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Pathogenic New World orthohantaviruses cause hantavirus cardiopulmonary syndrome (HCPS), a severe immunopathogenic disease in humans manifested by pulmonary edema and respiratory distress, with case fatality rates approaching 40%. High levels of inflammatory mediators are present in the lungs and systemic circulation of HCPS patients. Previous studies have provided insights into the pathophysiology of HCPS. However, the longitudinal correlations of innate and adaptive immune responses and disease outcomes remain unresolved. This study analyzed serial immune responses in 13 HCPS cases due to Sin Nombre orthohantavirus (SNV), with 11 severe cases requiring extracorporeal membrane oxygenation (ECMO) treatment and two mild cases. We measured viral load, levels of various cytokines, urokinase plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1). We found significantly elevated levels of proinflammatory cytokines and PAI-1 in five end-stage cases. There was no difference between the expression of active uPA in survivors' and decedents' cases. However, total uPA in decedents' cases was significantly higher compared to survivors'. In some end-stage cases, uPA was refractory to PAI-1 inhibition as measured by zymography, where uPA and PAI-1 were strongly correlated to lymphocyte counts and IFN-γ. We also found bacterial co-infection influencing the etiology and outcome of immune response in two cases. Unsupervised Principal Component Analysis and hierarchical cluster analyses resolved separate waves of correlated immune mediators expressed in one case patient due to a sequential co-infection of bacteria and SNV. Overall, a robust proinflammatory immune response, characterized by an imbalance in T helper 17 (Th17) and regulatory T-cells (Treg) subsets, was correlated with dysregulated inflammation and mortality. Our sample size is small; however, the core differences correlated to survivors and end-stage HCPS are instructive.

Background/aim: Hantavirus is a rodent borne zoonosis caused by the members of the virus family Bunyaviridae, genus Hantavirus. In this study, we aimed to determine the role of peripheral blood leukocyte ratio in differential diagnosis of Hantavirus disease., Materials and Methods: The medical records of patients at the Düzce University Medical Faculty were examined retrospectively. A total of 20 patients diagnosed with hantavirus infection confirmed by serologic tests were included in the study (Group 1). The other group consisted of 30 patients suspected of hantavirus infection but found negative (Group 2). Demographic, clinical and laboratory characteristics, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and lymphocyte/monocyte (LMR) ratios of both groups were compared., Results: As a result of the istatistics analysis, no difference was found between the groups’ age, sex, and clinical complaints except lethargy-weakness (P = 0.004) and diarrhea (P < 0.001). Hemogram analysis showed a significant difference between the groups in terms of leukocyte, hemoglobin, hematocrit, platelet, mean platelet volume (P < 0.05) and PLR (P = 0.001) and LMR (P = 0.003) values from peripheral blood leukocyte ratios., Conclusion: In conclusion, NLR, PLR, and LMR ratios may be useful for clinicians in differential diagnosis of Hantavirus in patients presenting with similar symptoms of Hantavirus disease., Competing Interests: The authors have no conflicts of interest to declare. No funding support was used to carry out the research., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

Objectives : Hantavirus infection and leptospirosis are infectious diseases transmitted by rodents. The clinical picture is nonspecific, often involving the kidneys but other organs can be affected too. Clinical and biochemical clues to make a difference between these two entities will be described. Methods : A retrospective analysis was performed on a database of patients presenting between January 2012 and September 2017 at the emergency department of the university hospital Leuven, Belgium. Patients were selected on the basis of a compatible clinical picture, biochemistry, and microbiological evidence. Presenting complaints and clinical examination were compared. Blood, taken at presentation, was used for hematological and biochemical analysis. Results : Sixteen patients with hantavirus infection and eight patients with leptospirosis were identified. All patients complained about general malaise and fever. Other frequent complaints were myalgia and a headache. Patients with leptospirosis often experienced photo- or sonophobia.Looking for neck stiffness and eye lesions might help to diagnose leptospirosis.Differences in biochemistry between viral and bacterial disease could be recognized; high C-reactive protein (CRP) and leukocytosis with left shift favor leptospirosis, elevated lactate dehydrogenase (LDH) favors viral infection. Abnormal liver function with raised total bilirubin is often seen in cases with leptospirosis. Conclusion : This study demonstrates some subtle clues that may help to differentiate between hantavirus infection and leptospirosis in patients presenting to a hospital in a nonendemic region of the world. Because of small number of patients, we could not identify significant clinical or biochemical tests. Serology remains the gold standard.

Hantavirus cardiopulmonary syndrome (HCPS) is characterized by capillary leak, pulmonary edema (PE), and shock, which leads to death in up to 40% of patients. Treatment is supportive, including mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO). Hemodynamic monitoring is critical to titrate therapy and to decide ECMO support. Transpulmonary thermodilution (TPTD) provides hemodynamic and PE data that have not been systematically used to understand HCPS pathophysiology. We identified 11 HCPS patients monitored with TPTD: eight on MV, three required ECMO. We analyzed 133 measurements to describe the hemodynamic pattern and its association with PE. The main findings were reduced stroke volume, global ejection fraction (GEF), and preload parameters associated with increased extravascular lung water and pulmonary vascular permeability compatible with hypovolemia, myocardial dysfunction, and increased permeability PE. Lung water correlated positively with heart rate (HR, r = 0.20) and negatively with mean arterial pressure ( r = -0.27) and GEF ( r = -0.36), suggesting that PE is linked to hemodynamic impairment. Pulmonary vascular permeability correlated positively with HR ( r = 0.31) and negatively with cardiac index ( r = -0.49), end-diastolic volume ( r = -0.48), and GEF ( r = -0.40), suggesting that capillary leak contributes to hypovolemia and systolic dysfunction. In conclusion, TPTD data suggest that in HCPS patients, increased permeability leads to PE, hypovolemia, and circulatory impairment.

