{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T05:23:46Z","timestamp":1784179426268,"version":"3.55.0"},"reference-count":30,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T00:00:00Z","timestamp":1656028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Netherlands Centre for One Health Ph.D. Research Program","award":["HEALTH-F3-2013-602525"],"award-info":[{"award-number":["HEALTH-F3-2013-602525"]}]},{"name":"EU project Platform foR European Preparedness Against (Re-)emerging Epidemics","award":["HEALTH-F3-2013-602525"],"award-info":[{"award-number":["HEALTH-F3-2013-602525"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Puumala orthohantavirus (PUUV) is endemic in Europe and can cause hemorrhagic fever with renal syndrome (nephropathia epidemica). Disease features include fever, thrombocytopenia, and acute kidney injury (AKI). This retrospective cohort study of forty PUUV patients aims to characterize associations of serum immunological, hemostatic or kidney injury markers to disease severity. While interleukin-18 (IL-18) was significantly increased in severely thrombocytopenic patients (&lt;100 \u00d7 109 platelets\/L) compared to patients with higher platelet counts, RANTES was significantly decreased in these patients. These data suggest that patients with significant thrombocytopenia might have experienced pronounced Th1 immune responses. When kidney dysfunction was used as the primary disease outcome, recently identified AKI biomarkers (Cystatin C, insulin-like growth factor-binding protein 7, Nephrin, and trefoil factor 3) were significantly upregulated in patients with severe PUUV infection, defined as the estimated glomerular filtration rate (eGFR) below 30 m\/min\/1.73 m2. The increased expression of these markers specifically indicates pathology in glomeruli and proximal tubuli. Furthermore, E-selectin was significantly higher while interferon gamma-induced protein 10 (IP-10) was significantly lower in PUUV patients with more severe kidney dysfunction compared to patients with higher eGFR-values. Increased E-selectin illustrates the central role of endothelial cell activation, whereas decreased IP-10 could indicate a less important role of this cytokine in the pathogenesis of kidney dysfunction.<\/jats:p>","DOI":"10.3390\/v14071377","type":"journal-article","created":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T22:50:23Z","timestamp":1656283823000},"page":"1377","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Serum Markers Associated with Disease Severity in a Bosnian Hemorrhagic Fever with Renal Syndrome Cohort"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1845-7511","authenticated-orcid":false,"given":"Danny","family":"Noack","sequence":"first","affiliation":[{"name":"Department of Viroscience, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9599-1999","authenticated-orcid":false,"given":"Maja","family":"Travar","sequence":"additional","affiliation":[{"name":"Department for Clinical Microbiology, University Clinical Center of Republika Srpska, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Department for Microbiology and Immunology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Republika Srpska, Bosnia and Herzegovina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Visnja","family":"Mrdjen","sequence":"additional","affiliation":[{"name":"Department for Clinical Microbiology, University Clinical Center of Republika Srpska, 78000 Banja Luka, Bosnia and Herzegovina"},{"name":"Department for Microbiology and Immunology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Republika Srpska, Bosnia and Herzegovina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5607-7395","authenticated-orcid":false,"given":"Jolanda J. C.","family":"Voermans","sequence":"additional","affiliation":[{"name":"Department of Viroscience, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5877-8526","authenticated-orcid":false,"given":"David","family":"van de Vijver","sequence":"additional","affiliation":[{"name":"Department of Viroscience, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Molenkamp","sequence":"additional","affiliation":[{"name":"Department of Viroscience, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5204-2312","authenticated-orcid":false,"given":"Marion P. G.","family":"Koopmans","sequence":"additional","affiliation":[{"name":"Department of Viroscience, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Goeijenbier","sequence":"additional","affiliation":[{"name":"Department of Viroscience, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Intensive