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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.

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.

Hantaviruses are widespread zoonotic pathogens found around the globe. Depending on their geographical location, hantaviruses can cause two human syndromes, haemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). HPS and HFRS have many commonalities amongst which excessive activation of immune cells is a prominent feature. Hantaviruses replicate in endothelial cells (ECs), the major battlefield of hantavirus-induced pathogenesis, without causing cytopathic effects. This indicates that a misdirected response of human immune cells to hantaviruses is causing damage. As dendritic cells (DCs) orchestrate antiviral immune responses, they are in the focus of research analysing hantavirus-induced immunopathogenesis. In this review, we discuss the interplay between hantaviruses and DCs and the immunological consequences thereof.

Several case reports have described hypopituitarism following orthohantavirus infection, mostly following Puumala virus. The pathogenesis of this seemingly rare complication of orthohantavirus infection remains unknown. This review explores the possible pathophysiological mechanisms of pituitary damage due to orthohantavirus infection. In only three out of the 28 reported cases, hypopituitarism was detected during active infection. In the remaining cases, detection of pituitary damage was delayed, varying from two months up to thirteen months post-infection. In these cases, hypopituitarism remained undetected during the acute phase of infection or only occurred weeks to months post infection. Both ischemic and hemorrhagic damage of the pituitary gland have been detected in radiographic imaging and post-mortem studies in the studied case reports series. Ischemic damage could be caused by hypotension and/or vasospasms during the acute phase of hemorrhagic fever with renal syndrome (HFRS) while hemorrhage could be caused by thrombocytopenia, thrombopathy, and other known causes of coagulation disorders during orthohantavirus infection. Also, hypophysitis due to the presence of auto-antibodies have been suggested in the literature. In conclusion, a significant number of case reports and series describe hypopituitarism after orthohantavirus infection. In most cases hypopituitarism was diagnosed with a delay and therefore could very well be underreported. Clinicians should be aware of this potential endocrine complication, with substantial morbidity, and if unrecognized, significant mortality.

Central diabetes insipidus (DI) was detected in a patient with hemorrhagic fever with renal syndrome (HFRS) who had been molecularly and serologically diagnosed with Hantaan virus infection. We recommend that clinicians differentiate central DI in HFRS patients with a persistent diuretic phase even when pituitary MRI findings are normal.

Background: Information on the sequential appearance, duration, and magnitude of clinical and laboratory parameters in hemorrhagic fever with renal syndrome (HFRS) is limited., Methods: Analysis of clinical and laboratory parameters obtained serially in 81 patients with HFRS, of whom 15 were infected with Dobrava virus and 66 with Puumala virus., Results: The initial signs/symptoms, appearing on median day 1 of illness, were fever, headache, and myalgia. These were present in 86%, 65%, and 40% of patients and had a median duration of 4, 4, and 5.5 days, respectively. The signs/symptoms were followed by myopia (appearance on day 5), insomnia (day 6), oliguria/anuria (day 6), polyuria (day 9), and sinus bradycardia (day 9.5). These were present in 35%, 30%, 28%, 91%, and 35% of patients; their median duration was 2, 2, 2, 7, and 1 day, respectively. Laboratory abnormalities, including thrombocytopenia, elevated alanine aminotransferase, CRP, procalcitonin, creatinine, diminished glomerular filtration rate, and leukocytosis, were ascertained on admission to hospital or on the following day (day 5 or 6 of illness) and were established in 95%, 87%, 99%, 91%, 94%, 87%, and 55% of patients, and had a median duration of 4, 3, 7, 3, 9, 8, and 2 days, respectively. Comparison of patients infected with Dobrava and Puumala viruses found several differences in the frequency, magnitude, and duration of abnormalities, indicating that Dobrava virus causes the more severe HFRS., Conclusions: In the majority of patients, the classic clinical distinction into febrile, hypotonic, oliguric, polyuric, and convalescent phases of illness is unclear., Competing Interests: The authors have declared that no competing interests exist.

Background: Hemorrhagic fever with renal syndrome (HFRS) is a rodent borne zoonosis, caused by the members of the family Bunyaviridae, genus Hantavirus. The main clinical features of the infection by this virus family are fever, thrombocytopenia and acute kidney injury., Objective: The aim of our study was to identify, for the first time, characteristic features of HFRS in the Albanian population., Study Design: The study comprised 33 consecutive patients admitted with suspected HFRS from April 2011-April 2016 at one center. Clinical diagnosis was confirmed by ELISA and real-time PCR. Statistical analysis was performed to identify prognostic markers and indicators of disease severity., Results: The virus strain causing HFRS was Dobrava type in all 33 cases. The disease outbreaks occurred during the period June-July. Mean hospital stay was 15.7±6.9days. 29 (88%) of the patients were male. The mean age was 39.7±14.1. 16 (48.5%) patients were from Northeast Albania. 8 (24.2%) patients required dialysis. The strongest correlation was the inverse relationship of nadir platelet count with urea and creatinine, p<0.0001, p<0.0079 respectively. Creatinine and hyponatremia were inversely correlated p=0.0007, whereas hyponatremia and nadir platelet count had the highest sensitivity and specificity for development of severe AKI, 92.6%, 100%; 88.9%, 83.3% respectively. Mortality rate was 9.09%., Conclusion: HFRS is a severe viral disease in Albania caused by Dobrava strain. It is associated with high mortality, 9.09% in our cohort. In our study, thrombocytopenia, urinary volume, hyponatremia were indicators of more severe disease., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Haemorrhagic fever with renal syndrome (HFRS) is characterised by an uncontrolled immune response that causes vascular leakage. Adiponectin (APN) is an adipocytokine involved in prorevascularisation and immunomodulation. To investigate the possible effects of APN in the pathogenesis of HFRS, total and high molecular weight (HMW) APN levels in the plasma of patients with HFRS were quantified using enzyme-linked immunosorbent assay (ELISA). Compared with those in healthy controls, the plasma total and HMW APN levels in patients were elevated to different degrees from the fever onset and remained high at the convalescent phase. Consistent with these results, western blot analysis additionally showed that low molecular weight (LMW), middle molecular weight (MMW), and HMW APN levels were all elevated and contributed to the elevation of the total APN level. Importantly, sustained high levels of total and HMW APN at the convalescent phase were significantly higher in patients with critical disease than those in patients with mild or moderate disease. Moreover, total and HMW APN levels negatively correlated with white blood cell count and positively correlated with platelet count and serum albumin level. These results may provide insights into understanding the roles of total and HMW APN in the pathogenesis of HFRS.