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.

The family Hantaviridae mostly comprises rodent-borne segmented negative-sense RNA viruses, many of which are capable of causing devastating disease in humans. In contrast, hantavirus infection of rodent hosts results in a persistent and inapparent infection through their ability to evade immune detection and inhibit apoptosis. In this study, we used Tula hantavirus (TULV) to investigate the interplay between viral and host apoptotic responses during early, peak and persistent phases of virus infection in cell culture. Examination of early-phase TULV infection revealed that infected cells were refractory to apoptosis, as evidenced by the complete lack of cleaved caspase-3 (casp-3C) staining, whereas in non-infected bystander cells casp-3C was highly abundant. Interestingly, at later time points, casp-3C was abundant in infected cells, but the cells remained viable and able to continue shedding infectious virus, and together these observations were suggestive of a TULV-associated apoptotic block. To investigate this block, we viewed TULV-infected cells using laser scanning confocal and wide-field deconvolution microscopy, which revealed that TULV nucleocapsid protein (NP) colocalized with, and sequestered, casp-3C within cytoplasmic ultrastructures. Consistent with casp-3C colocalization, we showed for the first time that TULV NP was cleaved in cells and that TULV NP and casp-3C could be co-immunoprecipitated, suggesting that this interaction was stable and thus unlikely to be solely confined to NP binding as a substrate to the casp-3C active site. To account for these findings, we propose a novel mechanism by which TULV NP inhibits apoptosis by spatially sequestering casp-3C from its downstream apoptotic targets within the cytosol.

Introduction: Oropouche fever is an under-reported and emerging infectious disease caused by Oropouche virus (OROV). Its incidence is under-estimated mainly due to clinical similarities with other endemic arboviral diseases and the lack of specific diagnostic tests. We report the first outbreak of Oropouche fever in a western region of the Peruvian Amazon in Huanuco, Peru., Methods: A transversal study was carried out during an outbreak in the western Region of Huanuco, Peru between January and July of 2016. Blood samples of 268 patients with acute febrile syndrome were collected and analyzed for OROV via RT- PCR and genetic sequencing., Results: Of all 268 patients, 46 (17%) cases tested positive for OROV. The most common symptoms reported were headache with a frequency of 87% (n = 40) followed by myalgia with 76% (n = 35), arthralgia with 65.2% (n = 30), retro-ocular pain 60.8% (n = 28) and hyporexia with 50% (n = 23). Some patients showed a clinical presentation suggestive of severe OROV infection, of which 4.3% (n = 2) had low platelet count, 8.6% (n = 4) had intense abdominal pain, and 2.1% (n = 1) had a presentation with thoracic pain., Conclusion: This study reports an outbreak of OROV in a region where this virus was not previously identified. The disease caused by OROV is an emerging, underdiagnosed infection that requires further research to determine its virulence, pathogenesis, host range and vectors involved in the urban and sylvatic cycles as well as identifying new genotypes to implement sensitive and specific diagnostic tools that can be applied to endemic regions., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Hantaviruses are emerging rodent-borne negative-strand RNA viruses associated with severe human diseases. Zoonotic transmission occurs via aerosols of contaminated rodent excreta and cells of the human respiratory epithelium represent likely early targets. Here we investigated cellular factors involved in entry of the pathogenic Old and New World hantaviruses Hantaan virus (HTNV) and Andes virus (ANDV) into human respiratory epithelial cells. Screening of a kinase inhibitor library using a biocontained recombinant vesicular stomatitis virus pseudotype platform revealed differential requirement for host kinases for HTNV and ANDV entry and provided first hints for an involvement of macropinocytosis. Examination of a selected panel of well-defined inhibitors of endocytosis confirmed that both HTNV and ANDV enter human respiratory epithelial cells via a pathway that critically depends on sodium proton exchangers and actin, hallmarks of macropinocytosis. However, HTNV and ANDV differed in their individual requirements for regulatory factors of macropinocytosis, indicating virus-specific differences., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Viral infection-associated kidney diseases are an emerging public health issue in both developing and developed countries. Many new viruses have emerged with new paradigms of kidney injury, either directly through their cytopathic effect or indirectly through immune-mediated glomerulopathy, tubulointerstitial disease, and acute kidney injury as part of multiorgan failure. Herein, we will discuss Parvovirus, which causes glomerulopathy, and Hanta, Ebola, and Dengue viruses, which cause viral hemorrhagic fever and acute kidney injury. Clinical manifestations also depend on extrarenal organ systems involved. Diagnosis of these viral infections is mainly based on a high index of suspicion, serologic testing, and isolation of viral DNA/RNA. Management is largely conservative, as specific antiviral agents are unavailable., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

We performed a literature review in order to improve our understanding of how landscape and climate drivers affect HCPS outbreaks. Anthropogenic landscape changes such as forest loss, fragmentation and agricultural land uses are related with a boost in hantavirus reservoir species abundance and hantavirus prevalence in tropical areas, increasing HCPS risk. Additionally, higher precipitation, especially in arid regions, favors an increase in vegetational biomass, which augments the resources for reservoir rodents, also increasing HCPS risk. Although these relationships were observed, few studies described it so far, and the ones that did it are concentrated in few places. To guide future research on this issue, we build a conceptual model relating landscape and climate variables with HCPS outbreaks and identified research opportunities. We point out the need for studies addressing the effects of landscape configuration, temperature and the interaction between climate and landscape variables. Critical landscape thresholds are also highly relevant, once HCPS risk transmission can increase rapidly above a certain degree of landscape degradation. These studies could be relevant to implement preventive measures, creating landscapes that can mitigate disease spread risk.