Care, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2463-027X","authenticated-orcid":false,"given":"Barry","family":"Rockx","sequence":"additional","affiliation":[{"name":"Department of Viroscience, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"vez009","DOI":"10.1093\/ve\/vez009","article-title":"Identifying the patterns and drivers of Puumala hantavirus enzootic dynamics using reservoir sampling","volume":"5","author":"Laenen","year":"2019","journal-title":"Virus Evol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1017\/S0950268809991348","article-title":"A serosurvey reveals Bosnia and Herzegovina as a Europe\u2019s hotspot in hantavirus seroprevalence","volume":"138","author":"Hukic","year":"2010","journal-title":"Epidemiol. Infect."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1002\/jmv.2179","article-title":"Characteristics of puumala and Dobrava infections in Croatia","volume":"66","author":"Nichol","year":"2002","journal-title":"J. Med. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.virusres.2013.12.042","article-title":"HFRS and hantaviruses in the Balkans\/South-East Europe","volume":"187","author":"Korva","year":"2014","journal-title":"Virus Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"399","DOI":"10.3389\/fcimb.2020.00399","article-title":"Orthohantavirus Pathogenesis and Cell Tropism","volume":"10","author":"Noack","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"567","DOI":"10.3389\/fimmu.2017.00567","article-title":"Serum Cytokine Profiles Differentiating Hemorrhagic Fever with Renal Syndrome and Hantavirus Pulmonary Syndrome","volume":"8","author":"Khaiboullina","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8658507","DOI":"10.1155\/2018\/8658507","article-title":"Urinary Clusterin Is Upregulated in Nephropathia Epidemica","volume":"2018","author":"Martynova","year":"2018","journal-title":"Dis. Markers"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Korva, M., Rus, K.R., Pavleti\u010d, M., Saksida, A., Knap, N., Jelov\u0161ek, M., Smrdel, K.S., Jakupi, X., Humolli, I., and Dedushaj, J. (2019). Characterization of Biomarker Levels in Crimean\u2013Congo Hemorrhagic Fever and Hantavirus Fever with Renal Syndrome. Viruses, 11.","DOI":"10.3390\/v11080686"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"580478","DOI":"10.3389\/fcimb.2020.580478","article-title":"Development of a Comparative European Orthohantavirus Microneutralization Assay with Multi-Species Validation and Evaluation in a Human Diagnostic Cohort","volume":"10","author":"Hoornweg","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e6","DOI":"10.1111\/1469-0691.12291","article-title":"Hantavirus infections","volume":"21","author":"Saksida","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_11","unstructured":"(2021, April 15). UKidney. eGFR Calculator. 2007\u20132022. Available online: https:\/\/www.ukidney.com\/nephrology-resources\/egfr-calculator."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100220","DOI":"10.1016\/j.xcrm.2021.100220","article-title":"MAIT cell activation is associated with disease severity markers in acute hantavirus infection","volume":"2","author":"Maleki","year":"2021","journal-title":"Cell Rep. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Martynova, E., Davidyuk, Y., Kabwe, E., Garanina, E., Shakirova, V., Pavelkina, V., Uskova, Y., Stott, R., Foster, T., and Markelova, M. (2021). Cytokine, Chemokine, and Metalloprotease Activation in the Serum of Patients with Nephropathia Epidemica from the Republic of Tatarstan and the Republic of Mordovia, Russia. Pathogens, 10.","DOI":"10.3390\/pathogens10050527"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Vangeti, S., Strandin, T., Liu, S., Tauriainen, J., R\u00e4is\u00e4nen-Sokolowski, A., Cabrera, L., Hassinen, A., M\u00e4kel\u00e4, S., Mustonen, J., and Vaheri, A. (2021). Monocyte subset redistribution from blood to kidneys in patients with Puumala virus caused hemorrhagic fever with renal syndrome. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009400"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4685288","DOI":"10.1155\/2022\/4685288","article-title":"Serum Cytokine Alterations Associated with Age of Patients with Nephropathia Epidemica","volume":"2022","author":"Shakirova","year":"2022","journal-title":"BioMed Res. Int."