Puumala Hantavirus Infection Research Articles

Age-related effects of chronic hantavirus infection on female host fecundity.

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.

Effect of Puumala hantavirus infection on human umbilical vein endothelial cell hemostatic function: platelet interactions, increased tissue factor expression and fibrinolysis regulator release.

Puumala virus (PUUV) infection causes over 5000 cases of hemorrhagic fever in Europe annually and can influence the hemostatic balance extensively. Infection might lead to hemorrhage, while a recent study showed an increased risk of myocardial infarction during or shortly after PUUV infection. The mechanism by which this hantavirus influences the coagulation system remains unknown. Therefore we aimed to elucidate mechanisms explaining alterations seen in primary and secondary hemostasis during PUUV infection. By using low passage PUUV isolates to infect primary human umbilical vein endothelial cells (HUVECs) we were able to show alterations in the regulation of primary- and secondary hemostasis and in the release of fibrinolysis regulators. Our main finding was an activation of secondary hemostasis due to increased tissue factor (TF) expression leading to increased thrombin generation in a functional assay. Furthermore, we showed that during infection platelets adhered to HUVEC and subsequently specifically to PUUV virus particles. Infection of HUVEC with PUUV did not result in increased von Willebrand factor while they produced more plasminogen activator inhibitor type-1 (PAI-1) compared to controls. The PAI-1 produced in this model formed complexes with vitronectin. This is the first report that reveals a potential mechanism behind the pro-coagulant changes in PUUV patients, which could be the result of increased thrombin generation due to an increased TF expression on endothelial cells during infection. Furthermore, we provide insight into the contribution of endothelial cell responses regarding hemostasis in PUUV pathogenesis.

Climate Variability and the Occurrence of Human Puumala Hantavirus Infections in Europe: A Systematic Review.

Hantaviruses are distributed worldwide and are transmitted by rodents. In Europe, the infection usually manifests as a mild form of haemorrhagic fever with renal syndrome (HFRS) known as nephropathia epidemica (NE), which is triggered by the virus species Puumala. Its host is the bank vole (Myodes glareolus). In the context of climate change, interest in the role of climatic factors for the disease has increased. A systematic review was conducted to investigate the association between climate variability and the occurrence of human Puumala hantavirus infections in Europe. We performed a literature search in the databases MEDLINE, EMBASE and Web of Science. Studies that investigated Puumala virus infection and climatic factors in any European country with a minimum collection period of 2 years were included. The selection of abstracts and the evaluation of included studies were performed by two independent reviewers. A total of 434 titles were identified in the databases, of which nine studies fulfilled the inclusion criteria. The majority of studies were conducted in central Europe (Belgium, France and Germany), while only two came from the north (Sweden) and one from the south (Bosnia). Strong evidence was found for a positive association between temperature and NE incidence in central Europe, while the evidence for northern Europe so far appears insufficient. Results regarding precipitation were contradictory. Overall, the complex relationships between climate and hantavirus infections need further exploration to identify specific health risks and initiate appropriate intervention measures in the context of climate change.

NK cell activation in human hantavirus infection explained by virus-induced IL-15/IL15Rα expression.

Clinical infection with hantaviruses cause two severe acute diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). These diseases are characterized by strong immune activation, increased vascular permeability, and up to 50% case-fatality rates. One prominent feature observed in clinical hantavirus infection is rapid expansion of natural killer (NK) cells in peripheral blood of affected individuals. We here describe an unusually high state of activation of such expanding NK cells in the acute phase of clinical Puumala hantavirus infection. Expanding NK cells expressed markedly increased levels of activating NK cell receptors and cytotoxic effector molecules. In search for possible mechanisms behind this NK cell activation, we observed virus-induced IL-15 and IL-15Rα on infected endothelial and epithelial cells. Hantavirus-infected cells were shown to strongly activate NK cells in a cell-cell contact-dependent way, and this response was blocked with anti-IL-15 antibodies. Surprisingly, the strength of the IL-15-dependent NK cell response was such that it led to killing of uninfected endothelial cells despite expression of normal levels of HLA class I. In contrast, hantavirus-infected cells were resistant to NK cell lysis, due to a combination of virus-induced increase in HLA class I expression levels and hantavirus-mediated inhibition of apoptosis induction. In summary, we here describe a possible mechanism explaining the massive NK cell activation and proliferation observed in HFRS patients caused by Puumala hantavirus infection. The results add further insights into mechanisms behind the immunopathogenesis of hantavirus infections in humans and identify new possible targets for intervention.

