Hantavirus Infections among Military Forces.

INTRODUCTION: Hantaviruses cause two kinds of clinical syndromes. Hemorrhagic fever with renal syndrome is caused by Hantaan virus in Asia, Puumala virus (PUUV) and Dobrava virus in Europe, and Seoul virus worldwide. Hantavirus cardiopulmonary syndrome is caused by Sin Nombre virus in North America and Andes virus and related viruses in Latin America. All hantaviruses are carried by rodents and insectivores. Humans are infected via inhaled aerosols of rodent excreta. In the history, there are several epidemics of acute infectious diseases during many wars, which have been suggested or proven to be caused by various hantaviruses. MATERIALS AND METHODS: Literature review of 41 original publications and reviews published between 1943 and 2022 was performed. Among them, 23 publications handle hantavirus infections among military forces, and the rest 17 hantavirus infections themselves. RESULTS: A large epidemic during World War II in 1942 among German and Finnish soldiers in Northern Finland with more than 1,000 patients was most probably caused by PUUV. During Korean War in 1951-1954,∼ 3,200 cases occurred among United Nations soldiers in an epidemic caused by Hantaan virus. During Balkan war from 1991 to 1995, numerous soldiers got ill because of hantavirus infection caused by PUUV and Dobrava virus. Several other reports of cases of various hantavirus infections especially among U.S. soldiers acting in South Korea, Germany, Bosnia, and Kosovo have been described in the literature. CONCLUSIONS: Military maneuvers usually include soil removal, spreading, digging with accompanied dust, and living in field and other harsh conditions, which easily expose soldiers to rodents and their excreta. Therefore, the risks of hantavirus infections in military context are obvious. All military infections have been caused by hantaviruses leading to hemorrhagic fever with renal syndrome.

Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis.

Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%, p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-λ and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses.

Avaliação da infecção por Hantavirus em amostras humanas e de roedores silvestres e sinantrópicos no Estado do Rio de Janeiro / Assessment for hantavirus infection in human specimens and wild and synanthropic rodents in Rio de Janeiro

A síndrome pulmonar por hantavírus (SPH) tem sido registrada no Brasil desde1993 e a transmissão para o homem ocorre através da inalação de partículas viraispresentes em aerossóis de excretas de roedores infectados. No Brasil, nove genótiposvirais caracterizados a partir de roedores e/ou humanos foram descritos, sendo seiscomprovadamente patogênicos. Desde os primeiros registros, mais de 1600 casoshumanos foram confirmados, com ampla distribuição entre a maioria dos estadosbrasileiros e alta taxa de letalidade. A SPH apresenta-se como doença febril agudacaracterizada pelo grave comprometimento cardiovascular e respiratório. Os pacientespodem exibir uma ampla variedade de manifestações clínicas, onde os sinais e sintomaspodem ser confundidos com os de outras doenças. Assim é necessário o diagnósticodiferencial separando casos de SPH de outros agravos com manifestações clínicassemelhantes, como é o caso da dengue. Embora não existam relatos de casos humanosno estado do Rio de Janeiro, foram encontradas evidências sorológicas em humanos econfirmação de circulação de hantavírus patogênico entre roedores silvestres, maisespecificamente, na espécie Oligoryzomys nigripes, no Parque Nacional da Serra dosÓrgãos, em Teresópolis. Neste cenário, este estudo teve como objetivos avaliar ainfecção por hantavírus em amostras humanas e em amostras de roedores silvestres esinantrópicos provenientes de diversos municípios fluminenses. Um total de 497amostras de soro de pacientes negativos para dengue pelos testes sorológicos, cedidaspelo LACEN/RJ, provenientes de 25 municípios, e de 235 amostras de roedoresprovenientes de sete municípios, foram analisadas através do ensaio imunoenzimáticopara detecção de anticorpos anti-hantavírus da classe IgM e IgG (ELISA IgM e IgG) ede testes moleculares...

Hantavirus pulmonary syndrome (HPS) has been registered in Brazil since 1993and transmission to humans occurs through inhalation of viral particles present inaerosols from excreta of infected rodents. In Brazil, nine viral genotypes characterizedfrom rodents and/or humans have been described, six of them pathogenic. Over 1.600human cases were confirmed, with wide distribution among most Brazilian states andhigh lethality. Hantavirus pulmonary syndrome presents as an acute febrile illnesscharacterized by severe cardiovascular and respiratory compromise. Patients mayexhibit a wide variety of clinical manifestations, where signs and symptoms can beconfused with other diseases. Thus the differential diagnosis of HPS is necessary fromother illnesses with similar clinical manifestations, such as dengue. There are no reportsof human cases in Rio de Janeiro state, until now, but serologic evidence in humans andconfirmation of circulating pathogenic hantavirus among wild rodents in ParqueNacional da Serra dos Órgãos in Teresopolis, related to the rodent Oligoryzomysnigripes were found. In this scenario, this study aimed to evaluate hantavirus infectionin human, wild and synanthropic rodents samples from different municipalities in Riode Janeiro state. Serum samples from 497 dengue fever seronegative patients, from 25municipalities provided by the LACEN/RJ, and 235 serum samples from rodents, fromseven municipalities, were analyzed by enzyme-linked immunosorbent assay fordetection of anti-hantavirus antibodies of IgM and IgG (IgM and IgG ELISA) andmolecular tests. Five human samples, from Valença, Vassouras and Nova Friburgomunicipalities, presented IgM antibodies against hantavirus...