Aim: to provide the morphological characteristics of experimental Hantavirus infection under heat stress conditions to identify the possibilities of its modeling in resistant laboratory animals., Material and Methods: Experiments were carried out on outbred albino mice that were divided into 4 groups: 1) intact mice unexposed to heating; 2) those exposed to heating; 3) Hantavirus-infected animals unexposed to preheating; 4) those exposed to preheating. The animals in Groups 2-4 were long exposed to heat stress at a temperature of 30 °C for 3 hours during 3 days. Strain Aa 60343 (PM-79-95) of the Far East genovariant of Hantaan virus (the genus Hantavirus, family Bunyaviridae) from the collection of the G.P. Somov Research Institute of Epidemiology and Microbiology was used to induce infection. The animals in Groups 3 and 4 were intraperitoneally injected with 700 FFU of Hantavirus per mouse. Materials (lung, liver, kidney, and spleen) taken from Groups 2-4 animals were collected for histological examination on days 1, 3, 7 and 14 of observation., Results: The intact albino mice in Group 1 showed no histopathological changes in the organs. After heat exposure, Group 2 animals were found to have an immunomorphological response in the interstitial tissues of the lung, liver and kidney in partial lymphoid hypoplasia of the spleen. There were no signs of inapparent infection in the presence of marked immunomorphological changes in the organs in Group 3 of hantavirus-infected animals unexposed to preheating. In Group 4, those exposed to preheating exhibited dystrophic and destructive changes in the target organs (lungs, kidneys) in the presence of immunodeficiency manifestations of manifestations that were more pronounced in dead animals., Conclusion: In an unresponsive model (adult albino mice), Hantavirus infection caused only obvious immunomorphological changes in the organs. Prolonged preheat stress in the hantavirus-infected animals promoted inapparent infection and morphological manifestations of induced secondary immunodeficiency that was responsible for the manifestation of an infectious process in some animals.

To gain insights into the pathogenicity of Imjin virus (MJNV), a newfound hantavirus isolated from the Ussuri white-toothed shrew (Crocidura lasiura), groups of Syrian hamsters (Mesocricetus auratus) of varying ages (<1, 5, 10, 14, 21, 35 and 56 days) were inoculated by the intraperitoneal route with 1000 pfu of MJNV strains 04-55 and 05-11. MJNV-infected Syrian hamsters, aged 21 days or less, exhibited reduced activity, weight loss, respiratory distress, hind-limb paralysis and seizures. Death ensued 1 to 6 days after onset of clinical disease. MJNV RNA was detected in brain and other major organs by RT-PCR and real time-PCR. Histopathological examination showed alveolar hemorrhage, interstitial pneumonia and severe pulmonary congestion; focal hepatic necrosis and portal inflammation; and acute meningoencephalitis. By immunohistochemistry, MJNV antigen was detected in pulmonary microvascular endothelial cells and glial cells. Older hamsters (35 and 56 days of age) developed subclinical infection without histopathological changes. Future studies are warranted to determine the pathophysiologic bases for the differential age susceptibility of Syrian hamsters to lethal MJNV disease., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Introduction: Hantavirus infections are characterized by both activation and dysfunction of the endothelial cells. The underlying mechanisms of the disease pathogenesis are not fully understood. Here we tested the hypothesis whether the polymorphisms of endothelial nitric oxide synthase, eNOS G894T, and inducible nitric oxide synthase, iNOS G2087A, are associated with the severity of acute Puumala hantavirus (PUUV) infection., Patients and Methods: Hospitalized patients (n = 172) with serologically verified PUUV infection were examined. Clinical and laboratory variables reflecting disease severity were determined. The polymorphisms of eNOS G894T (Glu298Asp, rs1799983) and iNOS G2087A (Ser608Leu, rs2297518) were genotyped., Results: The rare eNOS G894T genotype was associated with the severity of acute kidney injury (AKI). The non-carriers of G-allele (TT-homozygotes) had higher maximum level of serum creatinine than the carriers of G-allele (GT-heterozygotes and GG-homozygotes; median 326, range 102-1041 vs. median 175, range 51-1499 μmol/l; p = 0.018, respectively). The length of hospital stay was longer in the non-carriers of G-allele than in G-allele carriers (median 8, range 3-14 vs. median 6, range 2-15 days; p = 0.032). The rare A-allele carriers (i.e. AA-homozygotes and GA-heterozygotes) of iNOS G2087A had lower minimum systolic and diastolic blood pressure than the non-carriers of A-allele (median 110, range 74-170 vs.116, range 86-162 mmHg, p = 0.019, and median 68, range 40-90 vs. 72, range 48-100 mmHg; p = 0.003, respectively)., Conclusions: Patients with the TT-homozygous genotype of eNOS G894T had more severe PUUV-induced AKI than the other genotypes. The eNOS G894T polymorphism may play role in the endothelial dysfunction observed during acute PUUV infection.