Puumala hantavirus infection alters the odour attractiveness of its reservoir host.

The random-mixing assumptions of many parasite-transmission models are challenged if healthy individuals can alter their behaviour to reduce their risk of infection. Some pathogens reduce the attractiveness of their hosts' excretions, for example, potentially altering contact rates and thus the predicted force of infection for pathogens transmissible by contact with excretions. For bank voles (Myodes glareolus), contact with contaminated urine is an important route of transmission for Puumala hantavirus (PUUV); however, it is not known whether PUUV infection changes the voles' urinary odours or their attractiveness. Here, we use a Y-maze to test whether PUUV infection alters the attractiveness of male bank voles' urine. We presented wild-caught PUUV-free male and female bank voles with PUUV-infected conspecific urine, uninfected urine and a water control, and measured the relative and absolute latency to first visit, number of visits, and total time bank voles spent investigating each treatment over 30 min. PUUV infection significantly altered the bank voles' initial response to conspecific urine, with fewer visits and less time spent close to infected urine relative to uninfected urine, and less total time spent near the infected urine than the uninfected urine or control. These strong preferences weakened over the 30-min trial, however, partly due to a general decline in male activity, and there were no absolute differences between the treatments overall. This suggests that PUUV infection does change the attractiveness of bank vole urine to conspecifics, and we discuss the implications of these results for random-mixing assumptions.

Pathophysiology of a severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant

We recently described a patient with very severe Puumala hantavirus infection manifested by capillary leakage syndrome and shock. He was successfully treated with the bradykinin receptor antagonist, icatibant (Antonen et al., 2013). Here we report analysis of the pathophysiology which indicated pronounced complement activation, prolonged leukocytosis, extensive fibrinolysis, circulating histones, and defects in liver function. The patient had an uncommon HLA-phenotype, which may have contributed to the severe course of the disease.

Plasma pentraxin-3 and coagulation and fibrinolysis variables during acute Puumala hantavirus infection and associated thrombocytopenia.

Thrombocytopenia and altered coagulation characterize all hantavirus infections. To further assess the newly discovered predictive biomarkers of disease severity during acute Puumala virus (PUUV) infection, we studied the associations between them and the variables reflecting coagulation, fibrinolysis and endothelial activation. Nineteen hospital-treated patients with serologically confirmed acute PUUV infection were included. Acutely, plasma levels of pentraxin-3 (PTX3), cell-free DNA (cf-DNA), complement components SC5b-9 and C3 and interleukin-6 (IL-6) were recorded as well as platelet ligands and markers of coagulation and fibrinolysis. High values of plasma PTX3 associated with thrombin formation (prothrombin fragments F1+2; r = 0.46, P = 0.05), consumption of platelet ligand fibrinogen (r = -0.70, P < 0.001) and natural anticoagulants antithrombin (AT) (r = -0.74, P < 0.001), protein C (r = -0.77, P < 0.001) and protein S free antigen (r = -0.81, P < 0.001) and a decreased endothelial marker ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 domain 13) (r = -0.48, P = 0.04). Plasma level of AT associated with C3 (r = 0.76, P < 0.001), IL-6 (r = -0.56, P = 0.01) and cf-DNA (r = -0.47, P = 0.04). High cf-DNA coincided with increased prothrombin fragments F1+2 (r = 0.47, P = 0.04). Low C3 levels reflecting the activation of complement system through the alternative route predicted loss of all natural anticoagulants (for protein C r = 0.53, P = 0.03 and for protein S free antigen r = 0.64, P = 0.004). Variables depicting altered coagulation follow the new predictive biomarkers of disease severity, especially PTX3, in acute PUUV infection. The findings are consistent with the previous observations of these biomarkers also being predictive for low platelet count and underline the cross-talk of inflammation and coagulation systems in acute PUUV infection.

Spleen enlargement is a common finding in acute Puumala hantavirus infection and it does not associate with thrombocytopenia.

The pathogenesis of thrombocytopenia in Puumala hantavirus (PUUV) infection is probably multifactorial. We aimed to evaluate the possible spleen enlargement during acute PUUV infection, and to determine its association with thrombocytopenia and disease severity. Magnetic resonance imaging (MRI) of the spleen was performed in 20 patients with acute PUUV infection. MRI was repeated 5-8 months later. The change in spleen length was compared with markers describing the severity of the disease. In all patients, the spleen length was increased in the acute phase compared with the control phase (median 129 mm vs 111 mm, p < 0.001). The change correlated with maximum C-reactive protein value (r = 0.513, p = 0.021) and inversely with maximum leukocyte count (r = -0.471, p = 0.036), but not with maximum serum creatinine level or minimum platelet count. Enlarged spleen, evaluated by MRI, was shown to be a common finding during acute PUUV infection. However, it does not associate with thrombocytopenia and acute kidney injury.