Background: Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) in humans. Hantavirus infections are characterized by thrombocytopenia. Our objective was to assess the association of thrombocytopenia with disease severity in HFRS induced by Puumala hantavirus (PUUV)., Methods: Altogether 546 patients treated for acute serologically confirmed PUUV infection during 1982-2013 at Tampere University Hospital, Finland, were examined. Blood platelet count was determined daily and analysed in relation to different variables reflecting disease severity. The patients were divided into two groups according to the minimum platelet count: severe thrombocytopenia (<69 × 10(9)/L, i.e. below median) and no severe thrombocytopenia (≥69 × 10(9)/L)., Results: Thrombocytopenia (platelet count <150 × 10(9)/L) was detected in 90% of patients, and in 28% of patients platelet count was <50 × 10(9)/L. Patients with severe thrombocytopenia had longer stay (8 versus 7 days, p = 0.002) and greater weight gain (2.8 versus 2.0 kg, p < 0.001) at the hospital, higher blood leukocyte count (11.2 × 10(9)/L versus 9.6 × 10(9)/L, p < 0.001), plasma C-reactive protein (81 versus 59 mg/L, p < 0.001), maximum hematocrit (0.44 versus 0.42, p < 0.001), urinary protein excretion (1.7 versus 1.1 g/24 h, p = 0.002), and lower plasma albumin concentration (27 versus 32 g/L, p < 0.001) than patients without severe thrombocytopenia (comparisons between medians). Maximum creatinine concentration did not differ between patients with or without severe thrombocytopenia (median 235 versus 214 μmol/L, p = 0.217)., Conclusions: The severity of thrombocytopenia associates with the degree of inflammation and variables reflecting capillary leakage, but not with the severity of acute kidney injury in PUUV infected Finnish patients.

Objective: This retrospective study is aimed to investigate the clinical features of the patients with history of incomplete vaccination against hemorrhagic fever with renal syndrome (HFRS)., Methods: Data of 140 cases of hospitalized patients with HFRS were collected. The patients were divided into incomplete vaccinated group (n = 10) and unvaccinated group (n = 130) according to vaccination status. Demographic, clinical, and laboratory characteristics of the two groups' patients were compared through t test, Pearson χ(2) test, and Mann-Whitney test., Results: In comparison with the unvaccinated group, the incidence rate of vomiting and hypotensive-shock, the white blood cell (WBC) and platelet count, the level of blood urea nitrogen and albumin, total number of dialysis and hospitalization cost of patients in the incomplete vaccinated group have statistically significant differences., Conclusion: HFRS disease may still occur in individuals with a history of HFRS incomplete vaccination although the symptoms may be mild. Effective vaccination against HFRS needs sufficient doses and booster shot of the vaccine., (© 2015 Wiley Periodicals, Inc.)

Background: Thrombocytopenia is a common finding during viral hemorrhagic fever, which includes hemorrhagic fever with renal syndrome (HFRS). The 2 main causes for thrombocytopenia are impaired thrombopoiesis and/or increased peripheral destruction of platelets. In addition, there is an increased intravascular coagulation risk during HFRS, which could be due to platelet activation., Methods: Thrombopoiesis was determined by quantification of platelet counts, thrombopoietin, immature platelet fraction, and mean platelet volume during HFRS. The in vivo platelet activation was determined by quantification of soluble P-selectin (sP-selectin) and glycoprotein VI (sGPVI). The function of circulating platelets was determined by ex vivo stimulation followed by flow cytometry analysis of platelet surface-bound fibrinogen and P-selectin exposure. Intravascular coagulation during disease was determined by scoring for disseminated intravascular coagulation (DIC) and recording thromboembolic complications., Results: The levels of thrombopoietin, immature platelet fraction, and mean platelet volume all indicate increased thrombopoiesis during HFRS. Circulating platelets had reduced ex vivo function during disease compared to follow-up. Most interestingly, we observed significantly increased in vivo platelet activation in HFRS patients with intravascular coagulation (DIC and thromboembolic complications) as shown by sP-selectin and sGPVI levels., Conclusions: HFRS patients have increased thrombopoiesis and platelet activation, which contributes to intravascular coagulation., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The aim of the article is to study actual ration of patients suffered from hemorrhagic fever with renal syndrome (HFRS) and its interaction with the development of arterial hypertension (AH). 296 men aged 20–59 suffered from HFRS were under the care of physician within the period of 1 to 6 years. Among this group 49 cases of arterial hypertension have been registered after HFRS. Frequency method of food product consumption was used to define nutrition. A Russian questionnaire published by Institute of Nutrition (1997) was used. Actual nutrition in men suffered from HFRS is marked by basic nutrients unbalance that is: excessive cholesterol and fat consumption (due to saturated fatty acid), polyunsaturated fatty acid deficiency, sugar overuse and animal protein prevalence over vegetable proteins in patient ration. Atherogenic shift in a ration of patients with AH and suffered from HRFS has been exposed more strongly in all aged group but mostly evident in patients aged 40 and after. Alcohol consumption in men with AH and suffered from HFRS is higher than in healthy peers. Interaction between atherogenic unbalance on the main nutrients in patients with HFRS and arterial hypertension has been defined. Consumatory behavior correction is to be taken to prevent arterial hypertension in recovered patients suffered from HFRS.