Hantavirus infection in North America: a clinical review.

The recent outbreak of hantavirus in Yosemite National Park has attracted national attention, with 10 confirmed cases of hantavirus cardiopulmonary syndrome and thousands of more people exposed. This article will review the epidemiology, presentation, workup, and treatment for this rare but potentially lethal illness. The possibility of infection with hantavirus deserves consideration in patients with severe respiratory symptoms with rodent exposure or rural/wilderness travel. Accurate diagnosis requires a high index of suspicion. Hantavirus cardiopulmonary syndrome presents as a vague prodrome of fever, cough, myalgias, chills, and nausea followed by a rapidly worsening respiratory phase. Presumptive diagnosis can be made based on pulmonary interstitial edema on chest radiographs in association with leukocytosis, thrombocytopenia, and hemoconcentration. Suspected cases should be confirmed with a reference laboratory and reported to the appropriate public health authorities. Although treatment is primarily supportive, aggressive fluid administration should be avoided due to the risk of pulmonary edema. The cardiopulmonary phase of the disease can progress rapidly with catastrophic decompensation in as little as a few hours. Patients require rapid intensive care unit admission for monitoring, mechanical ventilation, vasoactive agents, and possibly extracorporeal mechanical ventilation. Emergency physicians should be aware of outbreaks and vigilant for hantavirus exposures, especially during the summer and early fall months.

[Hantavirus diseases]. / Malattie da Hantavirus.

Hantaviruses are emerging viruses that cause persistent chronic infections in their small mammal hosts. When these viruses are transmitted to humans, they can cause two clinical syndromes, hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). The understanding of the epidemiology, pathogenesis and natural history of these viruses has improved in recent years. The number of reported hantavirus infections is increasing worldwide and new hantaviruses are being discovered in many countries, so they now represent a public health problem of global concern. It is believed that hantavirus infections might be underestimated due to the frequently asymptomatic and nonspecific mild infections they cause as well as the lack of simple standardized diagnostic laboratory methods. In this review the current concepts regarding the epidemiology, ecology, clinical presentation, pathogenesis, diagnosis, and treatment of the infections associated with these emerging human pathogens are presented.

Human pathogenic hantaviruses and prevention of infection.

Hantaviruses are emerging viruses which are hosted by small mammals. When transmitted to humans, they can cause two clinical syndromes, hemorrhagic fever with renal syndrome or hantavirus cardiopulmonary syndrome. The review compiles the current list of hantaviruses which are thought to be pathogenic in humans on the basis of molecular or at least serological evidence. Whereas induction of a neutralizing humoral immune response is considered to be protective against infection, the dual role of cellular immunity (protection versus immunopathogenicity) is discussed. For active immunisation, inactivated virus vaccines are licensed in certain Asian countries. Moreover, several classical and molecular vaccine approaches are in pre-clinical stages of development. The development of hantavirus vaccines is hampered by the lack of adequate animal models of hantavirus-associated disease. In addition to active immunization strategies, the review summarizes other ways of infection prevention, as passive immunization, chemoprophylaxis, and exposition prophylaxis.

Hantaviruses.

Hantaviruses affect people worldwide, yet they remain poorly understood. This article explores the known history of hantaviruses. It describes diagnostic methods and potential options for treatment and prevention.

Steep rise in notified hantavirus infections in Germany, April 2010.

From January to April 2010, 396 hantavirus infections were notified in Germany, a considerable increase compared with previous years (mean: 83 for January-April 2004-2009) including the record-setting year, 2007 (n=232 January-April). Most patients are residents of known Puumala virus endemic areas in southern Germany. The recent increase in notified hantavirus infections is probably due to an increased population density of the main animal reservoir, the bank vole (Myodes glareolus).

Seoul virus suppresses NF-kappaB-mediated inflammatory responses of antigen presenting cells from Norway rats.

