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Thrombocytopenia is a cardinal symptom of hantavirus-induced diseases including Puumala virus (PUUV)-induced hemorrhagic fever with renal syndrome (HFRS), which is associated with impaired platelet function, bleeding manifestations and augmented thrombotic risk. However, the underlying mechanisms causing thrombocytopenia and platelet hypo-responsiveness are unknown. Thus, we investigated the direct and indirect impact of PUUV on platelet production, function and degradation. Analysis of PUUV-HFRS patient blood revealed that platelet hypo-responsiveness in PUUV infection was cell-intrinsic and accompanied by reduced platelet-leukocyte aggregates (PLAs) and upregulation of monocyte tissue factor (TF), whereas platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation was comparable to healthy controls. Plasma CXCL4 levels followed platelet count dynamics throughout disease course. PUUV activated both neutrophils and monocytes in vitro, but platelet desialylation, degranulation and GPIIb/IIIa activation as well as PLA formation and endothelial adhesion under flow remained unaltered in the presence of PUUV. Further, MEG-01 megakaryocytes infected with PUUV displayed unaltered polyploidization, expression of surface receptors and platelet production. However, infection of endothelial cells with PUUV significantly increased platelet sequestration. Our data thus demonstrate that although platelet production, activation or degradation are not directly modulated, PUUV indirectly fosters thrombocytopenia by sequestration of platelets to infected endothelium. Upregulation of immunothrombotic processes in PUUV-HFRS may further contribute to platelet dysfunction and consumption. Given the pathophysiologic similarities of hantavirus infections, our findings thus provide important insights into the mechanisms underlying thrombocytopenia and highlight immune-mediated coagulopathy as potential therapeutic target., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Hantavirus infections are part of the broad group of viral haemorrhagic fevers. They are also recognised as a distinct model of an emergent zoonotic infection with a global distribution. Many factors influence their epidemiology and transmission, such as climate, environment, social development, ecology of rodent hosts, and human behaviour in endemic regions. Transmission to humans occurs by exposure to infected rodents in endemic areas; however, Andes hantavirus is unique in that it can be transmitted from person to person. As hantaviruses target endothelial cells, they can affect diverse organ systems; increased vascular permeability is central to pathogenesis. The main clinical syndromes associated with hantaviruses are haemorrhagic fever with renal syndrome (HFRS), which is endemic in Europe and Asia, and hantavirus cardiopulmonary syndrome (HCPS), which is endemic in the Americas. HCPS and HFRS are separate clinical entities, but they share several features and have many overlapping symptoms, signs, and pathogenic alterations. For HCPS in particular, clinical outcomes are highly associated with early clinical suspicion, access to rapid diagnostic testing or algorithms for presumptive diagnosis, and prompt transfer to a facility with critical care units. No specific effective antiviral treatment is available., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Haemorrhagic fever with renal syndrome (HFRS) is a natural epidemic disease caused by various types of viruses of the genus Hantavirus, which are mainly transmitted by contact with the infected rodents and their droppings. Pregnancy complicated with HFRS is rare; however, adverse maternal and foetal outcomes may be noted. In this report, we describe a case involving a pregnant woman with HFRS who was in a state of multiple organ dysfunction syndrome (MODS) and was successfully treated with continuous renal replacement therapy (CRRT)., Case Presentation: A 32-year-old pregnant woman at 29 weeks of gestation was hospitalised for a fever and upper respiratory tract infection due to HFRS in winter. Persistent fever, coagulation disorder, thrombocytopenia, electrolyte imbalance, abnormal liver function, and renal failure were noted during the progression of the disease. The patient was treated with CRRT. She recovered after 21 days, and delivered a live infant by caesarean section at 38 weeks of gestation. Furthermore, obvious abnormalities were not detected during the follow-up of the mother and infant at 42 days, 3 months, 6 months, and 1 year after the delivery., Conclusions: Early diagnosis, timely application of CRRT, and comprehensive treatment may be essential for the successful treatment of patients with HFRS during pregnancy.

Hantaviruses can cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and have led to public health threat in China. The pathogenesis of HFRS is complex and involves capillary leakage due to the infection of vascular endothelial cells. Accumulating evidence has demonstrated that hantavirus can induce apoptosis in many cells, but the mechanism remains unclear. Our studies showed that Hantaan virus (HTNV) infection could induce TNF-related apoptosis-inducing ligand (TRAIL) expression in primary human umbilical vein endothelial cells (HUVECs) and sensitize host cells toward TRAIL-mediated apoptosis. Furthermore, TRAIL interference could inhibit apoptosis and enhance the production of HTNV as well as reduce IFN-β production, while exogenous TRAIL treatment showed reverse outcome: enhanced apoptosis and IFN-β production as well as a lower level of viral replication. We also observed that nucleocapsid protein (NP) and glycoprotein (GP) of HTNV could promote the transcriptions of TRAIL and its receptors. Thus, TRAIL was upregulated by HTNV infection and then exhibited significant antiviral activities in vitro , and it was further confirmed in the HTNV-infected suckling mice model that TRAIL treatment significantly reduced viral load, alleviated virus-induced tissue lesions, increased apoptotic cells, and decreased the mortality. In conclusion, these results demonstrate that TRAIL-dependent apoptosis and IFN-β production could suppress HTNV replication and TRAIL treatment might be a novel therapeutic target for HTNV infection., (Copyright © 2020 Chen, Wang, Luo, Li, Zhu, Lu, Zan, Zhong, Wang, Hu, Zhang, Xiong and Hou.)

