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We report molecular evidence of Tula virus infection in an immunocompetent patient from Germany who had typical signs of hantavirus disease. Accumulating evidence indicates that Tula virus infection, although often considered nonpathogenic, represents a threat to human health. [ABSTRACT FROM AUTHOR]

Background: Hantavirus disease is a zoonosis of increasing clinical importance. A new incidence peak was reached in Germany in 2012, with more than 2800 reported cases. These viruses are transmitted from small mammals to human beings. The disease begins with high fever and non-pathognomonic manifestations that can end in shock and organ failure. Methods: This article is based on a selective literature search, on the authors' experiences at the National Referral Laboratory for Hantavirus Infections (Nationales Konsiliarlaboratorium für Hantaviren), and on published recommendations from Germany and abroad. Results: Two hantavirus species cause clinically relevant infections in Germany. Puumala virus, which is transmitted by bank voles, causes large outbreaks of disease every 2 to 3 years in the southwestern and western regions of Germany and in the Bavarian Forest. Dobrava-Belgrad virus, transmitted by striped field mice, causes infections in the north and east of the country. Serological tests are available for primary and confirmatory diagnosis; moreover, viral nucleic acids can be amplified in the early phase of illness and compared with the viral nucleic acids from the reservoir hosts of the corresponding type of infection. Infections with American types of hantavirus have ca. 35% case fatality, and hantaviruses from southeastern Europe and Asia are also highly pathogenic; in contrast, the febrile illnesses caused by hantaviruses in Germany are usually relatively mild. Conclusion: When persons living in high-risk areas present with fever of unknown origin or with renal dysfunction of unknown origin, physicians should consider the possibility of a hantavirus infection and should initiate the appropriate diagnostic evaluation. [ABSTRACT FROM AUTHOR]

Background: Dobrava-Belgrade virus (DOBV) is a European hantavirus causing hemorrhagic fever with renal syndrome (HFRS) in humans with fatality rates of up to 12%. DOBV-associated clinical cases typically occur also in the northern part of Germany where the virus is carried by the striped field mouse (Apodemus agrarius). However, the causative agent responsible for human illness has not been previously isolated. Methodology/Principal Findings: Here we report on characterization of a novel cell culture isolate from Germany obtained from a lung tissue of "spillover" infected yellow necked mouse (A. flavicollis) trapped near the city of Greifswald. Phylogenetic analyses demonstrated close clustering of the new strain, designated Greifswald/Aa (GRW/Aa) with the nucleotide sequence obtained from a northern German HFRS patient. The virus was effectively blocked by specific antibodies directed against β3 integrins and Decay Accelerating Factor (DAF) indicating that the virus uses same receptors as the highly pathogenic Hantaan virus (HTNV). In addition, activation of selected innate immunity markers as interferon β and λ and antiviral protein MxA after viral infection of A549 cells was investigated and showed that the virus modulates the first-line antiviral response in a similar way as HTNV. Conclusions/Significance: In summary, our study reveals novel data on DOBV receptor usage and innate immunity induction in relationship to virus pathogenicity and underlines the potency of German DOBV strains to act as human pathogen. [ABSTRACT FROM AUTHOR]

Patients infected with human immunodeficiency virus type 1 (HIV-1) are considered to be at increased risk for 2009 H1N1 influenza-related complications.We performed an observational study after an outbreak of 2009 H1N1 influenza virus infection among a group of 15 HIV-1-infected schoolaged children in Germany in October 2009. Clinical course, kinetics of viral shedding, and antibody response among children with CD4 cell counts >350 cells/μL and 2009 H1N1 influenza virus coinfection did not appear to differ from that among healthy children. Oseltamivir shortened the duration of viral shedding. [ABSTRACT FROM AUTHOR]

We present the molecular identification of Apodemus agrarius (striped field mouse) as reservoir host of the Dobrava-Belgrade virus (DOBV) lineage DOBV-Aa in 3 federal states of Germany. Phylogenetic analyses provided evidence for multiple spillover of DOBV-Aa to A. flavicollis, a crucial prerequisite for host switch and genetic reassortment. [ABSTRACT FROM AUTHOR]

A cluster of 3 persons in Germany experienced hantavirus disease with renal insufficiency. Reverse transcription PCR-based genotyping revealed infection by Seoul hantavirus transmitted from pet rats. Seoul virus could be responsible for disease clusters in Europe, and infected pet rats should be considered a health threat.

