{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T06:42:39Z","timestamp":1792564959941,"version":"4.5.0"},"reference-count":79,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T00:00:00Z","timestamp":1679443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sigrid Jus\u00e9lius Foundation"},{"name":"Academy of Finland"},{"name":"Finnish Society of Sciences and Letters"},{"name":"Magnus Ehrnrooth Foundation"},{"name":"Competitive State Research Financing of the Responsibility Area of Tampere University Hospital"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The clinical outcome of Puumala hantavirus (PUUV) infection shows extensive variation, ranging from inapparent subclinical infection (70\u201380%) to severe hemorrhagic fever with renal syndrome (HFRS), with about 0.1% of cases being fatal. Most hospitalized patients experience acute kidney injury (AKI), histologically known as acute hemorrhagic tubulointerstitial nephritis. Why this variation? There is no evidence that there would be more virulent and less virulent variants infecting humans, although this has not been extensively studied. Individuals with the human leukocyte antigen (HLA) alleles B*08 and DRB1*0301 are likely to have a severe form of the PUUV infection, and those with B*27 are likely to have a benign clinical course. Other genetic factors, related to the tumor necrosis factor (TNF) gene and the C4A component of the complement system, may be involved. Various autoimmune phenomena and Epstein-Barr virus infection are associated with PUUV infection, but hantavirus-neutralizing antibodies are not associated with lower disease severity in PUUV HFRS. Wide individual differences occur in ocular and central nervous system (CNS) manifestations and in the long-term consequences of nephropathia epidemica (NE). Numerous biomarkers have been detected, and some are clinically used to assess and predict the severity of PUUV infection. A new addition is the plasma glucose concentration associated with the severity of both capillary leakage, thrombocytopenia, inflammation, and AKI in PUUV infection. Our question, \u201cWhy this variation?\u201d remains largely unanswered.<\/jats:p>","DOI":"10.3390\/v15030805","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T07:46:43Z","timestamp":1679471203000},"page":"805","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Puumala Hantavirus Infections Show Extensive Variation in Clinical Outcome"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2670-2345","authenticated-orcid":false,"given":"Antti","family":"Vaheri","sequence":"first","affiliation":[{"name":"Department of Virology, Medicum, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teemu","family":"Smura","sequence":"additional","affiliation":[{"name":"Department of Virology, Medicum, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Vauhkonen","sequence":"additional","affiliation":[{"name":"Department of Virology, Medicum, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5699-214X","authenticated-orcid":false,"given":"Jussi","family":"Hepojoki","sequence":"additional","affiliation":[{"name":"Department of Virology, Medicum, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2344-2755","authenticated-orcid":false,"given":"Tarja","family":"Sironen","sequence":"additional","affiliation":[{"name":"Department of Virology, Medicum, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2454-7479","authenticated-orcid":false,"given":"Tomas","family":"Strandin","sequence":"additional","affiliation":[{"name":"Department of Virology, Medicum, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1882-0691","authenticated-orcid":false,"given":"Johanna","family":"Tiet\u00e4v\u00e4inen","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland"},{"name":"Department of Internal Medicine, Tampere University Hospital, 33520 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuula","family":"Outinen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Tampere University Hospital, 33520 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6967-2401","authenticated-orcid":false,"given":"Satu","family":"M\u00e4kel\u00e4","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Tampere University Hospital, 33520 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4905-7564","authenticated-orcid":false,"given":"Ilkka","family":"P\u00f6rsti","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland"},{"name":"Department of Internal Medicine, Tampere University Hospital, 33520 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3462-2129","authenticated-orcid":false,"given":"Jukka","family":"Mustonen","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland"},{"name":"Department of Internal Medicine, Tampere University Hospital, 33520 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Vaheri, A., Henttonen, H., and Mustonen, J. 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