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  • Tietäväinen, Johanna; Laine, Outi; Mäkelä, Satu; Huhtala, Heini; Pörsti, Ilkka; Vaheri, Antti; Mustonen, Jukka (2021)
    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.
  • Koskela, Sirpa; Mäkelä, Satu; Strandin, Tomas; Vaheri, Antti; Outinen, Tuula; Joutsi-Korhonen, Lotta; Pörsti, Ilkka; Mustonen, Jukka; Laine, Outi (2021)
    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.
  • Ribas Salvador, Alexis; Guivier, Emmanuel; Xuereb, Anne; Chaval, Yannick; Cadet, Patrice; Poulle, Marie-Lazarine; Sironen, Tarja; Voutilainen, Liina; Henttonen, Heikki; Cosson, Jean-Francois; Charbonnel, Nathalie (2011)
  • Koskela, Sirpa M.; Joutsi-Korhonen, Lotta; Mäkelä, Satu M.; Huhtala, Heini; Vaheri, Antti I.; Pörsti, Ilkka; Mustonen, Jukka T.; Laine, Outi K. (2018)
    Coagulation abnormalities are associated with Puumala-virus-induced hemorrhagic fever with renal syndrome (PUUV-HFRS). We evaluated the coagulation capacity of plasma during acute PUUV-HFRS by measuring thrombin generation using calibrated automated thrombography (CAT). The study cohort comprised 27 prospectively collected, consecutive, hospital-treated patients with acute PUUV infection. Blood samples were drawn in the acute phase and at the control visit approximately 5 weeks later. To evaluate thrombin generation, the lag time of initiation, endogenous thrombin potential (ETP), and peak and time to peak thrombin concentration were assessed by CAT in platelet poor plasma without corn trypsin inhibitor. Plasma levels of d-dimer, fibrinogen and prothrombin fragments (F1 + 2) were also evaluated. When the acute phase was compared with the control phase, ETP was decreased (median 1154 nmol/l/min, range 67-1785 vs. median 1385 nmol/l/min, range 670-1970; P <0.001), while the lag time was prolonged (median 3.8 min, range 2.1-7.7 vs. median 2.9 min, range 2.0-4.1; P <0.001). Low ETP correlated with low peak thrombin concentration (r = 0.833, P <0.001). Prolonged time to peak associated with the lag time (r = 0.78, P <0.001). ETP was associated with thrombocytopenia (r = 0.472, P = 0.015) and weakly with fibrinogen level (r = 0.386, P = 0.047). The measured CAT parameters did not associate with d-dimer and F1 + 2 levels. Decreased ETP together with low peak and prolonged lag time indicate decreased plasma potential for thrombin generation in vitro. Together with low platelet count and enhanced fibrinolysis, this further refers to altered blood coagulation and increased propensity toward bleeding in acute PUUV-HFRS. Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.
  • Hautala, Timo; Partanen, Terhi; Sironen, Tarja; Rajaniemi, Saara-Mari; Hautala, Nina; Vainio, Olli; Vapalahti, Olli; Kauma, Heikki; Vaheri, Antti (2013)
  • Niskanen, Silja; Jääskeläinen, Anne; Vapalahti, Olli; Sironen, Tarja (2019)
    Puumala virus (PUUV) is the most common cause of hantavirus infection in Europe, with thousands of cases occurring particularly in Northern, Central and Eastern Europe and Russia. It causes a mild form of hemorrhagic fever with renal syndrome also known as nephropathia epidemica (NE) with clinical picture ranging from mild to severe. Currently, the laboratory diagnosis of NE is mainly based on serology. Here, we evaluated a real-time one-step qRT-PCR (PUUV-qRT-PCR) for detection of PUUV with 238 consecutive diagnostic serum samples from patients with suspected PUUV infection. The PUUV-qRT-PCR was both specific and sensitive for PUUV RNA. The analytical sensitivity (limit of detection) was estimated to be four copies of PUUV per reaction. Altogether 28 out of 30 (93%) PUUV IgM positive samples were positive also for PUUV RNA. No false positives were detected and the specificity was thus 100%. Interestingly, one sample was found positive in PUUV-qRT-PCR prior to subsequent IgM and IgG seroconversion. PUUV-qRT-PCR could be used for diagnostics in the early phase of NE infection and might be helpful especially in the rare severe cases when the patient's condition may deteriorate rapidly.