Two related hyperinflammatory syndromes are distinguished following infection of humans with hantaviruses: haemorrhagic fever with renal syndrome (HFRS) seen in Eurasia and hantavirus pulmonary syndrome (HPS) seen in the Americas. Fatality rates are high, up to 10% for HFRS and around 35%-40% for HPS. Puumala virus (PUUV) is the most common HFRS-causing hantavirus in Europe. Here, we describe recent insights into the generation of innate and adaptive cell-mediated immune responses following clinical infection with PUUV. First described are studies demonstrating a marked redistribution of peripheral blood mononuclear phagocytes (MNP) to the airways, a process that may underlie local immune activation at the site of primary infection. We then describe observations of an excessive natural killer (NK) cell activation and the persistence of highly elevated numbers of NK cells in peripheral blood following PUUV infection. A similar vigorous CD8 Tcell response is also described, though Tcell responses decline with viraemia. Like MNPs, many NK cells and CD8 T cells also localize to the lung upon acute PUUV infection. Following this, findings demonstrating the ability of hantaviruses, including PUUV, to cause apoptosis resistance in infected target cells, are described. These observations, and associated inflammatory cytokine responses, may provide new insights into HFRS and HPS disease pathogenesis. Based on similarities between inflammatory responses in severe hantavirus infections and other hyperinflammatory disease syndromes, we speculate whether some therapeutic interventions that have been successful in the latter conditions may also be applicable in severe hantavirus infections., (© 2019 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Many factors are involved in the epidemiology of hemorrhagic fever with renal syndrome (HFRS). Imported cases, as well as those by emigrants, have been reported in literature worldwide. Our goal is to document two cases of HFRS, imported by two immigrants from two countries, and to make a review of the imported HFRS literature data. We performed a systematic literature review (PRISMA guidelines) of imported cases of HFRS and herein describe our two clinical cases. We found 20 published papers, with 16 of them in English and 4 in other languages. Twenty-three patients with travel- or immigration-associated HFRS, including our two cases, were identified. We included only papers that were in English. The average age of the patients was 35.9 ± 15.13 years, and the ratio of male to female was 8:1. Imported disease from Europe to Europe occurred in seven cases, America to Europe occurred in four cases, Europe to America occurred in two cases, America to America occurred in two cases, Asia to Asia in one case, Asia to Europe in one case, and Europe to Asia in one case. The results of the two cited cases are based on the clinical-laboratory, anamnestic, and serologic data for both the patients who tested positive for HFRS. Our systematic analysis shows that international travelers are important sources of infectious diseases. HFRS related to travel and immigration is a rare event. Principal risk factors for travelers and immigrants are camping outside recommended areas or under unsuitable conditions. In recent years, various publications have shown that international travelers and immigrants have expanded the spectrum of imported infectious diseases. The literature data show that the actual reported numbers of imported case of HFRS are limited., (Copyright © 2018. Published by Elsevier Ltd.)

Hemorrhagic fever viruses are among the deadliest pathogens known to humans, and often, licensed medical countermeasures are unavailable to prevent or treat infections. Guinea pigs are a commonly used animal for the preclinical development of any experimental candidates, typically to confirm data generated in mice and as a way to validate and support further testing in nonhuman primates. In this chapter, we use Sudan virus (SUDV), a lethal filovirus closely related to Ebola virus, as an example of the steps required for generating a guinea pig-adapted isolate that is used to test a monoclonal antibody-based therapy against viral hemorrhagic fevers.

The European prototype of hantavirus, Puumala virus (PUUV), isolated from a common wild rodent, the bank vole (Myodes glareolus), causes nephropathia epidemica (NE). NE can perfectly mimic haemolytic-uraemic syndrome (HUS), progressing from an aspecific flu-like syndrome to acute kidney injury with thrombocytopaenia, and presenting with some signs of haemolytic anaemia and/or coagulopathy. Moreover, both NE and HUS can occur in local outbreaks. We report an isolated case of NE, initially referred for plasmapheresis for suspected HUS, although signs of overt haemolysis were lacking. Early suspicion of hantavirus infection, later confirmed by serology and reverse transcription polymerase chain reaction (RT-PCR), prevented subsequent excessive treatment modalities.

Background: Hantaviruses cause two distinct human diseases: hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe and hantavirus pulmonary syndrome (HPS) in America. In Europe, mainly Puumala, Dobrava and Seoul viruses cause HFRS. A total of 23 cases of HFRS were detected in Bulgaria over a 2‑year period 2013-2014. The aim of the study was to present epidemiology, clinical manifestations and laboratory findings of these patients., Methods: Patients with HFRS were diagnosed using PCR, ELISA and immunoblotting tests., Results: Dobrava-Belgrade virus (DOBV) was revealed as etiological agent in 16 (69.6%) patients and Puumala virus (PUUV) in 7 (30.4%) patients. All 23 patients were men aged 22-66 years of which 6 (26.1%) patients originated from regions in northern and western Bulgaria previously thought to be non-endemic. Patients with HFRS, despite the infecting hantavirus, manifested acute renal failure, asthenia and less pronounced hemorrhagic syndrome. Patients with DOBV infection were much more likely to present with arthromyalgia, severe headache, severe to moderately severe asthenoadynamia, abdominal pain, vomiting, hypotension, nervous system disorders as well as kidney enlargement, leucopenia and higher levels of blood creatinine, requiring hemodialysis procedures more often and for a longer period of time than patients with PUUV infection., Conclusions: The present report describes for the first time comparative analysis of epidemiological features, clinical manifestations and laboratory findings of DOBV and PUUV infections in Bulgaria.

