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  • 1.
    Connolly-Andersen, Anne-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Rasmuson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Öman, Mikael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Mesenteric Vein Thrombosis Following Platelet Transfusion in a Patient with Hemorrhagic Fever with Renal Syndrome: A Case Report2018In: TH open : companion journal to thrombosis and haemostasis, ISSN 2567-3459, Vol. 2, no 3, p. e261-e264Article in journal (Refereed)
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  • 2.
    Gröning, Remigius
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Walde, Jonatan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Rasmuson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Intravenous immunoglobulin therapy for COVID-19 in immunocompromised patients: A retrospective cohort study2024In: International Journal of Infectious Diseases, ISSN 1201-9712, E-ISSN 1878-3511, Vol. 144, article id 107046Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate the effectiveness of intravenous immunoglobulin (IVIG) as treatment for COVID-19 in immunocompromised patients.

    Methods: This retrospective study investigated outcomes for immunocompromised, vaccine non-responsive, patients that between September 2022 and April 2023 received IVIG as treatment for COVID-19 in the region of Västerbotten, Sweden. We analyzed clinical data, viral load, and anti-SARS-CoV-2 IgG binding and neutralization levels of patient serum samples and IVIG production batches. Primary and secondary outcomes were clinical cure and viral clearance, respectively.

    Results: Sixteen patients were analyzed. After a median COVID-19 duration of 4 weeks, a median 60 g IVIG infusion increased SARS-CoV-2 binding and neutralizing antibody levels, with broad in vitro activity against tested variants. The treatment resulted in abrogation of viremia in all patients and general improvement in 15 survivors that all met the primary endpoint. Thirteen patients met the secondary endpoint at follow-up after a median of four months. Two subjects with persistent SARS-CoV-2 carriage relapsed but were successfully retreated with IVIG.

    Conclusions: Antibodies in IVIG efficiently neutralized several SARS-CoV-2 variants. Treatment with IVIG was associated with clinical cure and viral clearance in immunocompromised patients. Our data suggests that IVIG could be a novel treatment alternative for COVID-19 for this patient category.

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  • 3.
    Pettersson, Lisa
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Rasmuson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Andersson, Charlotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hantavirus-specific IgA in saliva and viral antigen in the parotid gland in patients with hemorrhagic fever with renal syndrome2011In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 83, no 5, p. 864-870Article in journal (Refereed)
    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.

  • 4.
    Rasmuson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Cardiopulmonary involvement in Puumala hantavirus infection2015Doctoral 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. 

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  • 5.
    Rasmuson, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Andersson, Charlotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Norrman, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Haney, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus2011In: 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)
    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.

  • 6.
    Rasmuson, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Sörensen, Karen
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Hedström, Magnus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Cardiopulmonary involvement in Puumala hantavirus infection2013In: BMC Infectious Diseases, E-ISSN 1471-2334, Vol. 13, no 1, p. 501-Article in journal (Refereed)
    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.

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  • 7.
    Rasmuson, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Pourazar, Jamshid
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Linderholm, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Presence of activated airway T lymphocytes in human puumala hantavirus disease2011In: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 140, no 3, p. 715-722Article in journal (Refereed)
    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.

  • 8.
    Rasmuson, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Pourazar, Jamshid
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mohamed, Nahla
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Cytotoxic immune responses in the lungs correlate to disease severity in patients with hantavirus infection2016In: 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)
    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.

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  • 9. Scholz, Saskia
    et al.
    Baharom, Faezzah
    Rankin, Gregory
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Maleki, Kimia T.
    Gupta, Shawon
    Vangeti, Sindhu
    Pourazar, Jamshid
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Discacciati, Andrea
    Höijer, Jonas
    Bottai, Matteo
    Björkström, Niklas K.
    Rasmuson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ljunggren, Hans-Gustaf
    Klingström, Jonas
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Smed-Sörensen, Anna
    Human hantavirus infection elicits pronounced redistribution of mononuclear phagocytes in peripheral blood and airways2017In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 13, no 6, article id e1006462Article in journal (Refereed)
    Abstract [en]

    Hantaviruses infect humans via inhalation of virus-contaminated rodent excreta. Infection can cause severe disease with up to 40% mortality depending on the viral strain. The virus primarily targets the vascular endothelium without direct cytopathic effects. Instead, exaggerated immune responses may inadvertently contribute to disease development. Mononuclear phagocytes (MNPs), including monocytes and dendritic cells (DCs), orchestrate the adaptive immune responses. Since hantaviruses are transmitted via inhalation, studying immunological events in the airways is of importance to understand the processes leading to immunopathogenesis. Here, we studied 17 patients infected with Puumala virus that causes a mild form of hemorrhagic fever with renal syndrome (HFRS). Bronchial biopsies as well as longitudinal blood draws were obtained from the patients. During the acute stage of disease, a significant influx of MNPs expressing HLA-DR, CD11c or CD123 was detected in the patients' bronchial tissue. In parallel, absolute numbers of MNPs were dramatically reduced in peripheral blood, coinciding with viremia. Expression of CCR7 on the remaining MNPs in blood suggested migration to peripheral and/or lymphoid tissues. Numbers of MNPs in blood subsequently normalized during the convalescent phase of the disease when viral RNA was no longer detectable in plasma. Finally, we exposed blood MNPs in vitro to Puumala virus, and demonstrated an induction of CCR7 expression on MNPs. In conclusion, the present study shows a marked redistribution of blood MNPs to the airways during acute hantavirus disease, a process that may underlie the local immune activation and contribute to immunopathogenesis in hantavirus-infected patients.