  • Sironen, Tarja; Sane, Jussi; Lokki, Marja-Liisa; Meri, Seppo; Andersson, Leif C.; Hautala, Timo; Kauma, Heikki; Vuorinen, Sakari; Rasmuson, Johan; Evander, Magnus; Ahlm, Clas; Vaheri, Antti (2017)
    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.
  • Mantula, Paula; Tietavainen, Johanna; Clement, Jan; Niemelä, Onni; Pörsti, Ilkka; Vaheri, Antti; Mustonen, Jukka; Mäkelä, Satu; Outinen, Tuula (2020)
    Transient proteinuria and acute kidney injury (AKI) are characteristics of Puumala virus (PUUV) infection. Albuminuria peaks around the fifth day and associates with AKI severity. To evaluate albuminuria disappearance rate, we quantified albumin excretion at different time points after the fever onset. The study included 141 consecutive patients hospitalized due to acute PUUV infection in Tampere University Hospital, Finland. Timed overnight albumin excretion (cU-Alb) was measured during the acute phase in 133 patients, once or twice during the convalescent phase within three months in 94 patients, and at six months in 36 patients. During hospitalization, 30% of the patients had moderately increased albuminuria (cU-Alb 20-200 mu g/min), while 57% presented with severely increased albuminuria (cU-Alb >200 mu g/min). Median cU-Alb was 311 mu g/min (range 2.2-6460)
  • Tietavainen, Johanna; Mantula, Paula; Outinen, Tuula; Huhtala, Heini; Porsti, Ilkka H.; Niemela, Onni; Vaheri, Antti; Makela, Satu; Mustonen, Jukka (2019)
    Introduction: Puumala hantavirus (PUUV) causes a mild type of hemorrhagic fever with renal syndrome characterized by acute kidney injury (AKI), increased capillary leakage, and thrombocytopenia. Albuminuria and hematuria in dipstick urine test at hospital admission are known to predict the severity of upcoming AKI. Methods: We analyzed dipstick urine glucose in 195 patients with acute PUUV infection at hospital admission, and divided them into 2 categories according to the presence or absence of glucose in the dipstick urine test. Determinants of disease severity were analyzed in glucosuric and nonglucosuric patients. Results: Altogether, 24 of 195 patients (12%) had glucosuria. The patients with glucosuria had more severe AKI than patients without glucosuria (median maximum creatinine concentration 459 mmol/l, range 78-1041 mmol/l vs. 166 mmol/l, range 51-1499 mmol/l; P <0.001). The glucosuric patients had more severe thrombocytopenia (median minimum platelet count 41 x 10(9)/l, range 5-102 x 10(9)/l vs. 62 x 10(9)/l, range 3249 x 10(9)/l; P = 0.006), and more pronounced signs of increased capillary leakage (change in weight, maximum plasma hematocrit, minimum plasma albumin). The glucosuric patients were more often in clinical shock at admission (20.8% vs. 1.2%; P <0.001) and the length of hospital stay was longer (median 7.5 days, range 4-22 days vs. 6 days, range 2-30 days; P = 0.009). Conclusion: Glucosuria is relatively rare, but when present it predicts a more severe disease course in patients with acute PUUV infection.
  • Outinen, Tuula K.; Mantula, Paula; Jaatinen, Pia; Hämäläinen, Mari; Moilanen, Eeva; Vaheri, Antti; Huhtala, Heini; Mäkelä, Satu; Mustonen, Jukka (2019)
    Most cases of hemorrhagic fever with renal syndrome (HFRS) in Europe are caused by the Puumala hantavirus (PUUV). Typical features of the disease are increased vascular permeability, acute kidney injury (AKI), and thrombocytopenia. YKL-40 is an inflammatory glycoprotein involved in various forms of acute and chronic inflammation. In the present study, we examined plasma YKL-40 levels and the associations of YKL-40 with disease severity in acute PUUV infection. A total of 79 patients treated in Tampere University Hospital during 2005-2014 were studied. Plasma YKL-40 was measured in the acute phase, the recovery phase, and one year after hospitalization. Plasma YKL-40 levels were higher during the acute phase compared to the recovery phase and one year after hospitalization (median YKL-40 142 ng/mL, range 11-3320, vs. 45 ng/mL, range 15-529, vs. 32 ng/mL, range 3-213, p <0.001). YKL-40 level was correlated with the length of hospital stay (r = 0.229, p = 0.042), the levels of inflammatory markers-that is, blood leukocytes (r = 0.234, p = 0.040), plasma C-reactive protein (r = 0.332, p = 0.003), and interleukin-6 (r = 0.544, p <0.001), and maximum plasma creatinine level (r = 0.370, p = 0.001). In conclusion, plasma YKL-40 levels were found to be elevated during acute PUUV infection and correlated with the overall severity of the disease, as well as with the degree of inflammation and the severity of AKI.