The hanta hunting study: underdiagnosis of Puumala hantavirus infections in symptomatic non-travelling leptospirosis-suspected patients in the Netherlands, in 2010 and April to November 2011.

Leptospirosis and haemorrhagic fever with renal syndrome (HFRS) are hard to distinguish clinically since these two important rodent-borne zoonoses share hallmark symptoms such as renal failure and haemorrhage. Leptospirosis is caused by infection with a spirochete while HFRS is the result of an infection with certain hantaviruses. Both diseases are relatively rare in the Netherlands. Increased incidence of HFRS has been observed since 2007 in countries that border the Netherlands. Since a similar rise in incidence has not been registered in the Netherlands, we hypothesise that due to overlapping clinical manifestations, hantavirus infections may be confused with leptospirosis, leading to underdiagnosis. Therefore, we tested a cohort of non-travelling Dutch patients with symptoms compatible with leptospirosis, but with a negative diagnosis, during 2010 and from April to November 2011. Sera were screened with pan-hantavirus IgG and IgM enzyme-linked immunosorbent assays (ELISAs). Sera with IgM reactivity were tested by immunofluorescence assay (IFA). ELISA (IgM positive) and IFA results were confirmed using focus reduction neutralisation tests (FRNTs). We found hantavirus-specific IgG and/or IgM antibodies in 4.3% (11/255) of samples taken in 2010 and in 4.1% (6/146) of the samples during the 2011 period. After FRNT confirmation, seven patients were classed as having acute Puumala virus infections. A review of hantavirus diagnostic requests revealed that at least three of the seven confirmed acute cases as well as seven probable acute cases of hantavirus infection were missed in the Netherlands during the study period.

Urine soluble urokinase‐type plasminogen activator receptor levels correlate with proteinuria in Puumala hantavirus infection

Urokinase-type plasminogen activator receptor (uPAR) is upregulated during inflammation and known to bind to β3 -integrins, receptors used by pathogenic hantaviruses to enter endothelial cells. It has been proposed that soluble uPAR (suPAR) is a circulating factor that causes focal segmental glomerulosclerosis and proteinuria by activating β3 -integrin in kidney podocytes. Proteinuria is also a characteristic feature of hantavirus infections. The aim of this study was to evaluate the relation between urine suPAR levels and disease severity in acute Puumala hantavirus (PUUV) infection. A single-centre, prospective cohort study. Urinary suPAR levels were measured twice during the acute phase and once during convalescence in 36 patients with serologically confirmed PUUV infection. Fractional excretion of suPAR (FE suPAR) and of albumin (FE alb) was calculated. The FE suPAR was significantly elevated during the acute phase of PUUV infection compared to the convalescent phase (median 3.2%, range 0.8-52.0%, vs. median 1.9%, range 1.0-5.8%, P = 0.005). Maximum FE suPAR was correlated markedly with maximum FE alb (r = 0.812, P < 0.001) and with several other variables that reflect disease severity. There was a positive correlation with the length of hospitalization (r = 0.455, P = 0.009) and maximum plasma creatinine level (r = 0.780, P < 0.001) and an inverse correlation with minimum urinary output (r = -0.411, P = 0.030). There was no correlation between FE suPAR and plasma suPAR (r = 0.180, P = 0.324). Urinary suPAR is markedly increased during acute PUUV infection and is correlated with proteinuria. High urine suPAR level may reflect local production of suPAR in the kidney during the acute infection.

Endothelial activation and repair during hantavirus infection: association with disease outcome.