Hantavirus infection reduces antiviral defenses, increases regulatory responses, and causes persistent infection in rodent hosts. To address whether hantaviruses alter the maturation and functional activity of antigen presenting cells (APCs), rat bone marrow-derived dendritic cells (BMDCs) and macrophages (BMDMs) were generated and infected with Seoul virus (SEOV) or stimulated with TLR ligands. SEOV infected both DCs and macrophages, but copies of viral RNA, viral antigen, and infectious virus titers were higher in macrophages. The expression of MHCII and CD80, production of IL-6, IL-10, and TNF-alpha, and expression of Ifnbeta were attenuated in SEOV-infected APCs. Stimulation of APCs with poly I:C prior to SEOV infection increased the expression of activation markers and production of inflammatory cytokines and suppressed SEOV replication. Infection of APCs with SEOV suppressed LPS-induced activation and innate immune responses. Hantaviruses reduce the innate immune response potential of APCs derived from a natural host, which may influence persistence of these zoonotic viruses in the environment.

Hantavirus regulation of endothelial cell functions.

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.

An outbreak caused by hantavirus in the Black Sea region of Turkey, January-May 2009.

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.

Regulation of rodent-borne viruses in the natural host: implications for human disease.

Prevalence and transmission rates of rodent-borne viruses within host populations vary in time and space and among host-virus systems. Improving our understanding of the causes of these variations will lead to a better understanding of changes in disease risk to humans. The regulators of prevalence and transmission can be categorized into five major classes: (1) Environmental regulators such as weather and food supply affect transmission rates through their effect on reproductive success and population densities. (2) Anthropogenic factors, such as disturbance, may lead to ecosystem simplification and decreased diversity. These changes favor opportunistic species, which may serve as reservoirs for zoonotic viruses. (3) Genetic factors influence susceptibility of mice to infection or capacity for chronic shedding and may be related to population cycling. (4) Behavioral factors, such as fighting, increase risk of transmission of some viruses and result in different patterns of infection between male and female mice. Communal nesting may result in overwinter transmission in colder climates. (5) Physiologic factors control host response to infection and length of time the host remains infectious. Risk prediction is difficult because these regulators are numerous and often interact, and the relative importance of each varies according to the host species, season, year, and geographic location.

New ecological aspects of hantavirus infection: a change of a paradigm and a challenge of prevention--a review.

In the last decades a significant number of so far unknown or underestimated pathogens have emerged as fundamental health hazards of the human population despite intensive research and exceptional efforts of modern medicine to embank and eradicate infectious diseases. Almost all incidents caused by such emerging pathogens could be ascribed to agents that are zoonotic or expanded their host range and crossed species barriers. Many different factors influence the status of a pathogen to remain unnoticed or evolves into a worldwide threat. The ability of an infectious agent to adapt to changing environmental conditions and variations in human behavior, population development, nutrition, education, social, and health status are relevant factors affecting the correlation between pathogen and host. Hantaviruses belong to the emerging pathogens having gained more and more attention in the last decades. These viruses are members of the family Bunyaviridae and are grouped into a separate genus known as Hantavirus. The serotypes Hantaan (HTN), Seoul (SEO), Puumala (PUU), and Dobrava (DOB) virus predominantly cause hemorrhagic fever with renal syndrome (HFRS), a disease characterized by renal failure, hemorrhages, and shock. In the recent past, many hantavirus isolates have been identified and classified in hitherto unaffected geographic regions in the New World (North, Middle, and South America) with characteristic features affecting the lungs of infected individuals and causing an acute pulmonary syndrome. Hantavirus outbreaks in the United States of America at the beginning of the 10th decade of the last century fundamentally changed our knowledge about the appearance of the hantavirus specific clinical picture, mortality, origin, and transmission route in human beings. The hantavirus pulmonary syndrome (HPS) was first recognized in 1993 in the Four Corners Region of the United States and had a lethality of more than 50%. Although the causative virus was first termed in connection with the geographic name of its outbreak region the analysis of the individual viruses indicate that the causing virus of HPS was a genetically distinct hantavirus and consequently termed as Sin Nombre virus. Hantaviruses are distributed worldwide and are assumed to share a long time period of co-evolution with specific rodent species as their natural reservoir. The degree of relatedness between virus serotypes normally coincides with the relatedness between their respective hosts. There are no known diseases that are associated with hantavirus infections in rodents underlining the amicable relationship between virus and host developed by mutual interaction in hundreds of thousands of years. Although rodents are the major reservoir, antibodies against hantaviruses are also present in domestic and wild animals like cats, dogs, pigs, cattle, and deer. Domestic animals and rodents live jointly in a similar habitat. Therefore the transmission of hantaviruses from rodents to domestic animals seems to be possible, if the target organs, tissues, and cell parenchyma of the co-habitat domestic animals possess adequate virus receptors and are suitable for hantavirus entry and replication. The most likely incidental infection of species other than rodents as for example humans turns hantaviruses from harmless to life-threatening pathogenic agents focusing the attention on this virus group, their ecology and evolution in order to prevent the human population from a serious health risk. Much more studies on the influence of non-natural hosts on the ecology of hantaviruses are needed to understand the directions that the hantavirus evolution could pursue. At least, domestic animals that share their environmental habitat with rodents and humans particularly in areas known as high endemic hantavirus regions have to be copiously screened. Each transfer of hantaviruses from their original natural hosts to other often incidental hosts is accompanied by a change of ecology, a change of environment, a modulation of numerous factors probably influencing the pathogenicity and virulence of the virus. The new environment exerts a modified evolutionary pressure on the virus forcing it to adapt and probably to adopt a form that is much more dangerous for other host species compared to the original one.