Human infection with Puumala virus (PUUV), the most common hantavirus in Central Europe, causes nephropathia epidemica (NE), a disease characterized by acute kidney injury and thrombocytopenia. To determine the clinical phenotype of hantavirus-infected patients and their long-term outcome and humoral immunity to PUUV, we conducted a cross-sectional prospective survey of 456 patients in Germany with clinically and serologically confirmed hantavirus-associated NE during 2001-2012. Prominent clinical findings during acute NE were fever and back/limb pain, and 88% of the patients had acute kidney injury. At follow-up (7-35 mo), all patients had detectable hantavirus-specific IgG; 8.5% had persistent IgM; 25% had hematuria; 23% had hypertension (new diagnosis for 67%); and 7% had proteinuria. NE-associated hypertension and proteinuria do not appear to have long-term consequences, but NE-associated hematuria may. All patients in this study had hantavirus-specific IgG up to years after the infection.

An Israeli researcher working in Finland with Bank Voles, contracted an infectious viral disease and died. This was a rare event, but it is important to learn about this class of viruses and to be aware of the hazards while working in the field in close contact with wild animals. The virus termed Puumala belongs to the genus Hanta from the Bunyaviridae family. The natural reservoir is rodents, mice, rats and Bank Votes for the Puuamala strain. The disease is termed HFRS (hemorrhagic fever with renal syndrome), is prevalent in Asia and Europe, affecting 200,000 people a year, with 5-15% percent mortality (although in Finland mortality rate is 0.1%). The New World strains cause HPS (hemorrhagic pulmonary syndrome) affecting 200 people a year with 40% mortality. Virus is present in all rodents excretions, and route of infection is by aerosols, hand to mucus membranes contamination, by rodents bites and by contaminated food or water. More than 226 work related infections were documented. Treatment with Ribavirin helps in HFRS but not in HPS. The virus is stable in the environment for long periods, and research must be carried out at biosafety level 3. Working outdoors in rodent infested area, should be carried out using protective clothing, gloves, googles and face mask whenever aerosol producing tasks are performed. Both indoor and outdoor, it is important to adhere to self-hygienic procedures, especially hand washing.

Hantavirus-associated diseases represent emerging infections that are ranked in the highest priority group of communicable diseases for surveillance and epidemiological research. In the last years, several novel hantavirus species were described and the number of host reservoir species harboring hantaviruses is also increasing. Reports of cases with severe or atypical clinical courses become also more frequent. These facts raise more and more questions concerning host reservoir specificity, pathogenicity and molecular mechanism of pathogenesis. Hantavirus disease is characterized by vascular leakage due to increased capillary permeability. The infection manifests often in the lung (hantaviral cardiopulmonary syndrome; HCPS) or in the kidney (hemorrhagic fever with renal syndrome, HFRS). The underlying mechanisms of both syndromes are probably similar despite the difference in organ tropism. Characterization of hantaviral replication cycle and of patient-specific determinants will help to identify factors responsible for the clinical symptoms and course., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Since the first clinical description in 1994 of the so-called "Hantavirus Pulmonary Syndrome" (HPS) as a "newly recognized disease", hantavirus infections have always been characterized as presenting in two distinct syndromes, the so-called "Hemorrhagic Fever with Renal Syndrome" (HFRS) in the Old World, with the kidney as main target organ, in contrast to HPS in the New World, with the lung as main target organ. However, European literature mentions already since 1934 a mostly milder local HFRS form, aptly named "nephropathia epidemica" (NE), and caused by the prototype European hantavirus species Puumala virus (PUUV). Several NE reports dating from the 1980s and early 1990s described already non-cardiogenic HPS-like lung involvement, prior to any kidney involvement, and increasing evidence is now mounting that a considerable clinical overlap exists between HPS and HFRS. Moreover, growing immunologic insights point to common pathologic mechanisms, leading to capillary hyperpermeability, the cardinal feature of all hantavirus infections, both of the New and Old World. It is now perhaps time to reconsider the paradigm of two "different" syndromes caused by viruses of the same Hantavirus genus in the same Bunyaviridae family, and to agree on a common, more logical disease denomination, such as simply and briefly "Hantavirus fever"., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Hemorrhagic fever with renal syndrome is endemic in the Balkans with epidemic outbreaks and sporadic cases that have been recorded yearly since the disease was first recognized. The incidence of Balkan HFRS is modest, with approximately one hundred cases reported in most years. Seroepidemiological investigations conducted in several Balkan countries revealed an overall seroprevalence of 6% in Bosnia and Herzegovina, 1.6% in Croatia, 4% in Greece and 1.7% in Slovenia, respectively. The complex ecology of the Balkan Peninsula supports the existence of diverse rodent and insectivore species which harbor several pathogenic and non-pathogenic hantaviruses. Among them only Dobrava (DOBV) and Puumala (PUUV) viruses are associated with disease in humans. Comprehensive clinical studies compared clinical signs and symptoms between patients infected with either virus. A spectrum of clinical picture of the disease ranges from mild illness typical of PUUV infections to a severe form with fulminant hemorrhagic fever and an overall mortality rate of 9.8% among DOBV infected patients. While severe DOBV cases are recognized from Slovenia in the North to Greece in the South, PUUV infections are more frequent in northern part of the area. Balkans represent an area with a potential need for hantavirus vaccines, but due to co-existence of DOBV and PUUV causing HFRS in the same region, a universal vaccine is required., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Nephropathia epidemica (NE) is a haemorrhagic fever with renal syndrome (HFRS) caused by Puumala hantavirus (PUUV). Acute infection causes transient kidney injury, permeability disorder, and fluid retention, for example., Methods: B-type natriuretic peptide (BNP) and N-terminal peptide (NT-proBNP) during NE were investigated; disease severity and development of clinical symptoms were considered., Results: Mean concentrations were 80.2 pg/mL and 55.2 pg/mL for BNP, and 2362.5 pg/mL and 1057.0 pg/mL for NT-proBNP in males and females, respectively. Hospitalization was 6.3 versus 5.2 days (P = 0.01) and 5.9 versus 4.4 days (P = 0.01) for patients with elevated BNP (> 100 pg/mL) or NT-proBNP (> 300 pg/mL), respectively, compared to those with normal peptide concentrations. Weight change during hospitalization was -2.8 or -0.3 kg (P <0.05) in patients with elevated or normal BNP, respectively. Heart rate (r = -0.46, P = 0.001 and r = -0.37, P = 0.01), creatinine clearance (r = -0.46, P = 0.001 and r = -0.56, P = 0.000), blood haemoglobin concentration (r = -0.55, P = 0.000 and r = -0.52, P = 0.000), and C-reactive protein (r = -0.47, P = 0.001 and r = -0.36, P = 0.01) measured when the peptide samples were collected correlated with BNP and NT-proBNP, respectively. In addition, anterior chamber depth of eye and plasma BNP (r = -0.39, P < 0.05) displayed a correlation., Conclusions: BNP and NT-proBNP levels are associated with severity of several clinical features of acute NE.

