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Viruses
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Hantavirus Research in Finland
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Hantavirus Research in Finland

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 23953

Special Issue Editor

Prof. Dr. Jukka T. Mustonen

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Guest Editor
Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland

Special Issue Information

Dear Colleagues,

Puumala hantavirus (PUUV) infections are common in Finland, making this country the most endemic area of hantavirus infections per inhabitant. PUUV is the only human pathogenic hantavirus found in this country. The natural reservoir for PUUV is the bank vole (Myodes glareolus). Scientific research on the disease, previously described as nephropathia epidemica, started in Finland in the 1970s and PUUV was discovered in 1980. The structure of PUUV and serological diagnostics have been and are currently studied, as are the epidemiology, risk factors, and immune response of the infection, disease severity biomarkers, and host genetics. Other research topics include the pathogenesis of the main clinical manifestations, capillary leakage, thrombocytopenia, and acute kidney injury (AKI), as well as acute-phase complications and long-term prognosis of the infection. Studies on the pathogenesis and immune response may show the way towards optimal prophylaxis and treatment.

Studies on the dynamics and genetics of PUUV in bank vole populations have also been performed. Finnish scientists have worked together with many collaborators in European, Asian, and American countries. In these projects, hantaviruses other than PUUV have also been studied.

The present Special Issue includes reviews, original articles, and short communications about PUUV infections showing that the research continues actively in Finland.

Prof. Dr. Jukka T. Mustonen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Puumala virus
  • hantavirus infections
  • bank vole

Published Papers (11 papers)

