Nephropathia Epidemica Cases Research Articles

Differential Cytokine Responses and the Clinical Severity of Adult and Pediatric Nephropathia Epidemica.

Nephropathia epidemica (NE), caused by the hantavirus infection, is endemic in Tatarstan Russia. The majority of patients are adults, with infection rarely diagnosed in children. This limited number of pediatric NE cases means there is an inadequate understanding of disease pathogenesis in this age category. Here, we have analyzed clinical and laboratory data in adults and children with NE to establish whether and how the disease severity differs between the two age groups. Serum cytokines were analyzed in samples collected from 11 children and 129 adult NE patients during an outbreak in 2019. A kidney toxicity panel was also used to analyze urine samples from these patients. Additionally, serum and urine samples were analyzed from 11 control children and 26 control adults. Analysis of clinical and laboratory data revealed that NE was milder in children than in adults. A variation in serum cytokine activation could explain the differences in clinical presentation. Cytokines associated with activation of Th1 lymphocytes were prominent in adults, while they were obscured in sera from pediatric NE patients. In addition, a prolonged activation of kidney injury markers was found in adults with NE, whilst only a short-lasting activation of these markers was observed in children with NE. These findings support previous observations of age differences in NE severity, which should be considered when diagnosing the disease in children.

Cytokine, Chemokine, and Metalloprotease Activation in the Serum of Patients with Nephropathia Epidemica from the Republic of Tatarstan and the Republic of Mordovia, Russia.

Nephropathia Epidemica (NE), endemic to several Volga regions of Russia, including the Republic of Tatarstan (RT) and the Republic of Mordovia (RM), is a mild form of hemorrhagic fever with renal syndrome caused by infection with rodent-borne orthohantaviruses. Although NE cases have been reported for decades, little is known about the hantavirus strains associated with human infection in these regions. There is also limited understanding of the pathogenesis of NE in the RT and the RM. To address these knowledge gaps, we conducted comparative analyses of patients with NE in the RT and the RM. Clinical symptoms were more severe in patients with NE from the RM with longer observed duration of fever symptoms and hospitalization. Analysis of patient sera showed changes in the levels of numerous cytokines, chemokines, and matrix metalloproteases (MMPs) in patients with NE from both the RT and the RM, suggesting leukocyte activation, extracellular matrix degradation, and leukocyte chemotaxis. Interestingly, levels of several cytokines were distinctly different between patients NE from the RT when compared with those from the RM. These differences were not related to the genetic variation of orthohantaviruses circulating in those regions, as sequence analysis showed that Puumala virus (PUUV) was the causative agent of NE in these regions. Additionally, only the “Russia” (RUS) genetic lineage of PUUV was detected in the serum samples of patients with NE from both the RT and the RM. We therefore conclude that differences in serum cytokine, chemokine, and MMP levels between the RT and the RM are related to environmental factors and lifestyle differences that influence individual immune responses to orthohantavirus infection.

Isolation and Genetic Characterization of Puumala Orthohantavirus Strains from France.

Puumala orthohantavirus (PUUV) causes a mild form of haemorrhagic fever with renal syndrome (HFRS) called nephropathia epidemica (NE), regularly diagnosed in Europe. France represents the western frontier of the expansion of NE in Europe with two distinct areas: an endemic area (north-eastern France) where PUUV circulates in rodent populations, with the detection of many human NE cases, and a non-endemic area (south-western France) where the virus is not detected, with only a few human cases being reported. In this study, we describe the different stages of the isolation of two PUUV strains from two distinct French geographical areas: Ardennes (endemic area) and Loiret (non-endemic area). To isolate PUUV efficiently, we selected wild bank voles (Myodes glareolus, the specific reservoir of PUUV) captured in these areas and that were seronegative for anti-PUUV IgG (ELISA) but showed a non-negligible viral RNA load in their lung tissue (qRT-PCR). With this study design, we were able to cultivate and maintain these two strains in Vero E6 cells and also propagate both strains in immunologically neutral bank voles efficiently and rapidly. High-throughput and Sanger sequencing results provided a better assessment of the impact of isolation methods on viral diversity.

