Hemorrhagic fever with renal syndrome is caused by distinct virus species pertaining to the family of Bunyaviridae. There are major geographical differences in prevalence and severity, with the disease being a major public health concern in East Asia.
As per definition, HFRS patients present with the symptom triad of fever, hemorrhages, and renal insufficiency. The first symptoms are generally noted about two weeks after exposure to the causative pathogen, but much shorter and prolonged incubation periods have been described. However, distinct symptoms set in at different points in time after infection. Individuals who contracted the disease typically pass through five stages; fever, hypotension, oliguria, diuresis, and convalescence .
Of note, the disease will follow this exemplary course in only one out of three patients. In others, stages may not be readily distinguishable, and the characteristic signs may be absent. Stage two, the one marked by hypotension, is frequently skipped.
Laboratory analysis of blood and urine samples may reveal leukocytosis, thrombocytopenia, proteinuria, and microscopic hematuria as early as in the febrile stage of the disease. Coagulation tests yield the most characteristic results during the ensuing hypotensive stage of HFRS. Prolonged partial thromboplastin and prothrombin times imply a coagulopathy. During the oliguric stage of HFRS, platelet counts and urinary protein excretion normalize. However, creatinine and urea concentrations reach previously unsurpassed high values.
Although the aforementioned signs strongly support a suspicion of HFRS, they don't usually allow an early confirmation of that diagnosis. To date, the gold standard for HFRS diagnosis and identification of the causative pathogen is serological testing. ELISA, IFA and Western blot shall be mentioned as available alternatives for the detection of hantavirus-specific immunoglobulins type G and M. Their respective advantages and disadvantages have been reviewed elsewhere . All serological tests are based on an established immune response and may thus yield false-negative results if applied too early. Here, molecular biological techniques like real-time RT-PCR are presumably more reliable. However, false-negative results of RT-PCR have been reported, too . If renal biopsies are taken, immunohistochemical methods may be applied.
Treatment is largely symptomatic. Fluid resuscitation and avoidance of hemodynamic decompensation are of utmost importance. Repeated analysis of blood samples, namely of hematocrit and electrolyte levels, allows for a reliable assessment of the patients hydration status and thus permit necessary adjustments of fluid therapy. Early initiation of therapy significantly reduces the likelihood of renal failure.
Further measures depend on the severity of the disease and those symptoms experienced by the individual patient, and may comprise:
Studies regarding antiviral treatment of HFRS patients yielded contradictory results. Thus, no such compounds can be recommended at this moment.
Prognosis largely depends on the precise type of HFRS. Hantaan virus-induced HFRS is a severe disease and mortality rates may reach 15%. Infection with the Dobrava-Belgrade virus results in fatality in up to 10% of all cases  . In case of Seoul virus infection, the probability of death has been reported to be approximately 2%. For the remainder of HFRS, mortality is less than 1%.
Morbidity mainly results from irreversible kidney damage and may cause the necessity for dialysis and organ transplantation. However, if adequate treatment is provided in a timely manner, most patients recover without sequelae.
HFRS is not a homogeneous disease and may be triggered by a variety of viruses pertaining to the genus Hantavirus, which, in turn, is part of the family of Bunyaviridae. All these viruses are single-stranded RNA viruses of negative polarity; they possess a tripartite genome, i.e., their total RNA is distributed over three particles.
HFRS-inducing viruses differ largely in virulence and geographical distribution, a fact that is reflected in the many alternative, more specific designations of HFRS. In most cases, this zoonotic disease is transmitted by rodents that excrete the respective pathogen with urine, feces, and saliva. People exposed to these excretions are likely to inhale the pathogen. Bites have been reported to result in human infection and are presumably an important route of transmission from animals to animals. Human-to-human transmission has not yet been reported.
In detail, the following viruses may cause HFRS:
Although HFRS is classically considered an Eurasian disease, introduction of infected carriers into the New World allowed for virus propagation in now endemic carrier populations in America. While soldiers of the United States have indeed been the first people who were diagnosed with HFRS, during the Korean war in the 1950s and after being exposed to infected mice, it was not until decades later that the disease has been contracted in the United States itself. More recent studies indicate the presence of HFRS-associated pathogens in South America, too .