Aim: To investigate the antiviral effects of vectors expressing specific short hairpin RNAs (shRNAs) against Hantaan virus (HTNV) infection in vitro and in vivo., Methods: Based on the effects of 4 shRNAs targeting different regions of HTNV genomic RNA on viral replication, the most effective RNA interference fragments of the S and M genes were constructed in pSilencer-3.0-H1 vectors, and designated pSilencer-S and pSilencer-M, respectively. The antiviral effect of pSilencer-S/M against HTNV was evaluated in both HTNV-infected Vero-E6 cells and mice., Results: In HTNV-infected Vero-E6 cells, pSilencer-S and pSilencer-M targeted the viral nucleocapsid proteins and envelope glycoproteins, respectively, as revealed in the immunofluorescence assay. Transfection with pSilencer-S or pSilencer-M (1, 2, 4 μg) markedly inhibited the viral antigen expression in dose- and time-dependent manners. Transfection with either plasmid (2 μg) significantly decreased HTNV-RNA level at 3 day postinfectin (dpi) and the progeny virus titer at 5 dpi. In mice infected with lethal doses of HTNV, intraperitoneal injection of pSilencer-S or pSilencer-M (30 μg) considerably increased the survival rates and mean time to death, and significantly reduced the mean virus yields and viral RNA level, and alleviated virus-induced pathological lesions in lungs, brains and kidneys., Conclusion: Plasmid-based shRNAs potently inhibit HTNV replication in vitro and in vivo. Our results provide a basis for development of shRNA as therapeutics for HTNV infections in humans.

A 40-year-old Korean man developed hemorrhagic fever in Xi'an, which is one of the main endemic areas for this illness in China. According to the local epidemiological situation, his condition could have been due to hantavirus infection, but this was not confirmed. He presented with the typical symptoms of hemorrhagic fever and rapidly progressed to a severe multisystem illness. The clinical situation deteriorated rapidly after admission, and he became coinfected with methicillin-resistant Staphylococcus aureus, Acinetobacter baumannii, aspergillus, and mucor. The patient was successfully treated with appropriate fluid infusion, hemodynamic support, continuous renal replacement therapy, liver protectants, and antibacterials. This case indicates that the choice of antimicrobials and the required dose are crucial issues, and that the vaccination campaign for hemorrhagic fever in Xi'an needs greater attention.

The recent discovery of Seoul hantavirus (SEOV) presence in wild rat populations in the Netherlands has direct implications for Dutch clinicians and hantavirus diagnostics. SEOV is amongst the Old World hantaviruses which cause haemorrhagic fever and renal syndrome (HFRS) in humans. HFRS is characterised by a classical triad of fever, acute kidney injury and haemorrhage, but can show different signs and symptoms in specific cases. SEOV is transmitted from infected rats to humans by inhalation of aerosolised excreta. When compared with the known circulating hantaviruses in the Netherlands, Puumala (PUUV) and Tula (TULV), SEOV causes a more severe form of HFRS. Data from cohort studies undertaken in China and Northern Europe show differences in signs and symptoms at onset of disease, (haemorrhagic) complications and mortality. Furthermore, routine diagnostics currently available for hantavirus diagnosis in the Netherlands are not optimised for SEOV detection. The clinical outcome of an SEOV and PUUV infection will greatly benefit from an early diagnosis which will reduce the costs of unnecessary tests and treatments as well. The discovery of SEOV circulation in the Netherlands follows recent findings of SEOV infections in both rodents and humans in England, Wales, France, Belgium and Sweden, indicating the emerging character of SEOV and a high importance of this hantavirus for Public Health in large areas of Europe. Here, we review the current knowledge on the clinical manifestation of SEOV versus PUUV infections in humans, the treatment of clinical cases and diagnostics.

Background: Puumala hantavirus (PUUV) induces an acute tubulointerstitial nephritis and acute kidney injury (AKI). Our aim was to evaluate the prognosis of severe AKI associated with PUUV infection., Methods: We examined 556 patients who were treated at Tampere University Hospital during 1982-2013 for acute, serologically confirmed PUUV infection. Plasma creatinine was measured during hospitalization, convalescence, and 1, 2, and 5 years after the acute infection., Results: Plasma creatinine concentration was elevated (>100 μmol/l) in 459 (83%) patients, while altogether 189 patients (34%) had severe AKI defined as Kidney Disease: Improving Global Outcomes (KDIGO) stage 3, that is, plasma creatinine ≥353.6 μmol/l (4.0 mg/dl) or need of dialysis. There were no fatal cases during the hospitalization or the following 3 months. Fatality rate during the years following PUUV infection did not differ between patients who had suffered from severe AKI versus those without severe AKI. Post-hospitalization plasma creatinine values were available for 188 (34%) patients. One month after the acute infection, patients with prior severe AKI had higher median plasma creatinine concentration (82 µmol/l, range 54-184) than patients without severe AKI (74 µmol/l, range 55-109, p = 0.005). After 1 year, no significant difference existed in median plasma creatinine concentrations between patients with (71 µmol/l, range 36-123) and without prior severe AKI (72 µmol/l, range 34-116, p = 0.711). After 5 years all but 1 patient had normal creatinine levels., Conclusions: In contrast to the worldwide well-accepted KDIGO criteria, severe AKI associated with PUUV infection is not associated with excess fatality but has a very good prognosis, both in the short and long terms., (2015 S. Karger AG, Basel.)

Objective: To study the clinical characteristics of pediatric hemorrhagic fever with renal syndrome (HFRS), and to improve its understanding so as to reduce the misdiagnosis., Methods: A retrospective analysis was performed on the clinical data of 26 children with HFRS between January 2009 and December 2012., Results: The age of disease onset was mainly distributed between 7 and 14 years (23 cases, 88%), and the male-to-female ratio was 1.89:l. The clinical manifestations of pediatric HFRS varied. The early symptoms resembled those of a cold, and in the course of HFRS, most patients developed digestive symptoms such as vomiting and abdominal pain. The laboratory examinations usually implicated platelet changes, and the imaging examinations revealed polyserous effusions. The prominent complication was myocardial injury., Conclusions: Pediatric HFRS mainly occurs in school-age children, more commonly in males. HFRS does not have typical clinical manifestations or symptoms, so it should be distinguished from cold or appendicitis at the early stage. When applying the fluid replacement therapy, the cardiac function should be carefully monitored in case of heart failure.

