umu:diva-99100 (URN)10.1007/s10096-016-2592-1 (DOI)000373300000023 ()26873376 (PubMedID)
Anmärkning

Originally included in thesis in manuscript form

Tillgänglig från: 2015-02-04 Skapad: 2015-02-04 Senast uppdaterad: 2018-09-17Bibliografiskt granskad

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