1. Pathogens often cause detrimental effects to their hosts and, consequently, may influence host population dynamics that may, in turn, feed back to pathogen transmission dynamics. Understanding fitness effects of pathogens upon animal host populations can help to predict the risks that zoonotic pathogens pose to humans. 2. Here we determine whether chronic infection by Puumala hantavirus (PUUV) affects important fitness-related traits, namely the probability of breeding, reproductive effort and mother and offspring condition, in the bank vole (Myodes glareolus). Using 9 years empirical data in a PUUV endemic area in Central Finland, we found differences between reproductive characteristics of PUUV-infected and uninfected female bank voles. 3. Young infected females had a significantly higher, and old individuals lower, likelihood of reproducing than uninfected animals during the middle of the breeding season. The implication is that PUUV infection may have long-term deleterious effects that are observed at old age, while in young individuals, the infection may enhance breeding probability by directing resources towards current breeding. 4. Moreover, PUUV infection was related with the mother's body condition. Infected mothers were in poorer condition than uninfected mothers in the early breeding season, but were in better condition than uninfected mothers during the middle of the breeding season. Offspring body condition was positively associated with mother's body condition, which, in turn, was related to the PUUV infection status of the mother. 5. Our findings indicate that chronic infection may affect the reproduction of female hosts, but the effect is dependent on the host age. The effect of chronic hantavirus infection was small and density-independent and hence unlikely to contribute to the cyclic population dynamics of the host. However, the effects on a female's reproductive output might affect the abundance of young susceptible individuals in the population and hence influence the transmission and persistence of the pathogen. Although experimental and long-term capture-mark-recapture studies are required to further clarify the fitness effects of hantavirus infection and their consequences for pathogen dynamics, this study shows that the infection may have complex effects that are dependent on the age of the individual and the time of the breeding season., (© 2015 The Authors. Journal of Animal Ecology © 2015 British Ecological Society.)

Hantaviruses can be associated with severe form of hemorrhagic fever with renal syndrome although there are only a few cases reporting chronic kidney disease after hantavirus infection. We report a severe nonresolving chronic renal failure after protracted Dobrava hantavirus infection successfully treated with corticosteroids. Ten days after working in a basement a 33-year-old man fell seriously ill, with high fever, chills, diffuse myalgia, headache and abdominal pain. After hospital admission a diagnosis of hemorrhagic fever with renal syndrome caused by Dobrava hantavirus was made. Acute oliguric kidney injury developed in the first 3 days after admission, in a few days diuresis restored and he became polyuric. Nevertheless renal failure persisted and he needed hemodialysis. Because of nonresolving kidney failure, nephrogenic diabetes insipidus and renoparenchymal arterial hypertension persisting 2 months after onset of symptoms, a kidney biopsy was performed, showing severe necrotizing tubulointerstitial nephritis. High dose methylprednisolone therapy was started and his renal function significantly improved. Two months later a second renal biopsy showed persisting elements of active necrotizing tubulointerstitial nephritis. We decided to stop corticosteroid treatment and introduced aldosterone antagonist eplerenon as anti-fibrotic agent, and his renal function further improved and remained stable. Nine months later his serum creatinine concentration was 227 μmol/L, proteinuria 0.156 g/day and well controlled nephrogenic diabetes insipidus., (© 2013 The Authors. Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis.)

New World hantaviruses can cause hantavirus cardiopulmonary syndrome with high mortality in humans. Distinct virus species are hosted by specific rodent reservoirs, which also serve as the vectors. Although regional spillover has been documented, it is unknown whether rodent reservoirs are competent for infection by hantaviruses that are geographically separated, and known to have related, but distinct rodent reservoir hosts. We show that Andes virus (ANDV) of South America, carried by the long tailed pygmy rice rat (Oligoryzomys longicaudatus), infects and replicates in vitro and in vivo in the deer mouse (Peromyscus maniculatus), the reservoir host of Sin Nombre virus (SNV), found in North America. In experimentally infected deer mice, viral RNA was detected in the blood, lung, heart and spleen, but virus was cleared by 56 days post inoculation (dpi). All of the inoculated deer mice mounted a humoral immune response by 14 dpi, and produced measurable amounts of neutralizing antibodies by 21 dpi. An up-regulation of Ccl3, Ccl4, Ccl5, and Tgfb, a strong CD4⁺ T-cell response, and down-regulation of Il17, Il21 and Il23 occurred during infection. Infection was transient with an absence of clinical signs or histopathological changes. This is the first evidence that ANDV asymptomatically infects, and is immunogenic in deer mice, a non-natural host species of ANDV. Comparing the immune response in this model to that of the immune response in the natural hosts upon infection with their co-adapted hantaviruses may help clarify the mechanisms governing persistent infection in the natural hosts of hantaviruses.