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.

Hemorrhagic fever with renal syndrome (HFRS) is a serious public health issue in Far East Russia. Two different hantaviruses were isolated from rodents captured in the Khabarovsk region: Amur virus (AMRV; Khekhtsir/AP209/2005 strain from Apodemus peninsulae) and Hantaan virus (HTNV; Galkino/AA57/2002 strain from A. agrarius). Genetic analysis of the new isolates revealed that the M and L segments were apparently different between AMRV and HTNV, but S segments of the two viruses were closer. The antigenicities of AMRV, HTNV, and Seoul virus (SEOV) were differentiated by cross-neutralization. Serological differential diagnoses of 67 HFRS patients in the Prymorsky and Khabarovsk regions of Far East Russia were conducted using a neutralization test. The results revealed that the major cause of HFRS varied with location in Far East Russia: SEOV for Vladivostok city in the Prymorsky region, AMRV in rural areas of the Primorsky region, and probably HTNV for the Khabarovsk region.

To investigate the role of vascular endothelial growth factor (VEGF) in the increased permeability of vascular endothelial cells after Hantaan virus (HTNV) infection in humans, the concentration of VEGF in serum from HTNV infected patients was quantified with sandwich ELISA. Generally, the level of serum VEGF in patients was elevated to 607.0 (542.2-671.9) pg/mL, which was dramatically higher compared with healthy controls (P < 0.001). There was a rapid increase of the serum VEGF level in all patients from the fever onset to oliguric stage, at which the serum creatinine reached the peak level of the disease, indicating that VEGF may be involved in the pathogenesis of renal hyper-permeability. Moreover, the serum VEGF level at convalescent stage was positively correlated with the degree of the disease severity. The sustained high level of serum VEGF at convalescence was observed in critical HFRS patients, suggesting that VEGF would probably contribute to the renal recovery after the virus clearance. Taken together, our results suggested that the VEGF would be involved in the pathogenesis of renal dysfunction at the oliguric stage after HTNV infection, but may function as a recovery factor during the convalescence to help the body self-repair of the renal injury.

Two cases of hemorrhagic fever with renal syndrome are reported. Pulmonary symptoms were manifest in the form of atypical and nasocomial (bacterial) pneumonia.

Background: Hantaviruses of the family Bunyaviridae are emerging zoonotic pathogens which cause hemorrhagic fever with renal syndrome (HFRS) in the Old World and hantavirus pulmonary syndrome (HPS) in the New World. An immune-mediated pathogenesis is discussed for both syndromes. The aim of our study was to investigate cytokine expression during the course of acute Puumala hantavirus infection., Results: We retrospectively studied 64 patients hospitalised with acute Puumala hantavirus infection in 2010 during a hantavirus epidemic in Germany. Hantavirus infection was confirmed by positive anti-hantavirus IgG/IgM. Cytokine expression of IL-2, IL-5, IL-6, IL-8, IL-10, IFN-γ, TNF-α and TGF-β1 was analysed by ELISA during the early and late phase of acute hantavirus infection (average 6 and 12 days after onset of symptoms, respectively). A detailed description of the demographic and clinical presentation of severe hantavirus infection requiring hospitalization during the 2010 hantavirus epidemic in Germany is given. Acute hantavirus infection was characterized by significantly elevated levels of IL-2, IL-6, IL-8, TGF-β1 and TNF-α in both early and late phase compared to healthy controls. From early to late phase of disease, IL-6, IL-10 and TNF-α significantly decreased whereas TGF-β1 levels increased. Disease severity characterized by elevated creatinine and low platelet counts was correlated with high pro-inflammatory IL-6 and TNF-α but low immunosuppressive TGF-β1 levels and vice versa ., Conclusion: High expression of cytokines activating T-lymphocytes, monocytes and macrophages in the early phase of disease supports the hypothesis of an immune-mediated pathogenesis. In the late phase of disease, immunosuppressive TGF-β1 level increase significantly. We suggest that delayed induction of a protective immune mechanism to downregulate a massive early pro-inflammatory immune response might contribute to the pathologies characteristic of human hantavirus infection.

Hemorrhagic fever with renal syndrome (HFRS) is a potentially fatal infectious disease with worldwide distribution. Its etiologic agents are viruses of the genus Hantavirus of the virus family Bunyaviridae. Hypothetical ease of production and distribution of these agents, with their propensity to incapacitate victims and overwhelm health care resources, lend themselves as significant potential biological agents of terrorism. HFRS has protean clinical manifestations, which may mimic upper respiratory tract infection, nephrolithiasis, and Hantavirus pulmonary syndrome and may delay proper treatment. Sequelae of HFRS, such as hemorrhage, acute renal failure, retroperitoneal edema, pancreatitis, pulmonary edema, and neurologic symptoms, can be detected by different imaging modalities. Medical providers caring for HFRS patients must be aware of its radiologic features, which may help to confirm its clinical diagnosis. In this article, the authors review the epidemiology, pathophysiology, clinical presentation, diagnosis, treatment, and complications of HFRS.