Background. Endothelial activation and dysfunction play a central role in the pathogenesis of sepsis and viral hemorrhagic fevers. Hantaviral disease is a viral hemorrhagic fever and is characterized by capillary dysfunction, although the underlying mechanisms for hantaviral disease are not fully elucidated.Methods. The temporal course of endothelial activation and repair were analyzed during Puumala hantavirus infection and associated with disease outcome and a marker for hypoxia, insulin-like growth factor binding protein 1 (IGFBP-1). The following endothelial activation markers were studied: endothelial glycocalyx degradation (syndecan-1) and leukocyte adhesion molecules (soluble vascular cellular adhesion molecule 1, intercellular adhesion molecule 1, and endothelial selectin). Cytokines associated with vascular repair were also analyzed (vascular endothelial growth factor, erythropoietin, angiopoietin, and stromal cell-derived factor 1).Results. Most of the markers we studied were highest during the earliest phase of hantaviral disease and associated with clinical and laboratory surrogate markers for disease outcome. In particular, the marker for glycocalyx degradation, syndecan-1, was significantly associated with levels of thrombocytes, albumin, IGFBP-1, decreased blood pressure, and disease severity.Conclusions. Hantaviral disease outcome was associated with endothelial dysfunction. Consequently, the endothelium warrants further investigation when designing future medical interventions.

Increased Serum Kynurenine Level is Associated with Severity of Kidney Injury in Puumala Hantavirus Infection

Background: Nephropathiaepidemica (NE) caused by Puumalahantavirus is a mild type of hemorrhagic fever with renal syndrome (HFRS). An immune-mediated pathogenesis is discussed for NE. Catabolism of tryptophan (Trp) along the kynurenine (Kyn) pathway is dependent on indoleamine 2,3-dioxygenase (IDO), an enzyme whose activity is induced during immune responses. Because viral infections can induce strong immune responses, we wanted to analyse whether there is a correlation between the severity of HFRS and Kyn or Trp serum concentration. Methods: We retrospectively studied 60 patients hospitalised with acute Puumalahantavirus infection during an epidemic in Germany in the year 2012. The infection was confirmed by positive antihantavirus IgG and IgM serum antibody. Plasma levels of Kyn and Trp were measured by mass spectrometry on admission in the hospital. Based on median glomerular filtration rate (GFR 32 mL/min/1.73 m2), patients were divided into two groups: with mild (n=21) and severe disease (n=39). Results: Serum Kyn and Kyn/Trp ratios were significantly higher (p<0.0001) in hantavirus-infected patients than in healthy controls. Patients with severe disease had a longer hospital stay than patients with mild disease (p=0.001) and their serum CRP (p=0.004), Kyn (p<0.001) and Kyn/Trp (p=0.001) ratios were significantly higher than those of patients with mild disease. Sensitivity and specificity, as well as logistic regression analysis showed that among the analysed parameters serum Kyn level was the most sensitive and specific inflammatory marker associated with renal function. Conclusion: High serum Kyn concentrations in patients with NE caused by Puumalahantavirus are associated with a severe course of disease.

Maternal antibodies contribute to sex-based difference in hantavirus transmission dynamics.

Individuals often differ in their ability to transmit disease and identifying key individuals for transmission is a major issue in epidemiology. Male hosts are often thought to be more important than females for parasite transmission and persistence. However, the role of infectious females, particularly the transient immunity provided to offspring through maternal antibodies (MatAbs), has been neglected in discussions about sex-biased infection transmission. We examined the effect of host sex upon infection dynamics of zoonotic Puumala hantavirus (PUUV) in semi-natural, experimental populations of bank vole (Myodes glareolus). Populations were founded with either females or males that were infected with PUUV, whereas the other sex was immunized against PUUV infection. The likelihood of the next generation being infected was lower when the infected founders were females, underlying the putative importance of adult males in PUUV transmission and persistence in host populations. However, we show that this effect probably results from transient immunity that infected females provide to their offspring, rather than any sex-biased transmission efficiency per se. Our study proposes a potential contrasting nature of female and male hosts in the transmission dynamics of hantaviruses.

Regulatory T cell response correlates with the severity of human hantavirus infection

Hantaviruses are an important group of emerging zoonotic pathogens, with significant mortality rates. Immunopathology is thought to be important in hantaviral disease, but the balance between protective and harmful responses is unknown. We studied Puumala hantavirus (PUUV) infection, which causes hemorrhagic fever with renal syndrome (HFRS) with a generally mild but highly variable clinical course. Clinical data and blood samples were collected from 24 patients with acute PUUV infection, and analyzed by flow cytometry and quantitative PCR. The patients had a significantly increased frequency of CD4(+) and CD8(+) cells expressing the cell cycle marker Ki-67, but the magnitude of the effector T cell response did not correlate with disease severity. The frequency of FOXP3(+) regulatory T (Treg) cells expressing Ki-67 was also increased, and likewise did not correlate with disease outcome. In contrast, the level of FOXP3 expression, a surrogate of the suppressive phenotype, had a strong positive correlation with disease severity. This correlation was also found in samples taken 6-12 months after the HFRS. The best predictor of a severe disease course in HFRS was the FOXP3(+) Treg cell response, suggesting that the role of Treg cells in acute human hantaviral infections may be deleterious.