Introduction: Puumala virus (PUUV) infection is a viral hemorrhagic fever with renal syndrome (HFRS) characterized by thrombocytopenia and acute impairment of renal function. We aimed to assess whether genetic polymorphisms of platelet antigens together with those of von Willebrand factor (VWF) and plasminogen activator inhibitor (PAI-1) correlate with disease severity. Patients and methods 172 consecutive hospital-treated patients with serologically confirmed acute PUUV infection were included. Platelet glycoprotein (GP) IIIa T>C (rs5918), GP Ia T>C (rs1126643), GP Ib C>T (rs6065), GP VI T>C (rs1613662), VWF A>G (rs1063856) and PAI-1 A>G (rs2227631) were genotyped. The associations of the rarer alleles with variables reflecting the severity of the disease were analyzed., Results: PAI-1G-carriers had higher maximum creatinine level compared with the non-carriers (median 213 μmol/l, range 60-1499 μmol/l vs. median 122 μmol/l, range 51-1156 μmol/l, p = 0.01). The GG-genotypes had higher creatinine levels than GA- and AA-genotypes (medians 249 μmol/l, 204 μmol/l and 122 μmol/l, respectively, p = 0.03). Polymorphisms of GP VI and VWF associated with lower creatinine levels during PUUV infection. The minor C-allele of GP Ia associated with lower platelet counts (median 44 × 10(9)/l, range 20-90 × 10(9)/l vs median 64 × 10(9)/l, range 3-238 × 10(9)/l; p = 0.02)., Conclusions: Polymorphism of PAI-1, a major regulator of fibrinolysis, has an adverse impact on the outcome of kidney function in PUUV-HFRS. Platelet collagen receptor GP Ia polymorphism associates with lower platelet count., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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.

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.

The clinical presentation of hantavirus infections in India is unclear. We report here a case of hantavirus infection in a 46 year old quarry worker presenting with fever, abdominal pain, jaundice, thrombocytopenia and renal dysfunction. Seroconversion and rising anti-hantavirus IgG titers were taken as evidence of hantavirus infection. Clinicians should consider hantavirus infections in the differential diagnosis of acute febrile illness along with scrub typhus, leptospirosis and dengue.

We present a preliminary report of 12 laboratory-confirmed cases of haemorrhagic fever with renal syndrome (HFRS) in Turkey, diagnosed between January and May 2009 according to the clinical symptoms and serological confirmation. Studies are still ongoing to better understand the dynamics of the reservoir population as well as the epidemiological characteristics and risk factors among humans.

History and Admission Findings: A 19-year-old man was admitted to our hospital because of fever and exhaustion. During his hospital stay he had pain in the back and flanks., Investigations: The electrocardiogram (ECG) revealed ST-segment elevation in V1-V3, similar to that occurring in myocardial infarction. Renal function was decreased with proteinuria and the platelet count was decreased The symptoms and clinical findings aroused the suspicion of a Hantavirus infection, which was confirmed by antibody tests., Treatment and Course: The patient was treated symptomatically with paracetamol. After 5 days the patient felt better and had a normal temperature. The thrombocyte count and renal function normalised after 10 days in hospital., Conclusion: In case of a suspected peril-/ myocarditis a Hantavirus infection should be considered as a possible cause, which should be clarified by antibody tests.

Mice infected with Dhori virus (DHOV) develop a fulminant, systemic, and uniformly fatal illness that has many of the clinical and pathologic findings seen in H5N1 influenza A virus infection. However, the role of host's immune response in DHOV infection remains unclear. In this study, the concentrations of 23 inflammatory cytokines and chemokines were measured in the liver, lungs, and sera of mice during the course of DHOV infection. Liver function, level of viremia, and hematologic response were also monitored. Infected animals exhibited significant leucopenia and lymphopenia, which directly correlated with the disease progression. High yields of infectious virus along with strikingly elevated expression of various inflammatory mediators, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL-10, macrophage inflammatory protein (MIP)-1alpha, manocyte chemoattractant protein (MCP)-1, and interferon (IFN)-alpha, indicate that these responses play an important role in the observed disease and pathology. The overall clinical, pathologic, and immunologic responses of ICR mice to DHOV infection closely resemble those described for highly virulent influenza A virus infection in humans, thereby offering a realistic, safe, and alternative animal model for studying the pathogenesis and treatment of highly pathogenic avian influenza virus.

In Europe infection with Puumala or Dobrava viruses causes hemorrhagic fever with renal syndrome (HFRS). In the course of HFRS, mild neurological symptoms such as headache, vertigo, and nausea are common. However, the data about the occurrence of severe, potentially life-threatening neurological manifestations are rather scarce. Here, we present a case of HFRS with serologically proven Dobrava virus infection complicated by epileptic seizures and hemiparesis due to focal encephalitis., ((c) Wiley-Liss, Inc.)

Among rodents that carry hantaviruses, males are more likely to engage in aggression and to be infected than females. One mode of hantavirus transmission is via the passage of virus in saliva during wounding. The extent to which hantaviruses cause physiological changes in their rodent host that increase aggression and, therefore, virus transmission has not been fully documented. To assess whether steroid hormones and neurotransmitters contribute to the correlation between aggression and Seoul virus infection, Norway rats were trapped in Baltimore, Maryland and wounding, infection status, steroid hormones, and concentrations of neurotransmitters, including norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenol acetic acid (DOPAC), serotonin (5-HT), and 5-hydroxyindole-3-acetic acid (5-HIAA) in select brain regions were examined. Older males and males with high-grade wounds were more likely to have anti-Seoul virus IgG and viral RNA in organs than either juveniles or adult males with less severe wounds. Wounded males had higher circulating testosterone, lower hypothalamic 5-HIAA, and lower NE in the amygdala than males with no wounds. Infected males had higher concentrations of testosterone, corticosterone, NE in the hypothalamus, and DOPAC in the amygdala than uninfected males, regardless of wounding status. In the present study, wounded males that were infected with Seoul virus had elevated testosterone and reduced 5-HIAA concentrations, suggesting that these neuroendocrine mechanisms may contribute to aggression and the likelihood of transmission of hantavirus in natural populations of male Norway rats.