Major histocompatibility complex (MHC) class I and class II genes regulate the balance between appropriate aggressive responses and invading pathogens while minimizing the destruction of host tissue. Several studies have shown that in hemorrhagic fever with renal syndrome (HFRS) patients, the disease outcome is determined by a complex interaction between the virus and immunopathologic and human genetic factors. In Slovenia, the severity of the disease caused by Puumala virus (PUUV) is significantly lower than that of HFRS due to Dobrava virus (DOBV). We have determined 23 different HLA-B and 12 different HLA-DRB1 types in Slovenian HFRS patients. Comparison of HLA frequencies between healthy individuals and HFRS patients showed no strong association with the susceptibility for hantaviral infection. Significant associations were recognized when the patient group was separated according to the virus responsible for the infection. DOBV-infected patients have a significantly higher frequency of HLA-B*35 than PUUV-infected patients. For HLA class II genes, the biggest difference between the PUUV- and DOBV-infected groups of patients was in HLA-DRB1*13, where this phenotype was more frequent in PUUV-infected patients, especially in the severe form of the disease. HLA-B*07 could play a protective role in PUUV-caused HFRS in the Slovenian population. Our study shows diverse associations of HLA molecules with DOBV- and PUUV-induced HFRS, and therefore, we presume that different hantaviruses are presented differently through the same HLA molecules and that this might lead to either a more severe or a milder form of the disease. In line with this idea, we have noticed that HLA-B*35 might be a genetic risk factor for DOBV infection in the Slovenian population.

Objective and Design: The very late antigen-4 (VLA-4) bound to vascular cell adhesion molecule-1 could provide co-stimulatory signals for the activation of T lymphocytes, and these adhesion molecules play key roles in leukocyte adherence and propagation of inflammatory responses. We examined the levels of VLA-4 in the peripheral blood mononuclear cells (PBMC) of patients with hemorrhagic fever with renal syndrome (HFRS)., Materials and Methods: The levels of VLA-4 in PBMC samples collected from 53 patients by immunohistochemical staining were detected., Results: The expression of VLA-4 in PBMC of HFRS patients at different stages were significantly higher than those in normal controls (P < 0.05), except recovery stage (P > 0.05). The expression of VLA-4 in PBMC of HFRS patients at different types were significantly higher than those in healthy controls (P < 0.05). The levels of VLA-4 in patients with HFRS were positively correlated with serum levels of blood urea nitrogen (BUN) and creatinine (Cr)., Conclusions: VLA-4 might play an important role in the immunopathological lesions of HFRS. We found that VLA-4 levels were closely correlated to the severity of the HFRS and the degree of kidney damage.

The clinical picture of nephropathia epidemica (NE), a rodent-mediated Puumala virus (PUUV) zoonosis, appears to be different in paediatric and adult patients, since severe complications are seen only in adults. To confirm this clinical impression, we made a systematic literature review to determine whether the severity of NE is similar in children and adults. We searched PubMed for articles dealing with the clinical symptoms, physical signs and outcomes of patients with NE, published in English or the Nordic languages during the y 1968-2008, and found 53 containing sufficient original data in serologically confirmed cases. Forty-one of these described individual cases, 11 a series of consecutive patients and 1 both. The total number of patients was 537, of which 80 were paediatric cases. The frequency of benign symptoms and transient physical signs was quite similar in adults and children. However severe complications were reported only in adult patients (n = 26), of whom 9 died. The literature review confirmed the clinical impression that NE is milder in children than in adults. Children with PUUV infection rarely, if ever, need any invasive therapy.

Dobrava (DOBV) and Puumala (PUUV) viruses are endemic throughout the Balkans and cause haemorrhagic fever with renal syndrome (HFRS). The aim of this study was to assess the impact of two different hantaviruses on renal function in HFRS patients during the acute stage of illness. We also aimed to assess the DOBV and PUUV distribution between symptomatic HFRS patients and asymptomatic hantavirus antibody-positive subjects. The study included 264 symptomatic HFRS patients and 63 asymptomatic hantavirus antibody-positive healthy subjects. In our study, 131 (49.6%) HFRS patients were regarded as PUUV- and 69 (26.1%) as DOBV-infected patients, while in 64 (24.2%) of HFRS patients that showed all clinical and biochemical signs of HFRS, the causal hantavirus could not be determined with commercially available tests. DOBV-infected patients were associated with more requirements for haemodialysis treatment, lower diuresis and higher serum creatinine and urea values compared to PUUV-infected patients. PUUV was significantly predominant in asymptomatic hantavirus antibody-positive subjects (69.8%) compared to HFRS patients. DOBV was present in 17.5% of asymptomatic subjects and, interestingly, the preferential hantavirus serotype could not be determined in 12.7% of the asymptomatic antibody-positive subjects.

The authors report results of comparative analysis of 897 cases of hemorrhagic fever with renal syndrome diagnosed in the Upper Amur region in 1960-2005. All the patients were grouped by 5-year intervals depending on the severity of clinical condition. The frequency of CNS affection accompanied by acute psychic disorders, convulsive and meningeal syndromes varied significantly in different years. Pituitary hemorrhage was revealed at autopsy in 36.8% of the patients, pituitary necrosis in 5.2%, brainstem hemorrhage in 68.4%. A case of severe hemorrhagic fever with renal syndrome is described characterized by acute renal insufficiency and eclamptic convulsions with moderately manifest hemorrhagic syndrome preceding the favourable outcome.