Cardiopulmonary involvement in Puumala hantavirus infection

BackgroundHantavirus infections cause potentially life-threatening disease in humans world-wide. Infections with American hantaviruses may lead to hantavirus pulmonary syndrome characterised by severe cardiopulmonary distress with high mortality. Pulmonary involvement in European Puumala hantavirus (PUUV) infection has been reported, whereas knowledge of potential cardiac manifestations is limited. We aimed to comprehensively investigate cardiopulmonary involvement in patients with PUUV-infection.MethodsTwenty-seven hospitalised patients with PUUV-infection were examined with lung function tests, chest high-resolution CT (HRCT), echocardiography including speckle tracking strain rate analysis, ECG and measurements of cardiac biomarkers N-terminal pro-B-type natriuretic peptide (NT-ProBNP) and troponin T. Patients were re-evaluated after 3 months. Twenty-five age and sex-matched volunteers acted as controls for echocardiography data.ResultsTwo-thirds of the patients experienced respiratory symptoms as dry cough or dyspnoea. Gas diffusing capacity was impaired in most patients, significantly improving at follow-up but still subnormal in 38%. HRCT showed thoracic effusions or pulmonary oedema in 46% of the patients. Compared to controls, the main echocardiographic findings in patients during the acute phase were significantly higher pulmonary vascular resistance, higher systolic pulmonary artery pressure, lower left ventricular ejection fraction and impaired left atrial myocardial motion. Pathological ECG, atrial fibrillation or T-wave changes, was demonstrated in 26% of patients. NT-ProBNP concentrations were markedly increased and were inversely associated with gas diffusing capacity but positively correlated to pulmonary vascular resistance. Furthermore, patients experiencing impaired general condition at follow-up had significantly lower gas diffusing capacity and higher pulmonary vascular resistance, compared to those feeling fully recovered.ConclusionsIn a majority of patients with PUUV-infection, both cardiac and pulmonary involvement was demonstrated with implications on patients’ recovery. The results demonstrate vascular leakage in the lungs that most likely is responsible for impaired gas diffusing capacity and increased pulmonary vascular resistance with secondary pulmonary hypertension and right heart distress. Interestingly, NT-ProBNP was markedly elevated even in the absence of overt ventricular heart failure. The method of simultaneous investigations of important cardiac and respiratory measurements improves the interpretation of the underlying pathophysiologic mechanisms.

Landscape features and helminth co-infection shape bank vole immunoheterogeneity, with consequences for Puumala virus epidemiology

Heterogeneity in environmental conditions helps to maintain genetic and phenotypic diversity in ecosystems. As such, it may explain why the capacity of animals to mount immune responses is highly variable. The quality of habitat patches, in terms of resources, parasitism, predation and habitat fragmentation may, for example, trigger trade-offs ultimately affecting the investment of individuals in various immunological pathways. We described spatial immunoheterogeneity in bank vole populations with respect to landscape features and co-infection. We focused on the consequences of this heterogeneity for the risk of Puumala hantavirus (PUUV) infection. We assessed the expression of the Tnf-α and Mx2 genes and demonstrated a negative correlation between PUUV load and the expression of these immune genes in bank voles. Habitat heterogeneity was partly associated with differences in the expression of these genes. Levels of Mx2 were lower in large forests than in fragmented forests, possibly due to differences in parasite communities. We previously highlighted the positive association between infection with Heligmosomum mixtum and infection with PUUV. We found that Tnf-α was more strongly expressed in voles infected with PUUV than in uninfected voles or in voles co-infected with the nematode H. mixtum and PUUV. H. mixtum may limit the capacity of the vole to develop proinflammatory responses. This effect may increase the risk of PUUV infection and replication in host cells. Overall, our results suggest that close interactions between landscape features, co-infection and immune gene expression may shape PUUV epidemiology.