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  • 10. Sironen, Tarja
    et al.
    Sane, Jussi
    Lokki, Marja-Liisa
    Meri, Seppo
    Andersson, Leif C.
    Hautala, Timo
    Kauma, Heikki
    Vuorinen, Sakari
    Rasmuson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Vaheri, Antti
    Fatal Puumala Hantavirus Disease: Involvement of Complement Activation and Vascular Leakage in the Pathobiology2017In: Open Forum Infectious Diseases, ISSN 2328-8957, Vol. 4, no 4, article id ofx229Article in journal (Refereed)
    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.

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  • 11.
    Sundén-Cullberg, Jonas
    et al.
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden.
    Chen, Puran
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Häbel, Henrike
    Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Skorup, Paul
    Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden.
    Janols, Helena
    Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden.
    Rasmuson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Niward, Katarina
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Balkhed, Åse Östholm
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Chatzidionysiou, Katerina
    Rheumatology Division, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Asgeirsson, Hilmir
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden.
    Blennow, Ola
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden.
    Parke, Åsa
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden.
    Svensson, Anna-Karin
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden.
    Muvva, Jagadeeswara Rao
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Ljunggren, Hans-Gustav
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Horne, Anna-Carin
    Theme of Children’s and Women’s Health, Karolinska University Hospital, Stockholm, Sweden.
    Ådén, Ulrika
    Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Henter, Jan-Inge
    Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Sönnerborg, Anders
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Vesterbacka, Jan
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden.
    Nowak, Piotr
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden.
    Lampa, Jon
    Rheumatology Division, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Anakinra or tocilizumab in patients admitted to hospital with severe covid-19 at high risk of deterioration (IMMCoVA): a randomized, controlled, open-label trial2023In: PLOS ONE, E-ISSN 1932-6203, Vol. 18, no 12, article id e0295838Article in journal (Refereed)
    Abstract [en]

    Background: Anakinra and tocilizumab are used for severe Covid-19, but only one previous randomized controlled trial (RCT) has studied both. We performed a multi-center RCT comparing anakinra or tocilizumab versus usual care (UC) for adults at high risk of deterioration.

    Methods: The study was conducted June 2020 to March 2021. Eligibility required ≥ 5 liters/minute of Oxygen to maintain peripheral oxygen saturation at ≥ 93%, CRP > 70 mg/L, ferritin > 500 μg/L and at least two points where one point was awarded for lymphocytes < 1x 109/L; D-dimer ≥ 0.5 mg/L and; lactate dehydrogenase ≥ 8 microkatal/L. Patients were randomly assigned 1:1:1 to receive either a single dose of tocilizumab (8 mg/kg) or anakinra 100 mg IV QID for seven days or UC alone. The primary outcome was time to recovery.

    Results: Recruitment was ended prematurely when tocilizumab became part of usual care. Out of a planned 195 patients, 77 had been randomized, 27 to UC, 28 to anakinra and 22 to tocilizumab. Median time to recovery was 15, 15 and 11 days. Rate ratio for recovery for UC vs anakinra was 0.91, 0.47 to 1.78, 95% [CI], p = 0.8 and for UC vs tocilizumab 1.13, 0.55 to 2.30; p = 0.7. There were non-significant trends favoring tocilizumab (and to limited degree anakinra) vs UC for some secondary outcomes. Safety profiles did not differ significantly.

    Conclusion: Premature closure of trial precludes firm conclusions. Anakinra or tocilizumab did not significantly shorten time to clinical recovery compared to usual care. (IMMCoVA, NCT04412291, EudraCT: 2020–00174824).

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  • 12.
    Tuiskunen-Bäck, Anne
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Rasmuson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Thunberg, Therese
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Rankin, Gregory
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Wigren Byström, Julia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Andersson, Charlotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sjödin, Andreas
    CBRN Security and Defence, Swedish Defence Research Agency - FOI, Umeå, Sweden.
    Forsell, Mattias
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Clinical and genomic characterisation of a fatal Puumala orthohantavirus case with low levels of neutralising antibodies2022In: Infectious Diseases, ISSN 2374-4235, E-ISSN 2374-4243, Vol. 54, no 10, p. 766-772Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Orthohantaviruses are rodent-borne emerging viruses that cause haemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome in America. Transmission between humans have been reported and the case-fatality rate ranges from 0.4% to 40% depending on virus strain. There is no specific and efficient treatment for patients with severe HFRS. Here, we characterised a fatal case of HFRS and sequenced the causing Puumala orthohantavirus (PUUV).

    METHODS: PUUV RNA and virus specific neutralising antibodies were quantified in plasma samples from the fatal case and other patients with non-fatal PUUV infection. To investigate if the causing PUUV strain was different from previously known strains, Sanger sequencing was performed directly from the patient's plasma. Biopsies obtained from autopsy were stained for immunohistochemistry.

    RESULTS: The patient had approximately tenfold lower levels of PUUV neutralising antibodies and twice higher viral load than was normally seen for patients with less severe PUUV infection. We could demonstrate unique mutations in the S and M segments of the virus that could have had an impact on the severity of infection. Due to the severe course of infection, the patient was treated with the bradykinin receptor inhibitor icatibant to reduce bradykinin-mediated vessel permeability and maintain vascular circulation.

    CONCLUSIONS: Our data suggest that bradykinin receptor inhibitor may not be highly efficient to treat patients that are at an advanced stage of HFRS. Low neutralising antibodies and high viral load at admission to the hospital were associated with the fatal outcome and may be useful for future predictions of disease outcome.

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