Rodent-borne pathogenic hantaviruses cause two severe and often lethal zoonotic diseases: hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. Currently, no US FDA-approved therapeutics or vaccines are available for HFRS/HCPS. Infections with hantaviruses are not lytic, and it is currently not known exactly why infections in humans cause disease. A better understanding of how hantaviruses interfere with normal cell functions and activation of innate and adaptive immune responses might provide clues to future development of specific treatment and/or vaccines against hantavirus infection. In this article, the current knowledge regarding immune responses observed in patients, hantavirus interference with cellular proteins and signaling pathways, and possible approaches in the development of therapeutics are discussed.

Increased vascular permeability and vascular leakage are characteristic pathological changes in hemorrhagic fever with renal syndrome (HFRS). Vascular endothelial cells are the main targets of Hantaan virus, the etiological agent of the severe form of HFRS. Hantaan virus can induce extensive damage of small blood vessels and capillaries. In vitro infection of human umbilical vein endothelial cells by Hantaan virus can induce the expression of intercellular adhesion molecule-1 (ICAM-1). The involvement of this molecule is implied in human HFRS. In the present study, serum-soluble ICAM-1 (sICAM-1) levels were determined and their relationships with the clinical course and disease severity were investigated in 112 HFRS patients and 30 healthy controls. The results showed that the serum levels of sICAM-1 in HFRS patients at fever, hypotensive, oliguric, and polyuric phases were significantly higher than those in controls (p < 0.001). However, no significant differences between the serum concentrations of sICAM-1 in the milder and more severe groups of patients were observed (p > 0.05). It is suggested that sICAM-1 was involved in the progression of HFRS. Time-dependent determinations of sICAM-1 levels may be indicators for the progression of disease, and elevated levels of sICAM-1 were not suggested to be correlated to disease severity.

Aim: The clinical course and outcome of patients with haemorrhagic fever with renal syndrome (HFRS) caused by Puumala (PUUV) and Dobrava viruses (DOBV) were analyzed and whether it left long-term consequences on kidney function after 10 years was evaluated., Methods: Cross-sectional studies were conducted to test the kidney function and blood pressure of HFRS-affected patients and to follow them up 10 years after. Eighty-two PUUV- and 53 DOBV-induced HFRS patients and 14 and 31 participants 10 years after having contracted PUUV- and DOBV-related diseases, respectively were evaluated., Results: Serum creatinine concentrations were 279.5 and 410 mcmol/L in PUUV and DOBV groups, respectively (P = 0.005). There were six and 13 anuric (P < 0.05), none and seven dialysis-dependant (P < 0.05), and nine and 18 hypotensive patients (P < 0.05) in PUUV and DOBV groups, respectively. After 10 years, glomerular filtration rates were 122.1 + or - 11.1 and 104.7 + or - 20.2 mL/min (P < 0.05) in PUUV and DOBV groups, respectively., Conclusion: During the acute phase, DOBV causes more severe renal impairment than PUUV infection. After 10 years follow up, renal function was found within normal limits, although after DOBV infection glomerular filtration rate (GFR) was significantly lower than after PUUV infection.

Hantaviruses cause two vascular permeability-based diseases and primarily infect endothelial cells which form the primary fluid barrier of the vasculature. Since hantavirus infections are not lytic, the mechanisms by which hantaviruses cause haemorrhagic fever with renal syndrome (HFRS) or Hantavirus Pulmonary Syndrome (HPS) are indeterminate. HPS is associated with acute pulmonary oedema and HFRS with moderate haemorrhage and renal sequelae, perhaps reflecting the location of vast microvascular beds and endothelial cell reservoirs available for hantavirus infection. Endothelial cells regulate capillary integrity, and hantavirus infection provides a primary means for altering vascular permeability that contributes to pathogenesis. The central importance of endothelial cells in regulating oedema, vascular repair, angiogenesis, immune cell recruitment, platelet deposition as well as gas exchange and solute delivery suggest that a multitude of inputs and cellular responses may be influenced by hantavirus infection and contribute to pathogenic changes in vascular permeability. Here we focus on understanding hantavirus interactions with endothelial cells which are linked to vascular permeability, and provide insight into the contribution of endothelial cell responses in hantavirus pathogenesis.

Hantaviruses are rodent-borne viruses capable of causing human disease. The Seoul virus is a hantavirus that causes hemorrhagic fever with renal syndrome in East Asia. To our knowledge, we report the first domestically acquired case of hemorrhagic fever with renal syndrome caused by the Seoul virus, confirmed by serology testing, reverse-transcriptase polymerase chain reaction, and nucleotide sequence analysis. The patient presented with myalgias and fever, and developed acute renal failure.

In the present retrospective study, we described a series of 45 non-icteric leptospirosis and 44 nephropathia epidemica (NE) patients diagnosed in the northeast of France from 1995 to 2005 and compared their clinical picture and laboratory parameters, as well as some epidemiological data. Loin pain (P < 0.001), abdominal pains (P = 0.007), rise of blood pressure (P < 0.001) and pharyngitis (P = 0.01) were more frequently found in NE patients. Aspartate aminotransferase (ASAT) (P = 0,006), creatine phosphokinase (CPK) (P < 0.0001) and C-reactive protein (CRP) (P < 0.0001) were higher in leptospirosis, whereas creatinine (P = 0.009) was higher in NE. Leptospirosis mainly concerns occupational hazards, e.g. farmers, and leisure activities like swimming, and NE concerns professional foresters or leisure activities in the forest and the cleaning of attics. During hospitalisation, patients receiving antibiotics were more frequent among leptospirosis than among NE patients (80% versus 59%, P = 0.06). Among the various common clinical signs, only acute myopia appeared to be a pathognomonic but inconsistently observed clinical sign, which was only observed in 47% of NE cases.