Background: Hemorrhagic fever with renal syndrome (HFRS) has become an important public health concern because of the high incidence and mortality rates, and limited treatment and vaccination. Until now, clinical studies on characteristics and outcomes in critical patients with HFRS have been limited. The aim of this study was to observe the clinical characteristics and cumulative proportions surviving and explore the predictive effects and risk factors for prognosis., Methods: A detailed retrospective analysis of clinical records for critical HFRS patients was conducted. The patients enrolled were treated in the centre for infectious diseases, Tangdu Hospital, between January 2008 and August 2012. The clinical characteristics between the survivors and non-survivors were compared by Student's t-test or Chi-square test. The risk clinical factors for prognosis were explored by logistic regression analysis. The predictive effects of prognosis in clinical and laboratory parameters were analyzed by receiver operating characteristic (ROC) curves. The cumulative proportions surviving at certain intervals in the critical patients were observed by Kaplan-Meier survival analysis., Results: Of the 75 patients enrolled, the cumulative proportion surviving was 70.7% at the second week interval, with a 28-day mortality rate of 36.3%. The non-survivors tended to have higher frequencies of agitation, dyspnea, conjunctival hemorrhage, coma, cardiac failure, acute respiratory distress syndrome (ARDS) and encephalopathy (P < .05). ARDS, conjunctival hemorrhage and coma were risk factors for death in the critical patients with HFRS. The non-survivors were found to have lower serum creatinine (Scr) levels (P < .001) and higher incidences of prolonged prothrombin time (PT) (P = .006), activated partial thromboplastin time (APTT) (P = .003) and elevated white blood cells (WBC) levels (P = .005), and the laboratory parameters mentioned above reached statistical significance for predicting prognosis (P < .05)., Conclusion: The high fatality in critical patients with HFRS underscores the importance of clinicians' alertness to the occurrence of potentially fatal complications and changes in biochemical status to ensure that timely and systematically supportive treatment can be initiated when necessary.

Hantaviruses are the causative agents of haemorrhagic fever with renal syndrome (HFRS) in Eurasia and of hantavirus cardiopulmonary syndrome (HCPS) in the Americas. The case fatality rate varies between different hantaviruses and can be up to 40%. At present, there is no specific treatment available. The hantavirus pathogenesis is not well understood, but most likely, both virus-mediated and host-mediated mechanisms are involved. The aim of the present study was to investigate the association among Puumala hantavirus (PUUV) viral RNA load, humoral immune response and disease severity in patients with HFRS. We performed a study of 105 PUUV-infected patients that were followed during the acute phase of disease and for up to 1-3 months later. Fifteen of the 105 patients (14%) were classified as having moderate/severe disease. A low PUUV-specific IgG response (p <0.05) and also a higher white blood cell count (p <0.001) were significantly associated with more severe disease. The PUUV RNA was detected in a majority of patient plasma samples up to 9 days after disease onset; however, PUUV RNA load or longevity of viraemia were not significantly associated with disease severity. We conclude that a low specific IgG response was associated with disease severity in patients with HFRS, whereas PUUV RNA load did not seem to affect the severity of HFRS. Our results raise the possibility of passive immunotherapy as a useful treatment for hantavirus-infected patients., (© 2013 The Authors. Clinical Microbiology and Infection published by John Wiley & Sons Ltd on behalf of the European Society of Clinical Microbiology and Infectious Disease.)

Objectives: The aim of this study was to investigate the clinical characteristics and outcomes of critical patients with hemorrhagic fever with renal syndrome (HFRS) complicated by acute respiratory distress syndrome (ARDS)., Materials and Methods: To observe the demographic, epidemiological and clinical characteristics, and to explore the predictive effects for prognosis in laboratory findings, we conducted a detailed retrospective analysis of clinical records for critical patients with HFRS complicated by ARDS, treated at the center for infectious diseases, Tangdu Hospital, between January 2008 and December 2012., Results: A total of 48 critical patients with laboratory confirmed HFRS accompanied by ARDS were enrolled in the study, including 27 survivors and 21 non-survivors, with a fatality rate of 43.75%. Thirty-one individuals (64.6%) contracted HFRS between the months of September and December. The non-survivors tended to have lower incidence of overlapping phase (P = 0.025). There were no obvious differences in the needs for mechanical ventilation (MV) and renal replacement therapy (RRT), except for the need for vasoactive drugs between the survivors and non-survivors (P = 0.001). The non-survivors were found to have higher frequencies of encephalopathy, refractory shock and multiple organ dysfunction syndrome (MODS), lower incidences of acute renal failure (ARF) and secondary hypertension (P<0.05). The non-survivors tended to have lower levels of serum creatinine (Scr) (P<0.001) and fibrinogen (Fib) (P = 0.003), higher incidences of prolonged prothrombin time (PT) (P = 0.006) and activated partial thromboplastin time (APTT) (P = 0.020) and higher levels of aspartate aminotransferase (AST) (P = 0.015), and the laboratory parameters mentioned above reached statistical significance for predicting prognosis (P<0.05)., Conclusion: The high mortality rate of critical patients with HFRS complicated by ARDS emphasizes the importance of clinicians' alertness and timely initiation of systemic supportive therapy.