How Bank Vole-PUUV Interactions Influence the Eco-Evolutionary Processes Driving Nephropathia Epidemica Epidemiology-An Experimental and Genomic Approach.

In Europe, Puumala virus (PUUV) is responsible for nephropathia epidemica (NE), a mild form of hemorrhagic fever with renal syndrome (HFRS). Despite the presence of its reservoir, the bank vole, on most of French territory, the geographic distribution of NE cases is heterogeneous and NE endemic and non-endemic areas have been reported. In this study we analyzed whether bank vole-PUUV interactions could partly shape these epidemiological differences. We performed crossed-experimental infections using wild bank voles from French endemic (Ardennes) and non-endemic (Loiret) areas and two French PUUV strains isolated from these areas. The serological response and dynamics of PUUV infection were compared between the four cross-infection combinations. Due to logistical constraints, this study was based on a small number of animals. Based on this experimental design, we saw a stronger serological response and presence of PUUV in excretory organs (bladder) in bank voles infected with the PUUV endemic strain. Moreover, the within-host viral diversity in excretory organs seemed to be higher than in other non-excretory organs for the NE endemic cross-infection but not for the NE non-endemic cross-infection. Despite the small number of rodents included, our results showed that genetically different PUUV strains and in a lesser extent their interaction with sympatric bank voles, could affect virus replication and diversity. This could impact PUUV excretion/transmission between rodents and to humans and in turn at least partly shape NE epidemiology in France.

Detection and Genetic Characterization of Puumala Orthohantavirus S-Segment in Areas of France Non-Endemic for Nephropathia Epidemica.

Puumala virus (PUUV) in Europe causes nephropathia epidemica (NE), a mild form of hemorrhagic fever with renal syndrome (HFRS). The incidence of NE is highly heterogeneous spatially, whereas the geographic distribution of the wild reservoir of PUUV, the bank vole, is essentially homogeneous. Our understanding of the processes driving this heterogeneity remains incomplete due to gaps in knowledge. Little is known about the current distribution and genetic variation of PUUV in the areas outside the well-identified zones of NE endemicity. We trapped bank voles in four forests in French regions in which NE is considered non-endemic, but sporadic NE cases have been reported recently. We tested bank voles for anti-PUUV IgG and characterized the S segment sequences of PUUV from seropositive animals. Phylogenetic analyses revealed specific amino-acid signatures and genetic differences between PUUV circulating in non-endemic and nearby NE-endemic areas. We also showed, in temporal surveys, that the amino-acid sequences of PUUV had undergone fewer recent changes in areas non-endemic for NE than in endemic areas. The evolutionary history of the current French PUUV clusters was investigated by phylogeographic approaches, and the results were considered in the context of the history of French forests. Our findings highlight the need to monitor the circulation and genetics of PUUV in a larger array of bank vole populations, to improve our understanding of the risk of NE.

Δccr5 Genotype Is Associated with Mild Form of Nephropathia Epidemica.

Nephropathia Epidemica (NE), a mild form of hemorrhagic fever with renal syndrome (HFRS) and linked to hantavirus infection, is endemic in the Republic of Tatarstan. Several genetic markers of HFRS severity have been identified previously, including human leukocyte antigen (HLA) complexes and nucleotide polymorphism in the tumor necrosis factor alpha (TNFα) gene. Still, our understanding of the genetic markers of NE severity remains incomplete. The frequency of the C–C chemokine receptor type 5 (CCR5) gene wild type and gene with 32-base-pair deletion (Δ32CCR5) genotypes in 98 NE samples and 592 controls was analyzed using PCR. Along with the serum levels of 94 analytes, a lack of differences in the CCR5 genotype distribution between NE cases and the general population suggests that the CCR5 genotype does not affect susceptibility to hantavirus infection. However, in NE cases, significant variation in the serum levels of the host matrix metalloproteases between functional CCR5 homozygous and Δ32CCR5 heterozygous patients was detected. Also, the oliguric phase was longer, while thrombocyte counts were lower in functional CCR5 homozygous as compared to heterozygous NE cases. Our data, for the first time, presents the potential role of the CCR5 receptor genotype in NE pathogenesis. Our data suggests that NE pathogenesis in functional CCR5 homozygous and heterozygous NE patients differs, where homozygous cases may have more disintegration of the extracellular matrix and potentially more severe disease.