This study investigated the relationship between human platelet alloantigen (HPA) polymorphisms of glycoprotein IIb/IIIa and hemorrhagic fever with renal syndrome (HFRS). HPA-1 and HPA-3 genotyping was performed with allele-specific primer polymerase chain reaction in 104 patients with HFRS and 100 normal individuals as controls. The relationships between gene polymorphisms of HPAs and HFRS and the disease severity were analyzed. The results indicated no significant difference in HPA-1 genotype distributions (p > 0.05), but a significant difference in the distributions of genotype and allele frequencies of HPA-3 between HFRS patients and controls (p < 0.01). The distributions of HPA-3 genotype and allele frequencies differed significantly between patients with different clinical types and the HPA-3 b allele was more frequently observed in patients with more severe clinical types. These results indicate that HPA-3 polymorphism may be one of the inherited risk factors associated with the susceptibility of hantavirus infection and the disease severity of HFRS.

Background: The cellular immune response to Hantaan virus (HTNV) is incompletely understood, especially in humans., Methods: To investigate the cellular immunity during acute HTNV infection, the magnitude of the CD4(+) and CD8(+) T cell responses to HTNV nucleocapsid protein was quantitated by direct ex vivo interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot analysis, using an array of overlapping peptides., Results: We found that the combined frequencies of HTNV-specific T cells at the earliest available time point (5-8 days after fever onset) were significantly higher in patients who had mild or moderate hemorrhagic fever with renal syndrome (HFRS) than in those who had severe or critical HFRS (P= .006). Moreover, these frequencies were higher in patients with subsequent mild renal failure (maximum serum creatinine level, 707 micromol/L) (P= .006). Kinetic analysis showed that a decrease in the serum creatinine level during the acute phase of illness was often accompanied by an increase in the magnitude of IFN-gamma-producing T cells., Conclusion: Taken together with published data on the similar associations with neutralizing antibody, these data suggest that IFN-gamma-producing T cells may help reduce the risk of progression to acute renal failure caused by HTNV infection.

Serological and molecular evidence showed that a German female student became infected by Puumala hantavirus during mice trapping efforts in Finland. The incubation period before exhibiting clinical signs of nephropathia epidemica was as long as 6 weeks. Phylogenetic analysis of PUUV nucleic acid sequences amplified from the patient demonstrate that she was infected by the PUUV strain circulating at the place of her occupational exposure in Finland.

This study was conducted to determine the frequency, severity and outcome of cardiac findings in patients with acute Puumala hantavirus-induced nephropathia epidemica (NE). 70 consecutive, hospital-treated patients with serologically confirmed NE were prospectively examined using serial electrocardiograms (ECG), plasma troponin I, tumour necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and echocardiography (ECHO). Examinations were repeated after 3 and 12 months. ECG changes were observed in 57% of patients. Plasma troponin I levels remained normal in all. In six patients, ECHO showed left ventricular contraction abnormalities, and 1 patient had mild pericardial effusion. There were no differences in clinical or standard laboratory findings or in plasma TNF-alpha and IL-6 concentrations between patients with and without ECG or ECHO changes. During the follow-up, all acute-phase changes in ECG and ECHO reverted to normal, which probably reflects their benign nature. We conclude that abnormal cardiac findings are surprisingly common during NE.

Hemorrhagic fever with renal syndrome (HFRS) is a severe acute viral disease with pathological changes of impaired capillary and small vessels and thrombocytopenia. In this study, serum thrombospondin (TSP)-1 concentration in patients with HFRS was determined to explore its possible role in the pathogenesis of HFRS. The concentration of TSP-1 was measured using a competitive enzyme-linked immunoabsorbent assay. Significantly decreased levels of serum TSP-1 were observed in HFRS patients at febrile and hypotensive phases compared with those in the controls. The serum levels of TSP-1 in HFRS patients with more severe clinical types was reduced more profoundly than those in patients with milder clinical types at febrile and hypotensive phases, although the differences in TSP-1 were not significant. It was indicated that insufficient production or increased consumption of TSP-1, or both of these, may contribute to the impairment of capillary and small vessels and the development of hypotension at the early stage of HFRS, and the decreased degree may be associated with disease severity.

Pathogenic rodent-borne hantaviruses cause in humans generalized infections that involve the peripheral vascular bed and severely affect their permeability. We describe a 30-yr-old male patient with clinical symptoms characterizing five conventional phases of hemorrhagic fever with renal syndrome after an uncommonly severe hantavirus infection with the Puumala strain. Renal biopsy in this situation typically demonstrates acute hemorrhagic interstitial nephritis, particularly pronounced in the outer medulla. Hantaviruses are not cytopathic for most cells, and their interactions with endothelial cells that activate immune mechanisms play a key role in the pathogenesis of vascular dysfunction characterizing this disease.

Viral hemorrhagic fevers (VHFs) are diseases caused by the RNA virus from 4 different families (Flaviridiae, Arenaviridae, Bunyaviridae, and Filoviridae) that are acquired through the bite of an infected arthropod or by the inhalation of particles of rodent excreta. Among the VHFs, dengue and yellow fever are the most prevalent in tropical regions worldwide. The clinical presentation is characterized by fever, malaise, increased vascular permeability, and coagulation defects that can result in bleeding. Acute kidney injury is an uncommon complication but renal dysfunction has been associated with various VHFs. In this article we review the renal manifestations of dengue and yellow fever infections.