Puumala virus (PUUV) causes an acute hemorrhagic fever with renal syndrome (HFRS), a zoonosis also called nephropathia epidemica (NE). The reservoir host of PUUV is the bank vole (Myodes glareolus). Herein we review the main clinical manifestations of NE, acute kidney injury, increased vascular permeability, coagulation abnormalities as well as pulmonary, cardiac, central nervous system and ocular manifestations of the disease. Several biomarkers of disease severity have recently been discovered: interleukin-6, pentraxin-3, C-reactive protein, indoleamine 2,3-dioxygenase, cell-free DNA, soluble urokinase-type plasminogen activator, GATA-3 and Mac-2 binding protein. The role of cytokines, vascular endothelial growth hormone, complement, bradykinin, cellular immune response and other mechanisms in the pathogenesis of NE as well as host genetic factors will be discussed. Finally therapeutic aspects and directions for further research will be handled., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Acute pancreatitis is one of the rare complications of hemorrhagic fever with renal syndrome (HFRS), which easy to be misdiagnosed as acute abdomen, usually critically ill, poor treatment effect, highly mortality. In this study, we retrospectively analyzed to explore the clinical characteristics, 12 cases of hemorrhagic fever with renal syndrome complicated with acute pancreatitis treatment methods and prognosis., Methods: We conducted a retrospective study of HFRS in patients complicated with acute pancreatitis. 12 cases were collected from Ningbo first hospital between January 2001 and December 2012. Clinical information and laboratory parameters were obtained by reviewing literature and records., Results: Twelve from 156 cases (7.69%) HFRS complicated with acute pancreatitis. Men comprised more than half (75%) of the sample population, the mean age was (38 ± 19) years. Abdominal pain was the main clinical manifestations in all the patients, all of their serum amylase and serum lipase were increased, 10 patients were given the total abdomen CT examination, eight cases showed enlargement of the pancreas and surrounding leakage, two cases showed pancreatic necrosis and hemorrhage. Three cases complicated with pulmonary edema. In 12 cases, four of them received hemodialysis treatment, one gives surgical intervention. Eight cases were complete remission, three cases were partial remission and one case was death., Conclusions: Acute pancreatitis is one of rare of the serious complications of HFRS, whereas the correct diagnosis and clear the cause of disease is critical for improve the quality of life of patients and reduce the mortality, timely hemodialysis treatment is effective, early intervention can improve the prognosis.

Hantavirus is an RNA virus that can cause potentially fatal pulmonary and renal diseases in humans. Infections with Hantaviruses occur through inhalation of aerosol from rodent faeces, urine or saliva. The predominant virus type in Denmark is the Puumala virus, which causes the mildest form of haemorrhagic fever with renal syndrome, the so-called nephropathia epidemica (NE) with good prognosis (mortality 0.1-0.4%). The incidence of Hantavirus-infection in Denmark is about ten cases a year. The diagnosis of Hantavirus-infection is based on serology and/or polymerase chain reaction in blood or urine.

Hemorrhagic fever with renal syndrome (HFRS) is a zoonotic infectious disease caused by Hantaviruses, a group of RNA viruses belonging to the Bunyaviridae family. Humans may get the disease by contamination with excreta of carrier rodents. The disease typically manifests with the triad fever-thrombocytopenia-acute kidney injury (AKI). Although its global prevalence seems to be increasing, Hantavirus infection is still commonly overlooked, because of its clinical polymorphism and non-specific symptoms, particularly in mild cases. Until recently, the disease was virtually unknown in Romania, due to lack of physicians' awareness and of adequate laboratory diagnostic techniques. In this article, we present the first six cases of HFRS diagnosed in our country, based on serology testing. We review the existing literature on HFRS and discuss our findings in comparison with other reports. All our patients presented with fever, flu syndrome, bleeding, gastrointestinal symptoms, and oliguria. Among laboratory abnormalities, elevated serum creatinine and liver enzymes, high C-reactive protein, leukocytosis, low platelet count, and hematuria were constantly seen. Five patients required hemodialysis. All patients survived and five of them completely recovered their renal function, while only one patient retained a mild impairment of the glomerular filtration rate. From a clinical viewpoint, we believe that Hantavirus infection should be considered in all patients presenting with fever, thrombocytopenia, and AKI, when specific serology testing would be indicated. From a public health perspective, we suggest that future efforts in our country should be directed toward (1) increasing the understanding and the awareness of this disease among health care professionals, (2) educating the population at risk on the application of prophylactic measures, (3) expanding the availability of diagnostic laboratory tools, and (4) developing research on national zoonotic virus reservoirs.

Background/aim: Besides viral serotype, HLA haplotype and cytokine genes polymorphism are associated with clinical presentation of hemorrhagic fever with renal syndrome. Since these analyses are unavailable in routine clinical practice, the aim of this study was to assess clinical, laboratory and radiographic findings associated with clinical presentation of disease severity., Methods: A total of 30 patients (27 men and 3 women), average age 40 +/- 14.9 years, treated for hemorrhagic fever with renal syndrome from January 1, 1999 to December 31, 2009 in Clinical Center of Serbia, were included in the study. Nine patients (30%) had mild, 14 (46.7%) moderate and 7 (23.3%) severe form of the disease; 24 (800%) recovered, 6 (20%) died in the acute phase of the illness, and 19 patients (63.3%) required hemodialysis., Results: The average titer of antiviral antibodies in patients infected with Belgrade serotype virus were significantly higher in those with severe clinical presentation. Hypotension, anuria, macrohaematuria, pulmonary infiltration, pleural effusion, hepatomegalia and positive meningeal signs were more frequent in the patients with severe form of the disease. Statistically significant differences between groups with mild, moderate and severe clinical picture were found in serum total protein, albumin, calcium, glutamate pyruvate and glutamate oxaloacetate transaminase on admittance; serum creatinine and phosphorus concentration on day 14 and day 21; serum sodium and calciums on day 14; hemoglobine concentration on day 21. A statistically significant correlation was found between clinical presentation of the disease severity and platelet count, white blood cell count, hemoglobine concentration, serum calcium and serum transaminases on admittance. Multivariate analysis identified variables' combinations associated with clinical presentation of the disease., Conclusion: Our study confirmed that we can distinguish patients who will manifest different severities of the disease on the basis of careful consideration of laboratory and clinical findings on admission.