Plasma Levels of Soluble Urokinase-Type Plasminogen Activator Receptor Associate with the Clinical Severity of Acute Puumala Hantavirus Infection

ObjectivesUrokinase-type plasminogen activator receptor is a multifunctional glycoprotein, the expression of which is increased during inflammation. It is known to bind to β3-integrins, which are elementary for the cellular entry of hantaviruses. Plasma soluble form of the receptor (suPAR) levels were evaluated as a predictor of severe Puumala hantavirus (PUUV) infection and as a possible factor involved in the pathogenesis of the disease.DesignA single-centre prospective cohort study.Subjects and MethodsPlasma suPAR levels were measured twice during the acute phase and once during the convalescence in 97 patients with serologically confirmed acute PUUV infection using a commercial enzyme-linked immunosorbent assay (ELISA).ResultsThe plasma suPAR levels were significantly higher during the acute phase compared to the control values after the hospitalization (median 8.7 ng/ml, range 4.0–18.2 ng/ml vs. median 4.7 ng/ml, range 2.4–12.2 ng/ml, P<0.001). The maximum suPAR levels correlated with several variables reflecting the severity of the disease. There was a positive correlation with maximum leukocyte count (r = 0.475, p<0.001), maximum plasma creatinine concentration (r = 0.378, p<0.001), change in weight during the hospitalization (r = 0.406, p<0.001) and the length of hospitalization (r = 0.325, p = 0.001), and an inverse correlation with minimum platelet count (r = −0.325, p = 0.001) and minimum hematocrit (r = −0.369, p<0.001).ConclusionPlasma suPAR values are markedly increased during acute PUUV infection and associate with the severity of the disease. The overexpression of suPAR possibly activates β3-integrin in PUUV infection, and thus might be involved in the pathogenesis of the disease.

A severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant

A patient with severe capillary leakage syndrome caused by a Puumala hantavirus infection was treated with a single dose of icatibant, a bradykinin receptor antagonist, with a dramatic positive response. We suggest that this drug should be tested in a larger number of patients with severe hantavirus infection.

Human Puumala and Dobrava Hantavirus Infections in the Black Sea Region of Turkey: A Cross-Sectional Study

This study was carried out to better understand the epidemiology of hantaviruses in a province of Turkey (Giresun) where human hantavirus disease has recently been detected. In this cross-sectional study, a total of 626 blood samples from healthy people aged 15 and 84 years old were collected both in urban and rural areas in 2009. The sera were tested by enzyme-linked immunosorbent assay (ELISA), immunoblotting assay, and the focus reduction neutralization test (FRNT). We screened the samples by an ELISA and found that 65/626 samples reacted positively for the presence of hantavirus-reactive immunoglobulin G (IgG). Twenty of the 65 ELISA-positive samples could be confirmed by an immunobloting assay, and the overall seroprevalence was thereby calculated to 3.2% (20/626). The seroprevalence of the people living in wood areas or adobe houses 9/17 (52.9%) was significantly higher than among people living in concrete houses 10/47 (21.3%) (p=0.014). Finally, 3 of the 20 immunoblot-positive sera were confirmed as specific for the Puumala hantavirus serotype by FRNT, 1 serum was confirmed as Dobrava virus-specific, whereas 1 serum was found to be equally reactive to Dobrava and Saaremaa viruses. We will now focus on further investigations of the ecology and epidemiology of hantaviruses in humans and their carrier animals in Turkey, studies that have already been started and will be further intensified.

Elevated Cerebrospinal Fluid Neopterin Concentration Is Associated with Disease Severity in Acute Puumala Hantavirus Infection

Nephropathia epidemica (NE) caused by Puumala hantavirus (PUUV) is the most common hemorrhagic fever with renal syndrome (HFRS) in Europe. The infection activates immunological mechanisms that contribute to the pathogenesis and characteristics of the illness. In this study we measured cerebrospinal fluid (CSF) neopterin concentration from 23 acute-phase NE patients. We collected data on kidney function, markers of tissue permeability, haemodynamic properties, blood cell count, length of hospitalisation, inflammatory parameters, and ophthalmological properties. The neopterin levels were elevated (>5.8 nmol/L) in 22 (96%) NE-patients (mean 45.8 nmol/L); these were especially high in patients with intrathecal PUUV-IgM production (mean 58.2 nmol/L, P = 0.01) and those with elevated CSF protein concentrations (mean 63.6 nmol/L, P < 0.05). We also observed a correlation between the neopterin and high plasma creatinine value (r = 0.66, P = 0.001), low blood thrombocyte count (r = −0.42, P < 0.05), and markedly disturbed refractory properties of an eye (r = 0.47, P < 0.05). Length of hospitalisation correlated with the neopterin (r = 0.42, P < 0.05; male patients r = 0.69, P < 0.01). Patients with signs of tissue oedema and increased permeability also had high neopterin concentrations. These results reinforce the view that PUUV-HFRS is a general infection that affects the central nervous system and the blood-brain barrier.