Genetic Characterization of Small (s)-Segment Genome Puumala Virus Strain Kazan

The Republic of Tatarstan is one of the most active endemic regions for nephropathia epidemica (NE) in the Russian Federation. Annually, over 1000 cases of NE are registered, with an average mortality rate of 0.43 %. NE is a zoonosis where human become infected by inhaling a hantavirus-contaminated aerosol. Puumala virus is commonly detected in NE cases. Although NE cases have been registered in the region since 1958, little is known about the genetic variability of Puumala virus circulating in Tatarstan. We conducted phylogenetic analysis of the full length (1828 nt) small (S) segment genome sequence of Puumala virus RNA isolated from four bank voles (Myodes glareolus) captured during the 2014 outbreak. These virus sequences were compared to known sequences of Puumala viruses from nearby regions such as Samara and the Republic of Bashkortostan, as well as to European isolates. We found that there was over 89 % nucleotide identity between Puumala virus sequences isolated from the bank voles captured in Tatarstan. Sequence identity between Puumala viruses from the Tatarstan bank voles and the sequences from Republic of Bashkortostan and the Samara region were 90–95 %. Less similarity was found between Tatarstan sequences and Puumala strains circulating in Europe (79.7–87.7 %). Taken together, these data suggest that Puumala viruses circulating within the bank vole population in the Republic of Tatarstan are phylogenetically closer to the viruses circulating in neighboring regions of Russia.

Differences in the Serum VEGF Are Not Associated with Differences in Cytokine Isoforms in Nephropathia Epidemica

Nephropathia epidemica (NE) is an acute zoonosis, caused by Puumala virus, belongs to genus Hantavirus. Disturbed hemostasis is characteristic for the NE, where signs of increased vascular permeability and bleeding are described at early stage of the disease. Although pathogenesis of vascular permeability remains unknown, the vascular endothelial growth factor (VEGF) was suggested to play role. There are several isoforms of VEGF based on the alternate splicing of the exon 6 and 7. These isoforms differ in ability to support endothelial cells proliferation and survival. The isoform VEGF165 promotes endothelial cell growth and remodeling, while the isoform VEGF121 lacks such effect. We have found increased level of VEGF in serum from NE cases. The VEGF isoform analysis revealed presence of only VEGF165, while isoform VEGF121 was absent. Therefore, we suggest that VEGF in serum of NE cases function to promote endothelial cells proliferation and vascular remodeling.

Epidemiological dynamics of nephropathia epidemica in the Republic of Tatarstan, Russia, during the period of 1997-2013.

This report summarizes epidemiological data on nephropathia epidemica (NE) in the Republic of Tatarstan, Russia. NE cases identified in the period 1997-2013 were investigated in parallel with the hantavirus antigen prevalence in small rodents in the study area. A total of 13 930 NE cases were documented in all but one district of Tatarstan, with most cases located in the central and southeastern districts. The NE annual incidence rate exhibited a cyclical pattern, with the highest numbers of cases being registered once in every 3-5 years. The numbers of NE cases rose gradually from July to November, with the highest morbidity in adult males. The highest annual disease incidence rate, 64·4 cases/100 000 population, was observed in 1997, with a total of 2431 NE cases registered. NE cases were mostly associated with visiting forests and agricultural activities. The analysis revealed that the bank vole Myodes glareolus not only comprises the majority of the small rodent communities in the region, but also consistently displays the highest hantavirus prevalence compared to other small rodent species.