Andes virus (ANDV) and Sin Nombre virus (SNV) are rodent-borne hantaviruses that cause a highly lethal hemorrhagic fever in humans known as hantavirus pulmonary syndrome (HPS). There are no vaccines or specific drugs to prevent or treat HPS, and the pathogenesis is not understood. Syrian hamsters infected with ANDV, but not SNV, develop a highly lethal disease that closely resembles HPS in humans. Here, we performed a temporal pathogenesis study comparing ANDV and SNV infections in hamsters. SNV was nonpathogenic and viremia was not detected despite the fact that all animals were infected. ANDV was uniformly lethal with a mean time to death of 11 days. The first pathology detected was lymphocyte apoptosis starting on day 4. Animals were viremic and viral antigen was first observed in multiple organs by days 6 and 8, respectively. Levels of infectious virus in the blood increased 4 to 5 logs between days 6 and 8. Pulmonary edema was first detected ultrastructurally on day 6. Ultrastructural analysis of lung tissues revealed the presence of large inclusion bodies and substantial numbers of vacuoles within infected endothelial cells. Paraendothelial gaps were not observed, suggesting that fluid leakage was transcellular and directly attributable to infecting virus. Taken together, these data imply that HPS treatment strategies aimed at preventing virus replication and dissemination will have the greatest probability of success if administered before the viremic phase; however, because vascular leakage is associated with infected endothelial cells, a therapeutic strategy targeting viral replication might be effective even at later times (e.g., after disease onset).

Dobrava hantavirus (DOBV) infection was diagnosed in a previously healthy 46-y-old hunter suffering from severe haemorrhagic fever with renal syndrome (HFRS). Specific IgM antibodies against DOBV were identified by an immunofluorescence assay, while viral nucleic acid was detected by the molecular method, confirming the diagnosis. Our results reveal an existing risk of DOBV transmission to humans in Hungary.

Hantaviruses are cosmopolite anthropozoonosis considered as an emerging disease. Four pathogenic types for humans and part of the Bunyaviridae species are hosted by rodents and have been isolated: the Sin nombre virus responsible for the severe American respiratory form; the Hantaan and Seoul viruses responsible for hemorrhagic fevers with renal syndrome (HFRS) of severe to moderate expression in Asia and also in the Balkans; the Puumala virus responsible for HFRS of moderate expression or the socalled nephropathia epidemica in Europe. The Puumala virus is responsible for a minor form of the disease that is observed in areas of the Occidental sector of the ex-URSS, in Scandinavia and in the rest of Europe, notably in the North-East of France. The epidemic episodes occur every three years. They follow the proliferation of rodents, notably russet voles, the reservoir hosts, and their degree of infection. The concept of an occupation at risk in 20 to 49 year-old men (working in forests, agriculture, living near a forest, contact with wood) in an endemic area has not always been found. Its clinical form can vary greatly in its presentation. Basically it is a severe algic influenza syndrome accompanied by acute myopia in 38% of cases, but is nearly pathognomonic in the context. Respiratory involvement is frequent but benign. The initial syndrome can suggest an abdominal or urological surgical emergency, which is source of diagnostic and therapeutic errors. Early biological examination reveals thrombopenia and proteinuria. Then more or less severe acute kidney failure appears in slightly more than 50% of cases. Although it usually regresses with symptomatic treatment, after effects remain in some patients. The environmental changes, the geographical distribution depending on the biotope, the dynamics and behaviour of rodents and the viral circulation between them and its transmission to human beings and its risk factors must continue to be studied in order to gain further knowledge on the epidemiology of this anthropozoonosis.

The target organ for Puumala (PUU) and Dobrava (DOB) viruses is the kidney, but the impact on renal function seems far more important in DOB infection than in PUU infections. Aim of study was to estimate the renal failure and capillary leak during the acute stage of DOB-infection and PUU-infection. 50 patients with serological conformed diagnosis of acute hantavirus infection were included in the study. Diuresis, serum urea and creatinine were measured. Size of kidneys and presence of ascites was followed by ultrasonography. Enlargement of both kidneys were found in all (100%) patients. Ascites was present in 8/25 (32%) DOB patients; in 1/25 (4%) PUU patient and pleural effusion in four 4/25 (16%) DOB patients. The statistically significant difference in the mean urinary output was during 5th, 6th and 7th day of hospitalization (P<0,05). Serum creatinine and urea levels were at significantly higher levels for DOB than for PUU patients (P<0,05). Acute haemodialysis was needed in 7/25 (28 %) of the DOB patients. One DOB patient died. DOB virus infection is associated with a more severe kidney function disorders than PUU virus infection. Capillary leak, which caused swollen of kidney and ascites is probably the pathogenesis key factor.

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.

When hantaviruses hit the headlines with the advent in May 1993 of a new disease in the USA, and later in the New World from Canada to south Argentina, called "hantavirus pulmonary syndrome" (HPS), speculations in the lay press rose from the very beginning around the possibilities of a biological warfare (BW) weapon. Indeed, the responsible agent of HPS, hantavirus, was almost unknown at that moment in the New World, was airborne, seemed to target preferentially young adults, and induced a devastating cardio-pulmonary collapse with a high case-fatality rate (50%), often within hours. It quickly became clear, however, that the same scourge had been known for many years in the Old World under different and mostly milder presentations. With the rapidly increasing knowledge about hantaviruses, it also became clear that they lack many of the potentials of an "ideal" BW weapon, as will be explained in this paper.