In addition to the well-known clinical early symptoms of hantavirus disease (fever, flank and abdominal pain as well as arthralgia), unusual neurological changes in the context of infection come into focus. The spectrum of neurological symptoms ranges from transient myopia to severe pareses in the context of Guillain-Barré syndrome. In endemic areas, rapid IgM tests for initial assessment are of certain value for differential diagnosis. For therapeutic approaches, only supportive measures up to transient dialysis are available.Molecular genetic analysis and comparison of hantavirus strains of patients and mice from the same geographical area allowed molecular characterization of different outbreak regions. In the meantime, the Puumala viruses of the main outbreak regions in Germany are molecularly well characterized; therefore, the nucleotide sequence of the virus strain detected in a patient makes it possible to draw conclusions about the geographic region where the patient's infection took place.The human pathogenic hantaviruses being prevalent in Germany are the Puumala virus (reservoir: bank vole) and the Dobrava-Belgrade virus, genotype Kurkino (reservoir: striped field mouse). Recently, the molecular detection of further hantaviruses in patients with hantavirus disease was achieved. It can be concluded that also the Seoul virus (reservoir: rats) and the Tulavirus (reservoir: field mouse and related species) occasionally cause hantavirus disease in Germany.New results revealed that human infections can occur not only by the generally accepted route of inhalation of virus-containing aerosols, but also by ingestion of virus-containing materials.For patients with hantavirus infection or disease, it can be assumed that they are not infectious for their environment. A new systematic review could not confirm a human-to-human transmission previously postulated for South American hantaviruses.While all known human pathogenic hantaviruses are transmitted by rodents, other hantaviruses have been recently detected in shrews, moles, and bats. The clinical significance of these new viruses is quite unclear as yet., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

IntroductionTwo hantavirus species, Puumala (PUUV) and Dobrava-Belgrade (DOBV) virus (genotype Kurkino), are endemic in Germany. Recent PUUV outbreaks raised questions concerning increasing frequency of outbreaks and expansion of PUUV endemic areas.AimsTo describe the epidemiology of human PUUV and DOBV infections in Germany.MethodsWe conducted an observational retrospective study analysing national hantavirus surveillance data notified to the national public health institute and hantavirus nucleotide sequences from patients collected at the national consultation laboratory between 2001 and 2017. Matching molecular sequences with surveillance data, we conducted epidemiological, phylogenetic and phylogeographic analyses.ResultsIn total, 12,148 cases of symptomatic hantavirus infection were notified 2001-17 (mean annual incidence: 0.87/100,000; range: 0.09-3.51). PUUV infections showed a highly variable space-time disease incidence pattern, causing large outbreaks every 2-3 years with peaks in early summer and up to 3,000 annually reported cases. Sex-specific differences in disease presentation were observed. Of 202 PUUV nucleotide sequences obtained from cases, 189 (93.6%) fall into well-supported phylogenetic clusters corresponding to different endemic areas in Germany. DOBV infections caused few, mostly sporadic cases in autumn and winter in the north and east of Germany.ConclusionsThe frequency of PUUV outbreaks increased between 2001 and 2017 but our data does not support the suggested expansion of endemic areas. The epidemiology of PUUV and DOBV-Kurkino infections differs in several aspects. Moreover, the latter are relatively rare and combining efforts and data of several countries to identify risk factors and develop specific recommendations for prevention could be worthwhile.

Hantaviruses are so-called "emerging" and "re-emerging" viruses because of the new and sudden nature of their appearance. Human infections can lead to two distinct disease patterns, the Haemorrhagic Fever with Renal Syndrome and the Hantavirus Cardiopulmonary Syndrome. All known human pathogenic hantaviruses are transmitted through rodent hosts. There are three rodent-associated hantaviruses in Germany. The bank vole-associated Puumala virus (PUUV) is responsible for most of the human hantavirus infections. The Dobrava-Belgrade virus (DOBV) associated with the striped field mouse is causing hantavirus disease in the North and Northeast of Germany. The human pathogenicity of Tula virus (TULV) is still controversially discussed--the virus has been mainly associated with the common vole as the reservoir, but was molecularly detected also in the field and the water vole. More recently, two shrew-borne hantaviruses were described in Germany, i. e. Seewis virus in the common shrew and Asikkala virus in the pygmy shrew. Systematic studies about hantavirus infections of zoo, pet, companion and farm animals are still lacking. Hence, the aim of this review article is to summarise the current knowledge on this topic and raise the attention of veterinarians to potentially overlooked clinical disease patterns.