A poor general condition of patients with hemorrhagic fever and elevated creatinine should raise suspicion of a systemic infection with Hantavirus. This can often also cause ocular changes. Above all, changes of intraocular pressure, in our case bilateral acute angle-closure glaucoma, due to edema and hemorrhage in the ciliary body result in anterolateral rotation of the iris-lens diaphragm with closure of the chamber angle. It can also cause a transient myopia, and intraretinal hemorrhages can also occur. Hantavirus infection is mostly transmitted through red-backed voles in Europe. The predominant type in Europe is the Puumala virus that can lead to an epidemic nephropathy with high fever, headache, gastrointestinal complaints, and an impaired renal function to the point of renal failure. No specific treatment is needed, but adequate symptomatic therapy is of utmost importance. When the infection has been overcome, complete recovery is possible. Measures for prophylaxis should be taken with respect to contact with mice and their excreta.

Hantaviruses in Europe cause human hemorrhagic fever with renal syndrome (HFRS) with various degree of severity. The most severe form is caused by the Dobrava/Belgrade virus (DOBV), associated with the rodent Apodemus flavicollis. During the last decade cases of infection caused by DOBV have been reported in Central Europe. The present study is a report on two Czech patients with severe HFRS who were infected during their stay in a mountain hut in Northern Slovakia. The two patients, combined with a third case observed in the same year in a nearby village in the Czech Republic, suggest that this region in Central Europe has to be considered as endemic for HFRS., (Copyright © 2011 Wiley-Liss, Inc.)

This is the first case of virus-associated encephalitis/encephalopathy in which the pathogen was Hantaan virus. A 53-yr-old man presented fever, renal failure and a hemorrhagic tendency and he was diagnosed with hemorrhagic fever with renal failure syndrome (HFRS). In the course of his illness, mild neurologic symptoms such as dizziness and confusion developed and magnetic resonance images revealed a reversible lesion in the splenium of the corpus callosum. This case suggests that HFRS patients with neurologic symptoms like dizziness and mental slowing should be considered to have structural brain lesions and to require brain imaging studies.

Introduction: Hemorrhagic fever with renal syndrome (HFWRS) is an acute infectious disease with abrupt onset, high fever, renal failure and frequent hemorragies. HFWRS during the pregnancy has relatively low occurrence, with only few described cases mostly in the region of the former Soviet Union. Although, according to the data from the literature, the disease is less severe during the pregnancy, the eclampsy, stillbirth and fetal infection were also described., Material and Methods: During the summer period, June-September 2002 in the area of northeast Montenegro, and mainly among people whose job was connected with rural areas, the HFRS was observed more frequently. In that area during the stated period, 12 patients underwent treatment whose disease was confirmed by the IIF method at the Torlak Institute of Virology in Belgrade. Among the patients there were two pregnant women aged 23 and 29 (both in their second pregnancies), in the 23rd and 26th gestational week, respectively. The aim of this study is to present 2 case studies and to show the disease impact on fetal development., Results: The patients aged 23 and 29 yrs, were previously healthy women in their second pregnancies (23rd and 26th gestational week, respectively). The disease had typical beginning. The predictions made according to the laboratory abnormalities and the level of oliguria were that the disease would have a less severe course. Hemorrraghic syndrome was less prominent, and the laboratory analyses were normalized after 15 to 18 days. The monitoring of pregnancy during the disease period and after recovering showed no fetal suffering. The patients had PV delivery, in 39-th an 40-th, respectively. The newborns blood testing on Hantan viruses was done by ELISA method in Torlak Institute, Belgrade. Only the IgG antibodies (1/512), were detected, the IgM antibodies were not found. Two years later the tests were repeated, and showed negative results.

In 1978, hantaviruses were first described as the etiological agent of hemorrhagic fever with renal syndrome (HFRS) in Korea. Since then, numerous related, enveloped, negative-stranded RNA viruses have been identified, forming the genus Hantavirus within the family Bunyaviridae. These pathogens are distributed worldwide and thus can be classified, on the basis of phylogenetic origins, into Old World viruses or New World viruses (ie North, Central, and South America). Similarly, these viruses cause two major types of syndromes, corresponding respectively to their phylogenies: the original HFRS or the more recently described hantavirus pulmonary syndrome (HPS). As the hantavirus pulmonary syndrome is the primary hantaviral disease in North America, it will thus be the focus of this review.

History and Admission Findings: A 29-year-old woman in the early stage of pregnancy ( approximately 6 (th) week) presented in our hospital with influenza-like symptoms of fever, headache, aching limbs and tenderness over the costovertebral angle. Acute oliguric renal failure occurred within a few days., Investigations: Ultrasonography revealed symmetrically enlarged kidneys with a small amount of perirenal fluids. The blood count showed thrombocytopenia, and viral serology verified a recent infection with Puumala virus (species of Hantavirus)., Treatment and Course: Epidemic nephropathy was diagnosed. The patient underwent one session of hemodialysis and soon recovered without any residual renal damage. The pregnancy continued without any further complications., Conclusions: There are only few reports on infections with Puumala virus during pregnancy are. None of theses described any fetal abnormalities causes by the maternal infection, as in our patient. Hantavirus infections should be considered in differential diagnosis of acute renal failure in endemic regions.