The importance of bank vole density and rainy winters in predicting nephropathia epidemica incidence in Northern Sweden.

Pathogenic hantaviruses (family Bunyaviridae, genus Hantavirus) are rodent-borne viruses causing hemorrhagic fever with renal syndrome (HFRS) in Eurasia. In Europe, there are more than 10,000 yearly cases of nephropathia epidemica (NE), a mild form of HFRS caused by Puumala virus (PUUV). The common and widely distributed bank vole (Myodes glareolus) is the host of PUUV. In this study, we aim to explain and predict NE incidence in boreal Sweden using bank vole densities. We tested whether the number of rainy days in winter contributed to variation in NE incidence. We forecast NE incidence in July 2013–June 2014 using projected autumn vole density, and then considering two climatic scenarios: 1) rain-free winter and 2) winter with many rainy days. Autumn vole density was a strong explanatory variable of NE incidence in boreal Sweden in 1990–2012 (R2 = 79%, p<0.001). Adding the number of rainy winter days improved the model (R2 = 84%, p<0.05). We report for the first time that risk of NE is higher in winters with many rainy days. Rain on snow and ground icing may block vole access to subnivean space. Seeking refuge from adverse conditions and shelter from predators, voles may infest buildings, increasing infection risk. In a rainy winter scenario, we predicted 812 NE cases in boreal Sweden, triple the number of cases predicted in a rain-free winter in 2013/2014. Our model enables identification of high risk years when preparedness in the public health sector is crucial, as a rainy winter would accentuate risk.

Inflammatory cytokines kinetics define the severity and phase of nephropathia epidemica.

Nephropathia epidemica (NE) is a form of hemorrhagic fever with renal syndrome associated with the Puumala virus species of Hantavirus. The pathogenesis of NE is not well understood; therefore, investigating the inflammatory cytokine response to infection may provide useful knowledge in deciphering the pathophysiology of NE. Using Luminex and ELISA, we analyzed the serum of 137 NE cases and 44 controls to investigate if serum cytokines associate with different clinical presentations. Serum levels of TNF-α and IL-1β are associated with disease severity while upregulation of IL-6, CXCL10, CCL2 and CCL3 are associated with clinical presentation. Inflammatory cytokine kinetics associate with the severity and phase of NE. Our data support a role for inflammatory cytokines in the pathophysiology of NE.

Modelling seasonal and multi-annual variation in bank vole populations and nephropathia epidemica

Nephropathia epidemica (NE) is a human infection caused by Puumala virus (PUUV), which is naturally carried and shed by bank voles (Myodes glareolus). The objective was to develop a dynamic model of the NE cases and the bank vole population in both Finland and Belgium by defining the periodic components with a dynamic harmonic regression (DHR) model. The defined periodic components can be further used to adapt mechanistic Susceptible and Infective (SI) models regionally. Despite the difference in bank vole population dynamics and NE cases between the Western European temperate zone and boreal zones the DHR model was able to quantify the dynamics of NE cases in Belgium and Central Finland with a coefficient of determination (R2) of 0.70 and 0.82 respectively and to quantify the dynamics of bank vole population in Belgium and Central Finland with R2 of 0.80 and 0.98 respectively. DHR identified 18 month cycles in the bank vole population in Belgium. This approach demonstrated two year cycles in Belgian NE outbreaks. DHR identified three year cycles in Finnish bank vole populations which in turn cause three year cycles in the NE outbreaks in Central Finland. Because the bank vole population data in Finland was contemporary with the data of NE cases, the DHR showed a three month delay between the NE cases and the bank vole population in Central Finland. This approach may help us in our understanding of the spatial and temporal dynamics of NE cases and the bank vole populations in different regions.