For a long time hantaviruses were believed to be exclusively rodent-borne pathogens. Recent findings of numerous shrew- and mole-borne hantaviruses raise important questions on their phylogenetic origin. The objective of our study was to prove the presence and distribution of shrew-associated Seewis virus (SWSV) in different Sorex species in Central Europe. Therefore, a total of 353 Sorex araneus, 59 S. minutus, 27 S. coronatus, and one S. alpinus were collected in Germany, the Czech Republic, and Slovakia. Screening by hantavirus-specific L-segment RT-PCR revealed specific amplification products in tissues of 49 out of 353 S. araneus and four out of 59 S. minutus. S-segment sequences were obtained for 45 of the L-segment positive S. araneus and all four L-segment positive S. minutus. Phylogenetic investigation of these sequences from Germany, the Czech Republic, and Slovakia demonstrated their similarity to SWSV sequences from Hungary, Finland, Austria, and other sites in Germany. The low intra-cluster sequence variability and the high inter-cluster divergence suggest a long-term SWSV evolution in isolated Sorex populations. In 28 of the 49 SWSV S-segment sequences, an additional putative open reading frame (ORF) on the opposite strand to the nucleocapsid protein-encoding ORF was identified. This is the first comprehensive sequence analysis of SWSV strains from Germany, the Czech Republic, and Slovakia, indicating its broad geographical distribution and high genetic divergence. Future studies have to prove whether both S. araneus and S. minutus represent SWSV reservoir hosts or spillover infections are responsible for the parallel molecular detection of SWSV in both species.

Highly endemic and outbreak regions for human hantavirus infections are located in the southern, southeastern, and western parts of Germany. The dominant hantavirus is the bank vole transmitted Puumala virus (PUUV). In the eastern part of Germany, previous investigations revealed Tula virus (TULV) and Dobrava-Belgrade virus (DOBV) infections in the respective rodent reservoirs. Here, we describe a seroprevalence study in forestry workers from Brandenburg, eastern Germany, using IgG ELISA and immunoblot tests based on recombinant TULV, DOBV, and PUUV antigens. Out of the 563 sera tested, 499 from male and 64 from female workers, we found 41 out of the 499 (8.2%) sera from men (mean age 47 years) and 10 out of 64 (15.6%) from the women (mean age 48 years) anti-hantavirus-positive. The majority of the 51 seropositive samples reacted exclusively in the TULV (n=22) and DOBV tests (n=17). Focus reduction neutralization assay investigations on selected sera confirmed the presence of TULV- and DOBV-specific antibodies in the forestry workers. These investigations demonstrated a potential health threat for forestry workers and also the average population in non-endemic geographical regions where TULV and DOBV are circulating in the corresponding reservoir hosts. The infections in this region might be frequently overlooked due to their unspecific and mild symptoms., (© Springer-Verlag 2011)

Hepatitis A virus (HAV) infection is rarely fatal except in patients with chronic liver disease. In the case reported here, an elderly women died of HAV infection 12 years after incomplete HAV vaccination. The possible role of a concordant Rift Valley fever virus infection acquired in Kenya is discussed.

In Europe, hemorrhagic fever with renal syndrome results mainly from infection with Puumala virus (PUUV) or Dobrava virus. For 31 patients from a hantavirus disease outbreak in Lower Bavaria, a district in southeast Germany, serodiagnosis was undertaken by enzyme-linked immunosorbent assay, immunofluorescence assay, and immunoblot analysis. In a few of these cases, however, PUUV-specific typing of antibodies by these standard assays failed and a virus neutralization assay under biosafety level 3 conditions was required to verify the infection by this virus type. PUUV RNA was amplified by reverse transcription-PCR from acute-phase sera of three patients and was found to be very closely related to virus sequences obtained from bank voles (Clethrionomys glareolus) trapped in the same area. These findings link the outbreak with a novel PUUV lineage, "Bavaria," circulating in the local rodent population. The Bavaria lineage associated with the outbreak is only distantly related to other PUUV lineages from Germany.

Viral RNA was amplified by reverse transcription-PCR from a patient suffering from hemorrhagic fever with renal syndrome (HFRS) in Germany. The virus strain could be assigned to the Dobrava hantavirus (DOBV). This is the first molecular identification of human infection by DOBV in central Europe and the first proof that a virus strain related to the DOBV-Aa lineage, carried by Apodemus agrarius rodents, is able to cause HFRS.

Hantavirus species Tula (TULV) is carried by European common voles (Microtus spp.). Its pathogenic potential for humans is unknown. In a rural region of northeast Germany, a 43-year-old man became ill with fever, renal syndrome, and pneumonia. Typing of late acute- and convalescent-phase sera by focus reduction neutralization assay revealed the presence of neutralizing antibodies against TULV. Moreover, we detected TULV genetic material in Microtus arvalis animals that were trapped at places only a few kilometers from the home village of the patient. Phylogenetic analysis of completely sequenced genomic S segments from three virus strains grouped them within a third genetic lineage of the TULV species. This is the first case of hemorrhagic fever with renal syndrome and pulmonary involvement which can be associated with TULV infection.