The complex ecology of hantavirus in Paraguay.

Following an outbreak of hantavirus pulmonary syndrome (HPS) in the Paraguayan Chaco in 1995, Calomys laucha was identified as the rodent host for the hantavirus associated with these cases. To explore the possibility of additional hantaviruses in Paraguay, we collected 636 mammals from 10 of the 17 departments. Plasma from 27 animals in Alto Paraguay and Boquer6n in the Chaco and Neembucú and Itapúa in the eastern region had antibody to Andes virus antigens. Of these 27, five individuals (among four species) were positive for hantavirus RNA. Sera were collected from indigenous people in eastern Paraguay to ascertain whether persons were being infected with hantavirus outside of the Chaco. Seventeen percent were antibody-positive. These results suggest that several different hantaviruses are co-circulating in Paraguay, and that HPS cases occurring in eastern Paraguay may result from exposure to hantaviruses that are distinct from those in the Chaco.

Hantavirus infections in Europe.

Hantaviruses are enveloped RNA viruses each carried by a specific rodent species. Three hantaviruses, Puumala, Dobrava, and Saaremaa viruses, are known to cause haemorrhagic fever with renal syndrome. In Europe. Puumala causes a generally mild disease, nephropathia epidemica, which presents most commonly with fever, headache, gastrointestinal symptoms, impaired renal function, and blurred vision, whereas Dobrava infections often also have haemorrhagic complications. There are few available data about the clinical picture of confirmed Saaremaa infections, but epidemiological evidence suggests that it is less pathogenic than Dobrava, and that Saaremaa infections are more similar to nephropathia epidemica caused by Puumala. Along with its rodent host, the bank vole (Clethrionomys glareolus), Puumala is reported throughout most of Europe (excluding the Mediterranean region), whereas Dobrava, carried by the yellow-necked mouse (Apodemus flavicollis), and Saaremaa, carried by the striped field mouse (Apodemus agrarius), are reported mainly in eastern and central Europe. The diagnosis of acute hantavirus infection is based on the detection of virus-specific IgM. Whereas Puumala is distinct, Dobrava and Saaremaa are genetically and antigenically very closely related and were previously thought to be variants of the same virus. Typing of a specific hantavirus infection requires neutralisation antibody assays or reverse transcriptase PCR and sequencing.

Rescue of Hantaan virus minigenomes.

Hantavirus infections are a major public health concern worldwide. Their widespread geographical distribution and their ability to produce serious, often fatal, human disease underline the need for a system that allows manipulation of these viruses. We describe here the first successful establishment of a reverse genetics technology for Hantaan virus, the prototype of the genus Hantavirus. The system offers a unique opportunity to study the biology of hantaviruses, the pathogenesis of the diseases, and the efficacy of antiviral and prophylactic measures against hantavirus infections.

Hantavirus infections in Greece--an update.

Hantaviruses are emerging viruses spread worldwide and cause hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). Two pathogenic hantaviruses are present in Greece: Dobrava/Belgrade virus (DOBV) and Puumala virus (PUUV). The predominant one is DOBV, carried in Greece by the rodent Apodemus flavicollis. Most human infections are sporadic, but epidemic outbreaks were also described. The severity of the disease ranges from a mild or moderate form to severe and fatal cases. Several endemic foci for HFRS have been identified. Phylogenetic analysis of hantavirus sequences revealed a stable geographical distribution.

Hantavirus pulmonary syndrome associated with Monongahela virus, Pennsylvania.

The first two recognized cases of rapidly fatal hantavirus pulmonary syndrome in Pennsylvania occurred within an 8-month period in 1997. Illness in the two patients was confirmed by immunohistochemical techniques on autopsy material. Reverse transcription-polymerase chain reaction analysis of tissue from one patient and environmentally associated Peromyscus leucopus (white-footed mouse) identified the Monongahela virus variant. Physicians should be vigilant for such Monongahela virus-associated cases in the eastern United States and Canada, particularly in the Appalachian region.