Model‐Based Prediction of Nephropathia Epidemica Outbreaks Based on Climatological and Vegetation Data and Bank Vole Population Dynamics

Wildlife-originated zoonotic diseases in general are a major contributor to emerging infectious diseases. Hantaviruses more specifically cause thousands of human disease cases annually worldwide, while understanding and predicting human hantavirus epidemics pose numerous unsolved challenges. Nephropathia epidemica (NE) is a human infection caused by Puumala virus, which is naturally carried and shed by bank voles (Myodes glareolus). The objective of this study was to develop a method that allows model-based predicting 3 months ahead of the occurrence of NE epidemics. Two data sets were utilized to develop and test the models. These data sets were concerned with NE cases in Finland and Belgium. In this study, we selected the most relevant inputs from all the available data for use in a dynamic linear regression (DLR) model. The number of NE cases in Finland were modelled using data from 1996 to 2008. The NE cases were predicted based on the time series data of average monthly air temperature (°C) and bank voles' trapping index using a DLR model. The bank voles' trapping index data were interpolated using a related dynamic harmonic regression model (DHR). Here, the DLR and DHR models used time-varying parameters. Both the DHR and DLR models were based on a unified state-space estimation framework. For the Belgium case, no time series of the bank voles' population dynamics were available. Several studies, however, have suggested that the population of bank voles is related to the variation in seed production of beech and oak trees in Northern Europe. Therefore, the NE occurrence pattern in Belgium was predicted based on a DLR model by using remotely sensed phenology parameters of broad-leaved forests, together with the oak and beech seed categories and average monthly air temperature (°C) using data from 2001 to 2009. Our results suggest that even without any knowledge about hantavirus dynamics in the host population, the time variation in NE outbreaks in Finland could be predicted 3 months ahead with a 34% mean relative prediction error (MRPE). This took into account solely the population dynamics of the carrier species (bank voles). The time series analysis also revealed that climate change, as represented by the vegetation index, changes in forest phenology derived from satellite images and directly measured air temperature, may affect the mechanics of NE transmission. NE outbreaks in Belgium were predicted 3 months ahead with a 40% MRPE, based only on the climatological and vegetation data, in this case, without any knowledge of the bank vole's population dynamics. In this research, we demonstrated that NE outbreaks can be predicted using climate and vegetation data or the bank vole's population dynamics, by using dynamic data-based models with time-varying parameters. Such a predictive modelling approach might be used as a step towards the development of new tools for the prevention of future NE outbreaks.

Spatiotemporal dynamics of Puumala hantavirus in suburban reservoir rodent populations

The transmission of pathogens to susceptible hosts is dependent on the vector population dynamics. In Europe, bank voles (Myodes glareolus) carry Puumala hantavirus, which causes nephropathia epidemica (NE) in humans. Fluctuations in bank vole populations and epidemics in humans are correlated but the main factors influencing this relationship remain unclear. In Belgium, more NE cases are reported in spring than in autumn. There is also a higher incidence of human infections during years of large vole populations. This study aimed to better understand the link between virus prevalence in the vector, vole demography, habitat quality, and human infections. Three rodent populations in different habitats bordering Brussels city, Belgium, were studied for two years. The seroprevalence in voles was influenced first by season (higher in spring), then by vole density, vole weight (a proxy for age), and capture site but not by year or sex. Moreover, voles with large maximal distance between two captures had a high probability for Puumala seropositivity. Additionally, the local vole density showed similar temporal variations as the number of NE cases in Belgium. These results showed that, while season was the main factor influencing vole seroprevalence, it was not sufficient to explain human risks. Indeed, vole density and weight, as well as the local habitat, were essential to understanding the interactions in these host-pathogen dynamics. This can, in turn, be of importance for assessing the human risks.