Hantavirus pulmonary syndrome (HPS) is a severe and often fatal rodent-borne zoonosis. Maporal (MAP) virus is a newly discovered hantavirus that originally was isolated from an arboreal rice rat captured in central Venezuela. The results of this study indicate that MAP virus in the Syrian golden hamster (Mesocricetus auratus) can cause a disease that is clinically and pathologically remarkably similar to HPS. The similarities include the time course of clinical disease, presence of virus-specific IgG at the onset of clinical disease, subacute pneumonitis, rapid onset of diffuse alveolar edema in the absence of necrosis, hepatic-portal triaditis, mononuclear-cellular infiltrate in lung and liver, widespread distribution of hantaviral antigen in endothelial cells of the microvasculature of lung and other tissues, and variable lethality. These similarities suggest that the MAP virus-hamster system is a useful model for studies of the pathogenesis of HPS and for the evaluation of potential therapeutic agents.

We have determined the genomic sequence of an Andes virus (ANDV) strain isolated from an infected Oligoryzomys longicaudatus rodent trapped in Chile in 1997. This strain, for which we propose the designation Chile R123, reproduces essential attributes of hantavirus pulmonary syndrome (HPS) when injected intramuscularly into laboratory hamsters (Hooper et al., Virology 289 (2001) 6-14). The L, M, and S segment sequences of Chile R123 are 6562, 3671, and 1871 nt long, respectively, with an overall G+C content of 38.5%. These respective genome segments could encode a 247 kd RNA-dependent RNA polymerase (RdRP), 126 kd glycoprotein precursor (GPC), and 48 kd nucleocapsid (N) protein, in line with other Sigmodontine rodent-associated hantaviruses. Among hantaviruses for which complete genomic sequences are available, Chile R123 is most closely related to Sin Nombre virus (SNV) strain NM R11, with greater than 85% amino acid identity between translated L and S segments and 78% amino acid identity between translated M segments. Because Chile R123 shares essentially 100% amino acid identity in regions of overlap with partially sequenced Argentinian and Chilean ANDV strains, Syrian hamster pathogenicity and the potential for interhuman transmission are features likely common to all ANDV strains.

Forty-eight Sigmodon alstoni (Alston's cotton rat) were inoculated with Caño Delgadito (CDG) virus to extend our knowledge and understanding of the natural host relationships of the hantaviruses indigenous to the Americas. Infectious CDG virus was recovered from oropharyngeal secretions, urine, or solid tissues of nine of 12 animals killed on day 9 post-inoculation (PI), 14 of 24 animals killed on day 18 or 27 PI, and none of 12 animals killed on day 54 PI. In addition, virus-specific RNA was detected in the kidneys of six of the 12 animals killed on day 54 PI, and adult cotton rats inoculated with the kidneys of four animals killed on day 54 PI developed antibody to CDG virus. Collectively, the results indicate that CDG virus can establish lengthy (perhaps lifelong) infections in Alston's cotton rat and thus support the concept that S. alstoni is the principal host of CDG virus.

Hantaviruses are a newly emerging group of rodent-borne viruses that have significant zoonotic potential. Human infection by hantaviruses can result in profound morbidity and mortality, with death rates as high as 50%, and potentially long-term cardiovascular consequences. Hantaviruses are carried by peridomestic and wild rodents worldwide and have occasionally been linked to infections in laboratory rodents. Because these viruses have been associated with significant human disease, they have become the subject of intense scientific investigation. In this review the reader is introduced to the hantaviruses, including hantavirus diseases and their pathogenesis. A review of the biology, morphology, and molecular biology of the hantaviruses with a brief overview of the ecology and biology of hantavirus-rodent pairs is also included. The risks of occupational exposure to hantaviruses, diagnosis of hantavirus infections, and methods for handling potentially infected rodents and tissues are discussed as well.

Background: Nephropathia epidemica (NE) is a mild form of hemorrhagic fever with renal syndrome caused by Puumala hantavirus. Its long-term prognosis is considered favorable. Some reports suggest, however, that a previous hantavirus infection increases the risk of hypertension., Methods: We studied 46 previously healthy subjects (26 males and 20 females, mean age of 44 years) who had serologically confirmed NE three to seven years previously, and 38 healthy, seronegative controls (22 males and 16 females, mean age of 44 years). Ambulatory blood pressure (ABP) was monitored. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by 51CrEDTA and 131I-hippurate clearances, respectively. The filtration fraction (FF) was calculated. Quantitative 24-hour urinary protein excretion (UprotE) and timed overnight urinary excretion of alpha1-microglobulin were measured., Results: The NE patients had a higher mean ambulatory systolic BP than the controls (123 +/- 13 vs. 117 +/- 9 mm Hg, P = 0. 008). GFR and FF were increased in patients compared with controls (GFR, 120 +/- 20 vs. 109 +/- 14 mL/min/1.73 m2, P = 0.006; FF, 19 +/- 3 vs. 18 +/- 3%, P = 0.030), but ERPF did not differ between the groups. The patients also had higher UPE than the controls (median 0. 18 g/day, range 0.12 to 0.38 vs. median 0.14 g/day, range 0.09 to 0. 24, P < 0.001, respectively). The overnight urinary excretion rate of alpha1-microglobulin exceeded 7 microg/min in nine patients., Conclusion: Three to seven years after NE, the patients had higher GFR and FF, more proteinuria, and higher ambulatory systolic BP compared with the healthy controls. NE may thus cause mild renal lesions and alterations in BP in some patients.