Context: Hemorrhagic fever with renal syndrome (HFRS) caused by hantaviruses, is a severe systemic infection, with acute shock, vascular leakage, hypotension, and acute renal failure. Pituitary ischemia/infarction and necrosis are known causes of hypopituitarism, often remaining unrecognized due to subtle clinical manifestations. Cases of hypopituitarism after HFRS were previously only sporadically reported., Objective: The aim of this study was to determine, for the first time, the prevalence of hypopituitarism among HFRS survivors., Subjects and Methods: In 60 adults (aged 35.8+/-1.3 yr) who recovered from HFRS 3.7 +/- 0.5 yr ago (median 2 yr), assessment of serum T(4), free T(4), TSH, IGF-I, prolactin, cortisol, and testosterone (in males) was followed by insulin tolerance test and/or GHRH+GH-releasing peptide-6 stimulation tests., Results: Severe GH deficiency was confirmed in eight of 60 patients (13.3%): in five with multiple pituitary hormone deficiencies (MPHDs) and isolated in three. Thyroid axis deficiency was confirmed in five of 60 patients (8.3%), all with MPHD. Hypothalamus-pituitary-adrenal axis deficiency was observed in six of 60 (10.0%); in five with MPHD and isolated in one. Gonadal axis deficiency was confirmed in seven of 56 male subjects (12.5%): five with MPHD and isolated in two. Overall six patients (10.0%) had a single pituitary deficit (three GH, two gonadal, and one adrenal), and five (8.3%) had MPHD. The prevalence of patients having any endocrine deficiency was 18% (11 of 60)., Conclusion: A high prevalence of hypopituitarism after recovery from HFRS is identified, with magnetic resonance imaging revealing atrophic pituitary and empty sella. Awareness is raised to neuroendocrine consequences of HFRS because unrecognized hypopituitarism significantly affects the physical and psychological well-being.

beta(3) Integrin has been identified as a cellular receptor for Hantaan virus, which causes hemorrhagic fever with renal syndrome (HFRS). To investigate the relationship between intensity of the platelet membrane beta(3) integrin (CD61) and disease severity, the percentage of CD61-positive platelets and the mean fluorescence intensities (MFI) of platelet CD61 were determined in patients with HFRS by flow cytometry. The intensity levels of CD61 in patients with HFRS were significantly higher than those in the controls and correlated with the clinical phases of the disease. The CD61 intensity at the oliguric phase was inversely correlated with platelet count and serum albumin, and positively correlated with white blood cell count, blood urea nitrogen, serum creatinine, and alanine aminotransferase levels. The results suggest that the intensity levels of platelet CD61 were elevated and associated with clinical phases and disease severity in patients with HFRS, and the intensity of platelet beta(3) integrin in patients with HFRS may be indicative of disease severity.

Among rodents that carry hantaviruses, more males are infected than females. Male rats also have elevated copies of Seoul virus RNA and reduced transcription of immune-related genes in the lungs than females. To further characterize sex differences in antiviral defenses and whether these differences are mediated by gonadal hormones, we examined viral RNA in the lungs, virus shedding in saliva, and antiviral defenses among male and female rats that were intact, gonadectomized neonatally, or gonadectomized in adulthood. Following inoculation with Seoul virus, high amounts viral RNA persisted longer in lungs from intact males than intact females. Removal of the gonads in males reduced the amount of viral RNA to levels comparable with intact females at 40 days post-inoculation (p.i.). Intact males shed more virus in saliva than intact females 15 days p.i.; removal of the gonads during either the neonatal period or in adulthood increased virus shedding in females and decreased virus shedding in males. Induction of pattern recognition receptors (PRRs; Tlr7 and Rig-I), expression of antiviral genes (Myd88, Visa, Jun, Irf7, Ifnbeta, Ifnar1, Jak2, Stat3, and Mx2), and production of Mx protein was elevated in the lungs of intact females compared with intact males. Gonadectomy had more robust effects on the induction of PRRs than on downstream IFNbeta or Mx2 expression. Putative androgen and estrogen response elements are present in the promoters of several of these antiviral genes, suggesting the propensity for sex steroids to directly affect dimorphic antiviral responses against Seoul virus infection.

To asses the role of virus load in the pathogenesis of hemorrhagic fever with renal syndrome, the serum Dobrava virus RNA load in 46 patients was measured with a novel quantitative real-time reverse-transcriptase polymerase chain reaction assay and compared to the disease severity. The level of viremia, detected in 26 patients, ranged from 10(2)-10(8) copies/mL of serum. The patients with severe disease had, on average, higher viral RNA loads than patients with a milder course of disease (6.15 vs. 4.67 log(10) copies/mL; P = .053). These results suggest that the Dobrava virus load might be associated with the severity of disease.

Objective: Patients with typical clinical manifestations of Hemorrhagic fever with renal syndrome (HFRS) are becoming fewer. We conducted analysis on clinical features of HFRS in order to reduce the mistakes in diagnosis., Methods: 64 patients were diagnosed as HFRS during May, 2000 to June, 2006 in our hospital. All the patients' serological tests (HFRS-NP-specific IgM, IgG antibody) by ELISA method were positive. We collected their clinical manifestations and test results. SPSS 12.0 was used in our statistical analysis., Results: Among the 64 patients, 71.6% of all the cases occurred from Feb. to June. Most of patients were admitted to the hospital with untypical manifestation. Only 30.6% patients appeared headache, lumbago, and pain of orbital cavity. 32.8% patients had obviously signs of injection and hemorrhage. However, there were 90.6% patients with headache and 84.4% patients with nausea or vomit. Hypotensive or oliguric phases were absent in 56.3% patients. There were only 31.3% patients with all five stages. Thrombocytopenia (79.7%) and heavy proteinuria (71.9%) were common. But 54.7% of patients shown normal or even decreased white blood cell count. Only 2/3 of patients had elevated serum creatinine (Cr). Liver involved was common showing as elevated aminotransferase. ALT level was not always parallel to Cr level. There was an opposite trend between them., Conclusion: We must recognized the untypical manifestations of HFRS. Further study focus on pathogenesis was useful for diagnosis and therapy.

At present it is known 2 forms of hantavirus infections in humans: hemorrhagic fever with renal syndrome (HFRS) induced by viruses Hantaan, Seoul, Puumala and Dobrava/Belgrade; and hantaviral pulmonary syndrome, induced by Sin Nombre et al. A case of HRFS, induced by hantavirus Dobrava, is described. Features of this case are developed neurological manifestations against the background of renal pathology, and difficulties of clinical and laboratory diagnostics in practice.