A dynamic data-based model describing nephropathia epidemica in Belgium

Nephropathia epidemica (NE) is a human infection caused by Puumala virus (PUUV), which is naturally carried and shed by bank voles (Myodes glareolus). Population dynamics and infectious diseases in general, such as NE, have often been modelled with mechanistic SIR (Susceptible, Infective and Remove with immunity) models. Precipitation and temperature have been found to be indicators of NE, however most SIR models do not take them into account. The objective of this paper was to develop a dynamic model of incidences of NE in Belgium by taking into account climatological data. A multiple–input, single-output (MISO) transfer function was used to model the incidence of NE. In a first step, the NE cases were modelled based on data from 1996 until 2003 with an R T 2 of 0.68. In the next step the MISO model was validated for incidences of NE in Belgium from 2003 to 2008 ( R T 2 of 0.54). The output of the MISO models was the number of NE cases in Belgium over the time period 1996 until 2008 and the inputs were average measured monthly precipitation (mm), and temperature (°C) as well as estimated carrying capacity (vole ha−1). The monthly values of carrying capacity (K) were estimated for the whole period by using an existing mechanistic SIR model. K is related to the variation in seed production in Northern Europe, which has an effect on the population of bank voles. In the future, such modelling approaches may be used to predict and monitor forthcoming NE cases based on climate and vegetation data as a tool for prevention of NE cases.

Satellite Derived Forest Phenology and Its Relation with Nephropathia Epidemica in Belgium

The connection between nephropathia epidemica (NE) and vegetation dynamics has been emphasized in recent studies. Changing climate has been suggested as a triggering factor of recently observed epidemiologic peaks in reported NE cases. We have investigated whether there is a connection between the NE occurrence pattern in Belgium and specific trends in remotely sensed phenology parameters of broad-leaved forests. The analysis of time series of the MODIS Enhanced Vegetation Index revealed that changes in forest phenology, considered in literature as an effect of climate change, may affect the mechanics of NE transmission.

Hantavirus outbreak in Western Europe: reservoir host infection dynamics related to human disease patterns

Within Europe, Puumala virus (PUUV) is the causal agent of nephropathia epidemica (NE) in humans, a zoonotic disease with increasing significance in recent years. In a region of Belgium with a historically high incidence of NE, bank voles (the PUUV reservoir hosts), were monitored for PUUV IgG antibody prevalence in nine study sites before, during, and after the highest NE outbreak recorded in Belgium in 2005. We found that the highest numbers of PUUV IgG-positive voles coincided with the peak of NE cases at the regional level, indicating that a PUUV epizootic in bank voles directly led to the NE outbreak in humans. On a local scale, PUUV infection in voles was patchy and not correlated to NE incidence before the epizootic. However, during the epizootic period PUUV infection spread in the vole populations and was significantly correlated to local NE incidence. Initially, local bank-vole numbers were positively associated with local PUUV infection risk in voles, but this was no longer the case after the homogeneous spreading of PUUV during the PUUV outbreak.