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Research

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15 pages, 1617 KiB  
Article
Neutralizing Antibody Titers in Hospitalized Patients with Acute Puumala Orthohantavirus Infection Do Not Associate with Disease Severity
by Rommel Iheozor-Ejiofor, Katariina Vapalahti, Tarja Sironen, Lev Levanov, Jussi Hepojoki, Åke Lundkvist, Satu Mäkelä, Antti Vaheri, Jukka Mustonen, Alexander Plyusnin, Tomas M. Strandin and Olli Vapalahti
Viruses 2022, 14(5), 901; https://0-doi-org.brum.beds.ac.uk/10.3390/v14050901 - 26 Apr 2022
Cited by 4 | Viewed by 1824
Abstract
Nephropathia epidemica (NE), a mild form of haemorrhagic fever with renal syndrome (HFRS), is an acute febrile illness caused by Puumala orthohantavirus (PUUV). NE manifests typically with acute kidney injury (AKI), with a case fatality rate of about 0.1%. The treatment and management [...] Read more.
Nephropathia epidemica (NE), a mild form of haemorrhagic fever with renal syndrome (HFRS), is an acute febrile illness caused by Puumala orthohantavirus (PUUV). NE manifests typically with acute kidney injury (AKI), with a case fatality rate of about 0.1%. The treatment and management of hantavirus infections are mainly supportive, although neutralizing monoclonal antibodies and immune sera therapeutics are under investigation. In order to assess the potential use of antibody therapeutics in NE, we sought to determine the relationship between circulating PUUV neutralizing antibodies, PUUV nucleocapsid protein (N) IgG antibodies, and viral loads with markers of disease severity. The study included serum samples of extensively characterized patient cohorts (n = 116) from Tampere University Hospital, Finland. The results showed that upon hospitalization, most patients already had considerable neutralizing and anti-PUUV-N IgG antibody levels. However, contrary to expectations, neutralizing antibody titers from the first day of hospitalization did not appear to protect from AKI or correlate with more favorable disease outcomes. This indicates that further studies are needed to investigate the applicability of neutralizing antibodies as a therapy for hospitalized NE patients. Full article
(This article belongs to the Special Issue Hantavirus Research in Finland)
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12 pages, 276 KiB  
Article
Alcohol Consumption and Its Influence on the Clinical Picture of Puumala Hantavirus Infection
by Laura Tervo, Tuula K. Outinen, Satu Mäkelä, Jenna Mustalahti, Heini Huhtala, Ilkka Pörsti, Jaana Syrjänen, Jukka T. Mustonen and Onni Niemelä
Viruses 2022, 14(3), 500; https://0-doi-org.brum.beds.ac.uk/10.3390/v14030500 - 28 Feb 2022
Cited by 1 | Viewed by 1958
Abstract
Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome. Characteristic clinical findings include acute kidney injury (AKI), thrombocytopenia, and capillary leakage. Smoking increases the risk of severe AKI, but it is not known whether alcohol consumption predisposes patients to a more severe infection. [...] Read more.
Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome. Characteristic clinical findings include acute kidney injury (AKI), thrombocytopenia, and capillary leakage. Smoking increases the risk of severe AKI, but it is not known whether alcohol consumption predisposes patients to a more severe infection. Liver and pancreatic enzymes, as well as biomarkers of alcohol consumption (gamma-glutamyl transferase, GGT; carbohydrate-deficient transferrin, CDT; GGT-CDT combination; and ethyl glucuronide, EtG), were measured from 66 patients with acute PUUV infection during hospitalization and at the convalescence phase. Alcohol consumption was present in 41% of the study population, 15% showing signs of heavy drinking. Alcohol use did not affect the severity of PUUV induced AKI nor the overall clinical picture of the infection. Liver enzyme levels (GGT or alanine aminotransferase, ALT) were elevated in 64% of the patients, but the levels did not associate with the markers reflecting the severity of the disease. Serum amylase activities at the convalescent stage were higher than those at the acute phase (p < 0.001). No cases with acute pancreatitis were found. In conclusion, our findings indicate that alcohol consumption does not seem to affect the clinical course of an acute PUUV infection. Full article
(This article belongs to the Special Issue Hantavirus Research in Finland)