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Raadsen, M., Du Toit, J., Langerak, T., van Bussel, B., van Gorp, E., and Goeijenbier, M. (2021). Thrombocytopenia in Virus Infections. J. Clin. Med., 10.","DOI":"10.3390\/jcm10040877"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1097\/MBC.0000000000000117","article-title":"Plasma pentraxin-3 and coagulation and fibrinolysis variables during acute Puumala hantavirus infection and associated thrombocytopenia","volume":"25","author":"Laine","year":"2014","journal-title":"Blood Coagul. Fibrinolysis"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1007\/s10096-011-1392-x","article-title":"High pentraxin-3 plasma levels associate with thrombocytopenia in acute Puumala hantavirus-induced nephropathia epidemica","volume":"31","author":"Outinen","year":"2012","journal-title":"Eur. J. Clin. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Outinen, T.K., M\u00e4kel\u00e4, S.M., O Ala-Houhala, I., Huhtala, H.S., Hurme, M., Paakkala, A.S., P\u00f6rsti, I.H., Syrj\u00e4nen, J.T., and Mustonen, J.T. (2010). The severity of Puumala hantavirus induced nephropathia epidemica can be better evaluated using plasma interleukin-6 than C-reactive protein determinations. BMC Infect. Dis., 10.","DOI":"10.1186\/1471-2334-10-132"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Hansson, M., Gustafsson, R., Jacquet, C., Chebaane, N., Satchell, S., Thunberg, T., Ahlm, C., and Connolly, A.-M.F. (2020). Cystatin C and \u03b1-1-Microglobulin Predict Severe Acute Kidney Injury in Patients with Hemorrhagic Fever with Renal Syndrome. Pathogens, 9.","DOI":"10.3390\/pathogens9080666"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"R25","DOI":"10.1186\/cc12503","article-title":"Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury","volume":"17","author":"Kashani","year":"2013","journal-title":"Crit. Care"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"19117","DOI":"10.1038\/s41598-020-76050-0","article-title":"Glomerular filtration barrier dysfunction in a self-limiting, RNA virus-induced glomerulopathy resembles findings in idiopathic nephrotic syndromes","volume":"10","author":"Nusshag","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.ejogrb.2012.10.011","article-title":"Comparison of serum and urinary nephrin levels between normal pregnancies and severe preeclampsia","volume":"166","author":"Son","year":"2013","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Du, T.-Y., Luo, H.-M., Qin, H.-C., Wang, F., Wang, Q., Xiang, Y., and Zhang, Y. (2013). Circulating Serum Trefoil Factor 3 (TFF3) Is Dramatically Increased in Chronic Kidney Disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0080271"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Gunasekara, T., De Silva, P.M.C., Herath, C., Siribaddana, S., Siribaddana, N., Jayasumana, C., Jayasinghe, S., Cardenas-Gonzalez, M., and Jayasundara, N. (2020). The Utility of Novel Renal Biomarkers in Assessment of Chronic Kidney Disease of Unknown Etiology (CKDu): A Review. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17249522"},{"key":"ref_26","first-page":"379","article-title":"Hantavirus antigen detection in kidney biopsies from patients with nephropathia epidemica","volume":"46","author":"Groen","year":"1996","journal-title":"Clin. Nephrol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9811","DOI":"10.1128\/JVI.00568-11","article-title":"Pathogenic Old World Hantaviruses Infect Renal Glomerular and Tubular Cells and Induce Disassembling of Cell-to-Cell Contacts","volume":"85","author":"Grouls","year":"2011","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"468","DOI":"10.3109\/07853890.2011.573500","article-title":"Complement activation in Puumala hantavirus infection correlates with disease severity","volume":"44","author":"Sane","year":"2012","journal-title":"Ann. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Outinen, T.K., Mantula, P., Jaatinen, P., H\u00e4m\u00e4l\u00e4inen, M., Moilanen, E., Vaheri, A., Huhtala, H., M\u00e4kel\u00e4, S., and Mustonen, J. (2019). Glycoprotein YKL-40 Is Elevated and Predicts Disease Severity in Puumala Hantavirus Infection. Viruses, 11.","DOI":"10.3390\/v11090767"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Outinen, T.K., M\u00e4kel\u00e4, S., P\u00f6rsti, I., Vaheri, A., and Mustonen, J. (2021). Severity Biomarkers in Puumala Hantavirus Infection. Viruses, 14.","DOI":"10.3390\/v14010045"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/7\/1377\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:39:04Z","timestamp":1760139544000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/7\/1377"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,24]]},"references-count":30,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["v14071377"],"URL":"https:\/\/doi.org\/10.3390\/v14071377","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,24]]}}}