  • Vaheri, Antti; Henttonen, Heikki; Mustonen, Jukka (2021)
    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.
  • Mantula, Paula S.; Outinen, Tuula K.; Jaatinen, Pia; Hämäläinen, Mari; Huhtala, Heini; Pörsti, Ilkka H.; Vaheri, Antti; Mustonen, Jukka T.; Mäkelä, Satu M. (2018)
    Background Puumala hantavirus (PUUV) infected patients typically suffer from acute kidney injury (AKI). Adipokines have inflammation modulating functions in acute diseases including AKI. We examined plasma levels of three adipokines (resistin, leptin, and adiponectin) in acute PUUV infection and their associations with disease severity. Methods This study included 79 patients hospitalized due to acute PUUV infection. Plasma resistin, leptin, adiponectin, as well as IL-6 and CRP, were measured at the acute phase, recovery phase and one year after hospitalization. Results Plasma resistin levels were significantly higher in the acute phase compared to the recovery phase and one year after (median resistin 28 pg/mL (11-107) vs. 17 pg/mL (7-36) vs. 14 pg/mL (7-31), p= 353.6 mu mol/L) (OR 1.08, 95% CI 1.02-1.14). Neither plasma leptin nor adiponectin level had any correlation with creatinine concentration or the amount of albuminuria. Conclusions Plasma resistin independently associates with the severity of AKI in acute PUUV infection. The association of resistin with the amount of albuminuria suggests that the level of plasma resistin is not only influenced by renal clearance but could have some role in the pathogenesis of AKI during PUUV infection.
  • Charbonnel, Nathalie; Pages, Marie; Sironen, Tarja; Henttonen, Heikki; Vapalahti, Olli; Mustonen, Jukka; Vaheri, Antti (2014)
  • Lederer, Sabine; Lattwein, Erik; Hanke, Merle; Sonnenberg, Karen; Stoecker, Winfried; Lundkvist, Ake; Vaheri, Antti; Vapalahti, Olli; Chan, Paul K. S.; Feldmann, Heinz; Dick, Daryl; Schmidt-Chanasit, Jonas; Padula, Paula; Vial, Pablo A.; Panculescu-Gatej, Raluca; Ceianu, Cornelia; Heyman, Paul; Avsic-Zupanc, Tatjana; Niedrig, Matthias (2013)
  • Mustonen, Jukka; Vaheri, Antti; Pörsti, Ilkka; Mäkelä, Satu (2022)
    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.
  • Clement, Jan; Ahlm, Clas; Avsic-Zupanc, Tatjana; Botten, Jason; Chandran, Kartik; Jonsson, Colleen B.; Kariwa, Hiroaki; Klingstrom, Jonas; Klempa, Boris; Krueger, Detlev H.; Leirs, Herwig; Li, Dexin; Liang, Mifang; Markotic, Alemka; Papa, Anna; Schmaljohn, Connie S.; Tischler, Nicole D.; Ulrich, Rainer G.; Vaheri, Antti; Vial, Cecilia; Yanagihara, Richard; Maes, Piet (2020)
    The 2019 11th International Conference on Hantaviruses (ICH 2019) was organized by the International Society for Hantaviruses (ISH), and held on September 1-4, 2019, at the Irish College, in Leuven, Belgium. These ICHs have been held every three years since 1989. ICH 2019 was attended by 158 participants from 33 countries. The current report summarizes research presented on all aspects of hantavirology: ecology; pathogenesis and immune responses; virus phylogeny, replication and morphogenesis; epidemiology; vaccines, therapeutics and prevention; and clinical aspects and diagnosis.