17 pages, 1547 KiB  
Article
Increased Heparanase Levels in Urine during Acute Puumala Orthohantavirus Infection Are Associated with Disease Severity
by Luz E. Cabrera, Constanze Schmotz, Moin A. Saleem, Sanna Lehtonen, Olli Vapalahti, Antti Vaheri, Satu Mäkelä, Jukka Mustonen and Tomas Strandin
Viruses 2022, 14(3), 450; https://0-doi-org.brum.beds.ac.uk/10.3390/v14030450 - 22 Feb 2022
Cited by 3 | Viewed by 2015
Abstract
Old–world orthohantaviruses cause hemorrhagic fever with renal syndrome (HFRS), characterized by acute kidney injury (AKI) with transient proteinuria. It seems plausible that proteinuria during acute HFRS is mediated by the disruption of the glomerular filtration barrier (GFB) due to vascular leakage, a hallmark [...] Read more.
Old–world orthohantaviruses cause hemorrhagic fever with renal syndrome (HFRS), characterized by acute kidney injury (AKI) with transient proteinuria. It seems plausible that proteinuria during acute HFRS is mediated by the disruption of the glomerular filtration barrier (GFB) due to vascular leakage, a hallmark of orthohantavirus–caused diseases. However, direct infection of endothelial cells by orthohantaviruses does not result in increased endothelial permeability, and alternative explanations for vascular leakage and diminished GFB function are necessary. Vascular integrity is partly dependent on an intact endothelial glycocalyx, which is susceptible to cleavage by heparanase (HPSE). To understand the role of glycocalyx degradation in HFRS–associated proteinuria, we investigated the levels of HPSE in urine and plasma during acute, convalescent and recovery stages of HFRS caused by Puumala orthohantavirus. HPSE levels in urine during acute HFRS were significantly increased and strongly associated with the severity of AKI and other markers of disease severity. Furthermore, increased expression of HPSE was detected in vitro in orthohantavirus–infected podocytes, which line the outer surfaces of glomerular capillaries. Taken together, these findings suggest the local activation of HPSE in the kidneys of orthohantavirus–infected patients with the potential to disrupt the endothelial glycocalyx, leading to increased protein leakage through the GFB, resulting in high amounts of proteinuria. Full article
(This article belongs to the Special Issue Hantavirus Research in Finland)
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10 pages, 278 KiB  
Article
ABO and Rhesus Blood Groups in Acute Puumala Hantavirus Infection
by Johanna Tietäväinen, Outi Laine, Satu Mäkelä, Heini Huhtala, Ilkka Pörsti, Antti Vaheri and Jukka Mustonen
Viruses 2021, 13(11), 2271; https://0-doi-org.brum.beds.ac.uk/10.3390/v13112271 - 13 Nov 2021
Cited by 1 | Viewed by 1603
Abstract
Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome. We aimed to evaluate whether ABO and rhesus blood groups associate with the susceptibility or the severity of PUUV infection. We analyzed blood groups in 289 adult patients treated in Tampere University hospital due [...] Read more.
Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome. We aimed to evaluate whether ABO and rhesus blood groups associate with the susceptibility or the severity of PUUV infection. We analyzed blood groups in 289 adult patients treated in Tampere University hospital due to PUUV infection during the years 1982–2017. Patients’ blood group distribution was compared to that of healthy, voluntary blood donors living in the Tampere University Hospital responsibility area (n = 21,833). The severity of PUUV infection, as judged by the severity of acute kidney injury (AKI), thrombocytopenia, inflammation, capillary leakage, and the length of hospital care, was analyzed across the groups. The ABO and rhesus blood group distributions did not differ between the patients and blood donors. Patients with non-O blood groups had lower systolic blood pressure compared to patients with blood group O, but there was no difference in other markers of capillary leakage or in the severity of AKI. Minor deviations in the number of platelets and leukocytes were detected between the O and non-O blood groups. To conclude, patients with blood group O may be less susceptible to hypotension, but otherwise blood groups have no major influences on disease susceptibility or severity during acute PUUV infection. Full article
(This article belongs to the Special Issue Hantavirus Research in Finland)
14 pages, 1097 KiB  
Article