Objective: To know the genotype and subtype of hantavirus (HV) which infected persons in Hebei province., Methods: According to G2 coding region of 76-118 and R22 strains, specific type primers were designed to detect and identity the types of HV in HFRS patients' sera with RT-nested PCR. Nucleotides were assayed from partial products after purification and reclaim. Then, gene analysis was done with DNAStar package., Results: 17 out of 69 positive serum specimens were successfully detected by RT-PCR and the detection rate was 24.64%, among which, or= 14 days were 0. 17 positive specimens were all belonged to SEO. The nucleotide homology of 9 typical specimens was 92.0%-100%. Between HeB7 and other 8 specimens was 92%-95%, and they belonged to different subtypes. When HeB7 compared with R22 strain, it was 97.7%. HeB7 and R22 belonged to S1 subtype. The 8 specimens except HeB7 was 95.7%-100% and they all belonged to S3 subtype. When compared with 76-118 strain, 9 specimens' nucleotide homology was only 70.3%-72.7%, belonged to different type., Conclusion: SEO was the major type of HV from HFRS patients in Hebei province, S3 was the major subtype and S1 was also existed. In a certain area, the HV which belonged to the same type was correspondingly conservative, and had the characteristic of regional stability.

Unlabelled: The objective of this study was to investigate the prevalence of antibodies to hantaviruses among hemodialysis patients with end-stage renal failure in Kaunas and its district., Material and Methods: Serums of 218 patients from four dialysis centers of Kaunas district were tested by using the immunoglobulin G antibody-capture enzyme-linked immunosorbent assay (ELISA). The reactivity of ELISA-positive sera was proven in Western blot tests using various hantavirus recombinant nucleocapsid proteins. The yeast-expressed nucleocapsid proteins were used for testing., Results: Antibodies against Dobrava/Hantaan and Puumala hantaviruses were found in 16 patients (seroprevalence 7.4%). Most of the sera were positive for Dobrava hantavirus (81%). The ratio of males to females was 1.2:1. Seroprevalence was significantly higher in older patients., Conclusions: Results indicate that antibodies to two hantaviruses (Dobrava/Hantaan virus and Puumala virus) are prevalent among hemodialysis patients in Kaunas district with approximately the same seroprevalence as in neighboring countries.

Reported here are two cases of hantavirus pulmonary syndrome caused by Puumala virus infection, which rapidly resolved after initiation of corticosteroid treatment combined with continuous veno-venous hemodiafiltration. These cases emphasize the role of the inflammatory response in the pathogenesis of hantavirus pulmonary syndrome.

Hantavirus infection is seldom reported in Taiwan. The spectrum of clinical severity ranges from mild to severe and may cover Hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome (HFRS). We report a case of HFRS in a 24-year-old soldier presenting with fever, chills, abdominal pain and generalized myalgia. His clinical course progressed through febrile, hypotensive, oliguria and polyuria phases. Hantavirus infection was proven by serology at the second hospital week. The patient was successfully treated with supportive management. Clinicians should be alert to the possibility of HFRS when examining patients with symptoms of fever, renal function impairment, hemorrhagic tendency and with rural exposure in Taiwan.

The subjects of the study--patients with severe hemorrhagic fever with renal syndrome--were divided into two groups: those who were on hemodialysis, and those who were not. The study included evaluation of the phospholipid spectrum of erythrocyte membranes in the acute period and during recovery. The results revealed conformational shifts in the structure of the bilipid membrane layer, which were maximal during the acute phase of the disease, as well as less prominent and varied changes in the phospholipid spectrum during recovery. This allows determination of the terms of rehabilitation of the patients and substantiates administration of membrane stabilizers as a part of complex therapy of residual syndrome.

Infectious febrile nephropathies, initially described as epidemics during military campaigns in Europe and Asia at the turn of the 20(th) century, were eventually all unified under the rubric of hemorrhagic fever with renal syndrome (HFRS) and ascribed to infection from rodent-borne hantaviruses. At the end of the century, hantavirus pulmonary syndrome (HPS) was described throughout the Americas as a consequence of infection with the New World hantaviruses. The epidemiology and clinical manifestations of these diseases are linked to the ecology of their associated rodent hosts. Murine rodents (Old World mice and rats) are associated with the severe forms of HFRS in Asia and the Balkans due to Hantaan, Dobrava, and Seoul viruses. Hantaan virus causes an estimated 50-100,000 infections a year in China alone. Arvicoline rodents (voles) are associated with a mild form of HFRS in Europe called nephropathia epidemica due to Puumala virus. Sigmodontine rodents (New World rats and mice) are associated with approximately 200 HPS cases per year throughout the Americas caused by over a dozen viruses. The viruses are mainly transmitted as small-particle aerosols of rodent excreta, and the subsequent infections share cardiovascular shock as a prominent feature, although HFRS causes predominantly renal disease, while HPS causes a predominantly non-cardiogenic pulmonary edema - hemorrhage involvement varies in the syndromes on the basis of virus subtypes. Efforts are underway to refine prevention strategies, understand the pathogenesis of the shock, and identify therapeutic modalities.

Unlabelled: Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are classical diseases characterized by thrombocytopenia and microangiopathic hemolytic anemia. Microangiopathic hemolytic anemia is also a part of clinical picture in patients with hemorrhagic fever with renal syndrome (HFRS). Some overlap in other elements of clinical picture between TTP and HFRS is possible, which could pose difficulties in differential diagnosis. Early treatment of patients with TTP is essential and significantly improves the outcome, whereas the treatment of HFRS is mainly supportive. In the last ten years, we treated 13 patients with TTP and 17 patients with HFRS. Two patients with HFRS were initially treated as TTP because it was not possible to exclude TTP on the basis of clinical picture. Further clinical course and serologic tests excluded TTP and suggested HFRS., Conclusion: Sometimes it is difficult to distinguish HFRS from TTP because thrombocytopenia and microangiopathic hemolytic anemia are present in both diseases and overlaps in other parts of clinical picture are possible. The serious consequences of delay in the efficacious treatment of patients with TTP could also influence the physicians' decisions.