  • Rissanen, Ilona; Stass, Robert; Krumm, Stefanie A.; Seow, Jeffrey; Hulswit, Ruben J.G.; Paesen, Guido C.; Hepojoki, Jussi; Vapalahti, O.; Lundkvist, Åke; Reynard, Olivier; Volchkov, Viktor; Doores, Katie J.; Huiskonen, Juha T.; Bowden, Thomas A. (2020)
    The intricate lattice of Gn and Gc glycoprotein spike complexes on the hantavirus envelope facilitates host-cell entry and is the primary target of the neutralizing antibody-mediated immune response. Through study of a neutralizing monoclonal antibody termed mAb P-4G2, which neutralizes the zoonotic pathogen Puumala virus (PUUV), we provide a molecular-level basis for antibody-mediated targeting of the hantaviral glycoprotein lattice. Crystallographic analysis demonstrates that P-4G2 binds to a multi-domain site on PUUV Gc and may preclude fusogenic rearrangements of the glycoprotein that are required for host-cell entry. Furthermore, cryo-electron microscopy of PUUV-like particles in the presence of P-4G2 reveals a lattice-independent configuration of the Gc, demonstrating that P-4G2 perturbs the (Gn-Gc)4 lattice. This work provides a structure-based blueprint for rationalizing antibody-mediated targeting of hantaviruses.
  • Iheozor-Ejiofor, Rommel; Vapalahti, Katariina; Sironen, Tarja; Levanov, Lev; Hepojoki, Jussi; Lundkvist, Åke; Mäkelä, Satu; Vaheri, Antti; Mustonen, Jukka; Plyusnin, Alexander; Strandin, Tomas M.; Vapalahti, Olli (2022)
    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.
  • Strandin, Tomas; Mäkelä, Satu; Mustonen, Jukka; Vaheri, Antti (2018)
    Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) in humans. Both diseases are considered to be immunologically mediated but the exact pathological mechanisms are still poorly understood. Neutrophils are considered the first line of defense against invading microbes but little is still known of their role in virus infections. We wanted to study the role of neutrophils in HFRS using blood and tissue samples obtained from Puumala hantavirus (PUUV)-infected patients. We found that neutrophil activation products myeloperoxidase and neutrophil elastase, together with interleukin-8 (the major neutrophil chemotactic factor in humans), are strongly elevated in blood of acute PUUV-HFRS and positively correlate with kidney dysfunction, the hallmark clinical finding of HFRS. These markers localized mainly in the tubulointerstitial space in the kidneys of PUUV-HFRS patients suggesting neutrophil activation to be a likely component of the general immune response toward hantaviruses. We also observed increased levels of circulating extracellular histones at the acute stage of the disease supporting previous findings of neutrophil extracellular trap formation in PUUV-HFRS. Mechanistically, we did not find evidence for direct PUUV-mediated activation of neutrophils but instead primary blood microvascular endothelial cells acquired a pro-inflammatory phenotype and promoted neutrophil degranulation in response to PUUV infection in vitro. These results suggest that neutrophils are activated by hantavirus-infected endothelial cells and may contribute to the kidney pathology which determines the severity of HFRS.
  • Sane, J.; Ollgren, J.; Makary, P.; Vapalahti, O.; Kuusi, M.; Lyytikainen, O. (2016)
    Puumala hantavirus (PUUV) causes haemorrhagic fever with renal syndrome in humans, an endemic disease in Finland. We aimed to study recent trends in PUUV infections in Finland, to evaluate whether there are regional differences in seasonality and long-term cycles and whether the patterns have changed over time. We analysed serologically confirmed acute PUUV infections reported to the National Infectious Disease Register from 1 April 1995 to 31 March 2014. A total of 30 942 cases of PUUV infections were identified during the study period. The average annual incidence was 31 cases/100 000 person-years with the highest in Eastern Finland and the lowest in Southwestern Finland. Throughout Finland there was not an increasing trend in incidence but changes in incidence, seasonality and long-term cycles differed regionally. Long-term cycles supported by high Bayesian posterior probabilities (73-100%) differed between the south and the north, shifting from 3 to 4 years, respectively. Temporal changes in seasonality were most prominent in Southwestern Finland. The pattern of human PUUV infection epidemiology probably primarily reflects the spatio-temporal interaction between bank-vole population dynamics and climate.