Puumala virus reference strain for hantavirus serodiagnosis in France

Dear Editor, We read with great interest the paper of C. Strady et al. on leptospirosis and nephropathia epidemica (NE) in NorthEastern-France [1]. Herein, and as questioned already before [2], the authors refer once more to the French Institut Pasteur Humain or IPH strain 90-13 for screening Puumala virus (PUUV)-induced NE cases in France with IFA and/or ELISA. Isolation of this strain, announced as the first human PUUV isolate in France and in West-Europe, was published in 1995, and complete sequencing of its medium (M) RNA segment, respectively small (S) RNA segment was introduced in GenBank under respective accession numbers U22418 and U 22423 [3]. From the moment of its reported isolation in 1990, IPH 90-13 was acknowledged being more sensitive than other, nonautochthonous PUUV strains for picking up local French NE cases in IFA format [4]. However, a remarkable similarity was noted with CH 13891, a Belgian rodent strain already in use [4]. CH 13891 had been sent in 1987 by one of us (G vd G) to Pasteur Institute, Paris, in the frame of a Franco-Belgian collaboration to study emerging NE, and had been used successfully since then for serodiagnosing French NE cases, likewise in an IFA format [5]. This strain had been isolated in 1985 from a bank vole captured in the early ‘80s around Turnhout, North-Belgium [6], thus constituting in fact the earliest West-European PUUV isolate, available one year after Sotkamo, the prototype PUUV strain from Finland, and Hallnas from Sweden, both isolated in 1984. Moreover, the very first (1983) Belgian NE cases had been already serodiagnosed in IFA with this antigen, then called “Turnhout HFRS antigen” [7]. However, and as with so many other early hantavirus isolates (including also the Finnish Sotkamo) from the ‘80s pioneer times, CG 13891 was introduced in GenBank only years after a first characterisation, in this case finally in 1999. The Belgian rodent strain, isolated 5 years prior to the putative French human strain, appeared to have a 100% identical S and M RNA sequence pattern. The French and American authors of the original IPH 90-13 report concluded duly that a contamination with the Belgian CG 13891 had occurred earlier in the Paris lab, and published two successive Errata [8, 9]. They also corrected the GenBank situation, re-stating under accession numbers U22418 and U 22423 that “Sequence entry was originally reported as strain 90-13, but later found to be a laboratory contamination of strain CG 13891”. Nevertheless, many French clinicians and even serological labs continue nowadays to use the IPH 90-13 denomination for their serological diagnosis, thus referring in fact to a strain that is proven since 1999 to be non-existent [2]. In summary, and as confirmed again in the current study [1], the Paris and subsequently the Lyon reference labs for hemorrhagic fevers have been using from 1987 on CG 13891 in an IFA format, before adding from 2000 on an ELISA format, and later even a recombinant ELISA form, all derived from the same Belgian strain. In a technical paper describing the J. Clement (*) : P. Maes :M. Van Ranst Hantavirus Reference Centre, Laboratory of Clinical Virology & Rega Institute for Medical Research, University of Leuven, U.Z. Gasthuisberg, Herestraat, 49, B-3000 Leuven, Belgium e-mail: jan.clement@uzleuven.be

Risk Factors for Human Infection with Puumala Virus, Southwestern Germany

Puumala virus, which causes nephropathia epidemica (NE), is the most prevalent hantavirus in Germany; bank voles serve as the main reservoir. During 2001-2007, most NE cases reported from Germany occurred in the southwestern state of Baden-Württemberg. We investigated the influence of bank vole habitats (beech forest, seed plants), vole food supply (beechnut mast), climate factors (winter and spring temperatures), and human population density on spatial and temporal occurrence of NE cases in Baden-Württemberg. Using Poisson-regression analyses, we found that all these factors influenced disease incidence. Furthermore, an independent trend of increasing incidence predicted that incidence will nearly double each year. The regression model explained 75% of the annual variation in NE incidence. The results suggest that environmental drivers lead to increasing incidence of NE infections in the southern part or even other parts of Germany.

Cyclic hantavirus epidemics in humans — Predicted by rodent host dynamics

Wildlife-originated zoonotic diseases are a major contributor to emerging infectious diseases. Hantaviruses cause thousands of human disease cases annually worldwide, and understanding and predicting human hantavirus epidemics still poses unsolved challenges. Here we studied the three-level relationships between the human disease nephropathia epidemica (NE), its etiological agent Puumala hantavirus (PUUV) and the rodent host of the virus, the bank vole ( Myodes glareolus). A large and long-term data set (14 years, 2583 human NE cases and 4751 trapped bank voles) indicates that the number of human infections shows both seasonal and multi-annual fluctuations, is influenced by the phase of vole cycle and time of the year, and follows vole abundance with a lag of a few months. Our results suggest that although human hantavirus epidemics are preceded by high sero prevalence in the host population, they may be accurately predicted solely by the population dynamics of the carrier species, even without any knowledge about hantavirus dynamics in the host populations.