Hantavirus cardiopulmonary syndrome (HCPS), a rodent-borne zoonosis, has been endemic in the Americas for at least several decades. It is hypothesized that the 1991-1992 El Niño-southern oscillation (ENSO) caused increased precipitation that allowed an increase in rodent population densities, thereby increasing the possibility of transmission to humans. The result was a 1993-1994 outbreak of the disease in the Four Corners states of the southwestern United States. A second strong ENSO occurred in 1997-1998, after a period of considerable public education about the risks of hantavirus infection that began during the 1993-1994 outbreak. The caseload of HCPS increased 5-fold above baseline in the Four Corners states in 1998-1999. Regions that had received increased rainfall in 1998 were especially affected. A large majority of the 1998-1999 case patients reported indoor exposure to deer mice. Hantavirus outbreaks can occur in response to abiotic events, even in the face of extensive public education and awareness.

Hantavirus pulmonary syndrome (HPS) occurs in most infections with Sin Nombre virus and other North American hantaviruses. We report five cases of acute hantavirus infection that did not fit the HPS case definition. The patients had characteristic prodromal symptoms without severe pulmonary involvement. These cases suggest that surveillance for HPS may need to be expanded.

The etiologic hantavirus of the 1993 emergence of an acute pulmonary failure syndrome in the area around northwestern New Mexico was quickly recognized as related to the Hantaan virus responsible for the outbreak of Korean epidemic hemorrhagic fever (EHF) among UN troops in 1951. Discovery of the new disease which was named the hantavirus pulmonary syndrome (HPS) and its causative agent the Sine Nombre virus (SNV) inspired detailed comparisons between the two disorders. Major damage to the epithelial cells of the capillaries and arterioles throughout the body leading to extensive capillary leak and subsequent hypotension and shock was the common denominator. The lung capillaries and arterioles were the focus of attack that could lead to rapid pulmonary failure in HPS and the corresponding renal and retroperitoneal vessels that caused a more protracted illness in EHF, but both displayed remarkably similar peripheral blood abnormalities including abnormal mononuclear cells, immature neutrophilia, thrombocytopenia, and hemoconcentration characteristic enough to make blood smear examination a useful tool in early diagnosis. There are evidences that a heavy virus presence in the involved endothelial cells is accompanied by various mononuclear cells capable of generating potent immune response in these areas. Relevant toxic effects of systemically-administered high-dose interleukin-2 for resistant cancers include fever, chills, diarrhea, renal dysfunction, capillary leak syndrome accompanied by hypotension requiring aggressive pressor support, and occasional pleural effusions with diffuse pulmonary infiltrates and hypoxia severe enough to require ventilatory assistance. Peripheral blood mononuclear cells cultured in vitro with IL-2 secrete secondary cytokines such as IL-1, TNF-alpha, and interferon-gamma (IFN-gamma). TNF-alpha, implicated in the pathophysiology of septic shock, is capable of inducing adult respiratory distress syndrome (ARDS) in experimental animals and humans. The strong similarity of these effects to the manifestations noted in the hantavirus diseases justifies the conviction that these and other cytokines involved in potent immune responses would constitute the pathogenic toxic substances predicted by perceptive early investigators of EHF. This concept is favored by clear indications that in both diseases active virus infection disappears the first few days and the ages of involvement correlate with periods of immunocompetence. The paradox of systemic injections of IL-2 that risk hantavirus-type toxicities for treating renal cell carcinoma and melanoma might be avoided by giving potentially more efficacious plant mitogens like PHA as previously reported. The expanded disclosure of a collaborator's method suggesting superior potential for cancer cure involves a unique application of pokeweed mitogen that delivers various cellular and cytokine responses directly to the tumor.

A fatal case of hantaviral illness occurred in Louisiana, outside of the range of P. maniculatus, the rodent reservoir for Sin Nombre virus. Hantavirus RNA and antigens were detected in patient autopsy tissues, and nucleotide sequence analysis of amplified polymerase chain reaction (PCR) products identified a newly recognized unique hantavirus, provisionally named Bayou virus. Prominent features of the clinical illness are compatible with hantavirus pulmonary syndrome (HPS), but several features such as renal insufficiency and intraalveolar hemorrhage are more compatible with hemorrhagic fever with renal syndrome (HFRS), a disease associated with Eurasian hantaviruses.

Cynomolgus macaques (Macaca fascicularis) were experimentally infected with Puumala virus (strain Hällnäs), which causes nephropathia epidemica in humans in western Europe. During the first week after intratracheal inoculation, the monkeys exhibited signs of lethargy followed by mild proteinuria and microhematuria. Histopathologic changes during the first 7 weeks after infection were largely confined to abnormalities in medullary tubular cells of the kidneys, which coincided with the demonstration of viral antigen and viral RNA. The development of different classes of virus-specific plasma antibodies to the respective viral antigens were similar to those observed in humans with nephropathia epidemica. This first description of a nonhuman primate model for hantavirus infection shows that the cynomolgus macaque provides a suitable model with which to study the pathogenesis of Puumala virus infections and to evaluate new diagnostic methods, immunization strategies, and therapies.