Hormonal Defects Are Common during Puumala Hantavirus Infection and Associate with Disease Severity and Biomarkers of Altered Haemostasis
by Marlene Tarvainen, Satu Mäkelä, Outi Laine, Ilkka Pörsti, Sari Risku, Onni Niemelä, Jukka Mustonen and Pia Jaatinen
Viruses 2021, 13(9), 1818; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091818 - 13 Sep 2021
Cited by 3 | Viewed by 1769
Abstract
Central and peripheral hormone deficiencies have been documented during and after acute hantavirus infection. Thrombocytopenia and coagulation abnormalities are common findings in haemorrhagic fever with renal syndrome (HFRS). The associations between coagulation and hormonal abnormalities in HFRS have not been studied yet. Forty-two [...] Read more.
Central and peripheral hormone deficiencies have been documented during and after acute hantavirus infection. Thrombocytopenia and coagulation abnormalities are common findings in haemorrhagic fever with renal syndrome (HFRS). The associations between coagulation and hormonal abnormalities in HFRS have not been studied yet. Forty-two patients diagnosed with Puumala virus (PUUV) infection were examined during the acute phase and on a follow-up visit approximately one month later. Hormonal defects were common during acute PUUV infection. Overt (clinical) hypogonadism was identified in 80% of the men and approximately 20% of the patients had overt hypothyroidism. At the one-month follow-up visit, six patients had central hormone deficits. Acute peripheral hormone deficits associated with a more severe acute kidney injury (AKI), longer hospital stay and more severe thrombocytopenia. Half of the patients with bleeding symptoms had also peripheral hormonal deficiencies. Patients with free thyroxine levels below the reference range had higher D-dimer level than patients with normal thyroid function, but no thromboembolic events occurred. Acute phase hormonal abnormalities associate with severe disease and altered haemostasis in PUUV infection. Full article
(This article belongs to the Special Issue Hantavirus Research in Finland)
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11 pages, 721 KiB  
Article
The Clinical Presentation of Puumala Hantavirus Induced Hemorrhagic Fever with Renal Syndrome Is Related to Plasma Glucose Concentration
by Johanna Tietäväinen, Satu Mäkelä, Heini Huhtala, Ilkka H. Pörsti, Tomas Strandin, Antti Vaheri and Jukka Mustonen
Viruses 2021, 13(6), 1177; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061177 - 20 Jun 2021
Cited by 3 | Viewed by 2072
Abstract
Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome characterized by thrombocytopenia, increased capillary leakage, and acute kidney injury (AKI). As glucosuria at hospital admission predicts the severity of PUUV infection, we explored how plasma glucose concentration associates with disease severity. Plasma [...] Read more.
Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome characterized by thrombocytopenia, increased capillary leakage, and acute kidney injury (AKI). As glucosuria at hospital admission predicts the severity of PUUV infection, we explored how plasma glucose concentration associates with disease severity. Plasma glucose values were measured during hospital care in 185 patients with PUUV infection. They were divided into two groups according to maximum plasma glucose concentration: P-Gluc < 7.8 mmol/L (n = 134) and P-Gluc ≥ 7.8 mmol/L (n = 51). The determinants of disease severity were analyzed across groups. Patients with P-Gluc ≥7.8 mmol/L had higher hematocrit (0.46 vs. 0.43; p < 0.001) and lower plasma albumin concentration (24 vs. 29 g/L; p < 0.001) than patients with P-Gluc < 7.8 mmol/L. They presented with higher prevalence of pulmonary infiltrations and pleural effusion in chest radiograph, higher prevalence of shock and greater weight change during hospitalization. Patients with P-Gluc ≥ 7.8 mmol/L were characterized by lower platelet count (50 vs. 66 × 109/L; p = 0.001), more severe AKI (plasma creatinine 272 vs. 151 µmol/L; p = 0.001), and longer hospital treatment (8 vs. 6 days; p < 0.001) than patients with P-Gluc < 7.8 mmol/L. Plasma glucose level is associated with the severity of capillary leakage, thrombocytopenia, inflammation, and AKI in patients with acute PUUV infection. Full article
(This article belongs to the Special Issue Hantavirus Research in Finland)
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Review