Aim: The aim of the study was to examine and analyze the main epidemiologic and clinical data of 94 patients with hemorrhagic fever with renal syndrome (HFRS) hospitalized at the University Hospital for Infectious Diseases in Zagreb during the HFRS outbreak in Croatia in 2002., Patients and Methods: A total of 110 patients with clinical diagnosis HFRS were treated at the University Hospital for Infectious Diseases in Zagreb. In 110 of HFRS suspected patients, the clinical diagnosis was verified serologically in 94 patients and they were included in the retrospective study. In 93 patients the diagnosis was confirmed by enzyme-linked immunosorbent assay (ELISA), and in one patient by indirect immunofluorescence assay (IFA). Results were analyzed by the use of descriptive statistics., Results: Puumala (PUU) virus infection was verified in 80 (85.1%), Dobrava (DOB) infection in 8 (8.5%) and cross-reactive antibodies to both PUU and DOB viruses in 5 (5.3%) HFRS patients. In one patient who was confirmed by IFA the hantavirus serotype causing HFRS could not be determined. The localities of the presumed HFRS patient exposure to hantaviruses were mostly in the Zagreb area. Most patients were aged 21-50 (83.0%) and male (76.6%). The majority of HFRS cases occurred between May and August (75.5%). A high proportion of HFRS cases were found in the general population from Zagreb and its surroundings (78.7%). The majority of patients were hospitalized in the febrile stage of the disease (70.2%). The main symptoms were: fever (100%), headache (88.3%) and backache (87.2%). Oliguria was recorded in 56.4% and, anuria in 7.5% of patients, however, only three (3.2%) patients required hemodialysis. Six patients developed hemorrhagic manifestations, especially petechiae on the skin and mucosa. One patient in the convalescent stage had subarachnoidal bleeding. Six patients had pathologic electroencephalogram (EEG) findings and two developed epileptic seizures. Lumbar puncture was performed in 12 patients without inflammatory changes in the cerebrospinal fluid. Pathologic ECG findings were recorded in 30/79 (38.0%) patients, primarily including mild and translent disturbances such as sinus tachycardia, sinus bradycardia, nonspecific alteration of the final complex and incomplete right bundle branch block. Conventional chest radiography revealed abnormal findings in 23/84 (27.4%) patients. The abnormalities consisted of interstitial infiltrates and/or pleural effusions and atelectasis. The patients were divided into 4 groups according to the disease severity: mild in 74 (78.7%), moderate in 15 (16.0%), severe in 4 (4.2%), and very severe in one (1.1%) patient. The latter developed multiorgan failure and died., Conclusion: The largest outbreak of HFRS to date was recorded in Croatia in 2002. Ninety-four patients with clinical and serologically verified HFRS were treated at the Dr. Fran Mihaljević University Hospital for Infectious Disease, Zagreb. The majority of patients were hospitalized between May and August. Most patients had mild form of the disease primarily caused by PUU virus.

Hantaan virus (HTNV), a member of the genus Hantavirus, family Bunyaviridae, is an etiologic agent causing a serious human disease, hemorrhagic fever with renal syndrome (HFRS), with a mortality as high as 15% and is also a potential bioterrorism agent. It is urgently needed to develop anti-HTNV-neutralizing monoclonal antibodies (MAbs) for treatment and prevention of HTNV infection. In the present study, 18 murine MAbs directed against HTNV strain Chen were generated and characterized. Among these MAbs, 13 were directed against viral nucleocapsid protein (NP), four recognized the viral envelope glycoprotein G2 and one reacted with both NP and G2. Only those MAbs that recognize the epitopes on G2 were positive in hemagglutination inhibition (HI) test and had in vitro virus-neutralizing activity and in vivo protective activity against HTNV infection of susceptible mice. Since all the mice were protected by administration of the virus-neutralizing MAbs one day before and two days after HTNV challenge, these neutralizing MAbs are potentially useful for pre- and post-exposure prophylaxis and for immunotherapy of HTNV infection. Phase II clinical trials of these neutralizing MAbs for emergent treatment of patients with HTNV infection in early stages of HRFS are carried out in endemic areas in China.

The paper presents basic parameters that characterize the status of prevention, treatment, diagnosis, and rehabilitation in hemorrhagic fever with renal syndrome (HFRS). The data from the epidemiological surveillance in the republic indicate the poor epidemic situation: with decreased immunization there are rises in morbidity and viral infection from the main source bank voles. The paper suggests possible ways of improving preventive measures. The mechanism of improvement of health care to patients with HFRS is clinically considered. At the same it is recommended that comparative indices in specialized infection hospitals and in the infection units of central district hospitals should be taken into account while analyzing the medical and diagnostic aid to HFRS patients. Comparison of the above criteria for assessing the quality of diagnosis and treatment in different infection units revealed great differences. This paper presents some experience in organizing preventive, therapeutical, and diagnostic work in case of an Udmurtian active natural focus of HFRS.

Aim: To evaluate effect of hemodialysis on functional state of platelet-vascular and red cell components of hemostasis in patients suffering from severe hemorrhagic fever with renal syndrome (SHFRS)., Materials and Methods: Parameters of platelet-vascular and red cell hemostasis were studied in 51 patients with SHFRS who were divided into two groups. 27 patients of group 1 received conservative treatment, 24 patients of group 2 were put on dialysis., Results: In oliguria, red cell deformity, spontaneous and induced aggregation was similar in both groups. There was a statistically significant anemia, platelet hyperreaction., Conclusion: The detected disorders in hemostasis are attributed to severity of the disease but not effects of hemodialysis.

The authors describe the illness of a Czech soldier who while serving in the UNPROFOR forces in an area with the endemic occurrence of hantaviruses became infected with this agent and developed haemorrhagic fever with renal syndrome. The severe clinical course which called for seven haemodialyzation procedures led to the patient's recovery. The authors describe the course of the disease and epidemiological circumstances.