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13 pages, 2917 KiB  
Review
Severity Biomarkers in Puumala Hantavirus Infection
by Tuula K. Outinen, Satu Mäkelä, Ilkka Pörsti, Antti Vaheri and Jukka Mustonen
Viruses 2022, 14(1), 45; https://0-doi-org.brum.beds.ac.uk/10.3390/v14010045 - 28 Dec 2021
Cited by 8 | Viewed by 2158
Abstract
Annually, over 10,000 cases of hemorrhagic fever with renal syndrome (HFRS) are diagnosed in Europe. Puumala hantavirus (PUUV) causes most of the European HFRS cases. PUUV causes usually a relatively mild disease, which is rarely fatal. However, the severity of the infection varies [...] Read more.
Annually, over 10,000 cases of hemorrhagic fever with renal syndrome (HFRS) are diagnosed in Europe. Puumala hantavirus (PUUV) causes most of the European HFRS cases. PUUV causes usually a relatively mild disease, which is rarely fatal. However, the severity of the infection varies greatly, and factors affecting the severity are mostly unrevealed. Host genes are known to have an effect. The typical clinical features in PUUV infection include acute kidney injury, thrombocytopenia, and increased vascular permeability. The primary target of hantavirus is the endothelium of the vessels of different organs. Although PUUV does not cause direct cytopathology of the endothelial cells, remarkable changes in both the barrier function of the endothelium and the function of the infected endothelial cells occur. Host immune or inflammatory mechanisms are probably important in the development of the capillary leakage. Several immunoinflammatory biomarkers have been studied in the context of assessing the severity of HFRS caused by PUUV. Most of them are not used in clinical practice, but the increasing knowledge about the biomarkers has elucidated the pathogenesis of PUUV infection. Full article
(This article belongs to the Special Issue Hantavirus Research in Finland)
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15 pages, 644 KiB  
Review
Coagulopathy in Acute Puumala Hantavirus Infection
by Sirpa Koskela, Satu Mäkelä, Tomas Strandin, Antti Vaheri, Tuula Outinen, Lotta Joutsi-Korhonen, Ilkka Pörsti, Jukka Mustonen and Outi Laine
Viruses 2021, 13(8), 1553; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081553 - 06 Aug 2021
Cited by 13 | Viewed by 2723
Abstract
Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome (HFRS), also called nephropathia epidemica (NE), which is mainly endemic in Europe and Russia. The clinical features include a low platelet count, altered coagulation, endothelial activation, and acute kidney injury (AKI). Multiple connections [...] Read more.
Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome (HFRS), also called nephropathia epidemica (NE), which is mainly endemic in Europe and Russia. The clinical features include a low platelet count, altered coagulation, endothelial activation, and acute kidney injury (AKI). Multiple connections between coagulation pathways and inflammatory mediators, as well as complement and kallikrein–kinin systems, have been reported. The bleeding symptoms are usually mild. PUUV-infected patients also have an increased risk for disseminated intravascular coagulation (DIC) and thrombosis. Full article
(This article belongs to the Special Issue Hantavirus Research in Finland)
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14 pages, 291 KiB  
Review
Hantavirus Research in Finland: Highlights and Perspectives
by Antti Vaheri, Heikki Henttonen and Jukka Mustonen
Viruses 2021, 13(8), 1452; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081452 - 26 Jul 2021
Cited by 13 | Viewed by 2944
Abstract
Finland has the highest incidence of hantavirus infections globally, with a significant impact on public health. The large coverage of boreal forests and the cyclic dynamics of the dominant forest rodent species, the bank vole Myodes glareolus, explain most of this. We review [...] Read more.
Finland has the highest incidence of hantavirus infections globally, with a significant impact on public health. The large coverage of boreal forests and the cyclic dynamics of the dominant forest rodent species, the bank vole Myodes glareolus, explain most of this. We review the relationships between Puumala hantavirus (PUUV), its host rodent, and the hantavirus disease, nephropathia epidemica (NE), in Finland. We describe the history of NE and its diagnostic research in Finland, the seasonal and multiannual cyclic dynamics of PUUV in bank voles impacting human epidemiology, and we compare our northern epidemiological patterns with those in temperate Europe. The long survival of PUUV outside the host and the life-long shedding of PUUV by the bank voles are highlighted. In humans, the infection has unique features in pathobiology but rarely long-term consequences. NE is affected by specific host genetics and risk behavior (smoking), and certain biomarkers can predict the outcome. Unlike many other hantaviruses, PUUV causes a relatively mild disease and is rarely fatal. Reinfections do not exist. Antiviral therapy is complicated by the fact that when symptoms appear, the patient already has a generalized infection. Blocking vascular leakage measures counteracting pathobiology, offer a real therapeutic approach. Full article
(This article belongs to the Special Issue Hantavirus Research in Finland)
10 pages, 261 KiB  
Review
Central Nervous System and Ocular Manifestations in Puumala Hantavirus Infection
by Nina Hautala, Terhi Partanen, Anna-Maria Kubin, Heikki Kauma and Timo Hautala
Viruses 2021, 13(6), 1040; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061040 - 31 May 2021
Cited by 9 | Viewed by 2169
Abstract
Puumala hantavirus (PUUV), carried and spread by the bank vole (Myodes glareolus), causes a mild form of hemorrhagic fever with renal syndrome (HFRS) called nephropathia epidemica (NE). Acute high fever, acute kidney injury (AKI), thrombocytopenia, and hematuria are typical features of [...] Read more.
Puumala hantavirus (PUUV), carried and spread by the bank vole (Myodes glareolus), causes a mild form of hemorrhagic fever with renal syndrome (HFRS) called nephropathia epidemica (NE). Acute high fever, acute kidney injury (AKI), thrombocytopenia, and hematuria are typical features of this syndrome. In addition, headache, blurred vision, insomnia, vertigo, and nausea are commonly associated with the disease. This review explores the mechanisms and presentations of ocular and central nervous system involvement in acute NE. Full article
(This article belongs to the Special Issue Hantavirus Research in Finland)

Other

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8 pages, 234 KiB  
Brief Report
Long-Term Consequences of Puumala Hantavirus Infection
by Jukka Mustonen, Antti Vaheri, Ilkka Pörsti and Satu Mäkelä
Viruses 2022, 14(3), 598; https://0-doi-org.brum.beds.ac.uk/10.3390/v14030598 - 14 Mar 2022
Cited by 5 | Viewed by 1667
Abstract
Several viral infections are associated with acute and long-term complications. During the past two years, there have been many reports on post-infectious symptoms of the patients suffering from COVID-19 disease. Serious complications occasionally occur during the acute phase of Puumala orthohantavirus caused nephropathia [...] Read more.
Several viral infections are associated with acute and long-term complications. During the past two years, there have been many reports on post-infectious symptoms of the patients suffering from COVID-19 disease. Serious complications occasionally occur during the acute phase of Puumala orthohantavirus caused nephropathia epidemica. Severe long-term consequences are rare. Fatigue for several weeks is quite common. Hormonal insufficiencies should be excluded if the patient does not recover normally. Full article
(This article belongs to the Special Issue Hantavirus Research in Finland)
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