Nevertheless, the highest incidence rates are still reported from East Asia. In China, more than 100,000 cases are registered every year. The incidence of HFRS due to infection with Dobrava-Belgrade virus is much lower, with only about 100 cases reported per year . The Puumala virus causes about 10,000 annual cases of nephropathia epidemica in Europe . In Far East Russia, 100 to 200 patients contract Amur virus-induced HFRS every year . Seasonal variations have been observed and presumably depend on the population dynamics of carriers .
According to the above described etiology of HFRS, people who are frequently exposed to carriers, their urine, feces or saliva, may be considered to have a higher risk of contracting the disease. This may apply to farmers, campers, or anyone else who works or sleeps where infected animals may have passed. This hypothesis is supported by the fact that most cases of HFRS are reported in rural areas .
Hantaviruses are known to infect endothelial cells, lymphocytes, and macrophages, among other cells . This explains vascular damage and hemorrhages and implies the contribution of immune mechanisms to the pathogenesis of hemorrhagic fever. Indeed, infection with such pathogens induces a strong immune reaction, cytokine and mediator release, as well as complement activation. These pathophysiological events lead to vasodilatation and increased vascular permeability, thus exacerbating vascular dysfunction and triggering fever and hypotension. Moreover, extensive endothelial damage may lead to disseminated intravascular coagulopathy and thrombocytopenia.
In case of HFRS, the initial stages of fever and low blood pressure are followed by symptoms of renal failure, most likely provoked by local effects that add to renal vascular lesions. It has been proposed that deposition of immune complexes and complements may affect the kidneys. Hantaviruses also directly damage the renal podocytes . The latter may correspond to antibody-dependent cytotoxicity. However, considerable knowledge gaps remain regarding the mechanisms behind the oliguric, diuretic and convalescent stages of the disease.
In each country, the population should be educated regarding the risks of hantavirus infection, possible carriers and their natural habitats. In general, rodents are more common in rural areas, fields, and in barns. Additionally, they may be attracted to anywhere they smell food. Thus, in order to avoid exposure to their urine, feces and saliva, people should avoid sleeping outside houses, and store their foods out of reach of animals. Campers should consider the possibility that rodents urinate on accessible tables and if properly stored food is prepared here, it may become contaminated.
In China and Korea, vaccines are used to protect from HFRS  .
Hemorrhagic fever with renal syndrome (HFRS) is a type of viral hemorrhagic fever, and thus shows some pathophysiological and clinical similarities to Dengue fever, yellow fever, as well as ebola virus disease. Only those types of viral hemorrhagic fever that are triggered by viruses of the family of Bunyaviridae and that are characterized by renal failure are designated HFRS.
HFRS is a zoonotic disease. It may be induced by at least six different species of Hantavirus, namely the Hantaan virus, the Dobrava-Belgrade virus, the Seoul virus, the Puumala virus, the Saaremaa virus, and the Amur virus, and is usually contracted upon inhalation of airborne pathogens originating from urine and feces of infected rodents. The aforementioned viruses have mainly been encountered in distinct geographical areas of Asia and Europe, but the introduction of infected carries into Americas has lead to local outbreaks. In this context, it has to be mentioned that Korean hemorrhagic fever, Balkan hemorrhagic fever, nephropathia epidemica, are all terms that refer to HFRS, but those are used in determined countries if an infection with a particular virus species is detected.
Of note, hemorrhagic pulmonary syndrome is also caused by hantaviruses but constitutes a different entity .
Hemorrhagic fever with renal syndrome (HFRS) is a zoonotic disorder. There are distinctive viruses that may trigger this disease. They are all transmitted by rodents, but differ between different geographical areas. For instance, most cases of HFRS are registered in East Asia and are caused by the Hantaan virus. Such an infection results in a severe disease also referred to as Korean hemorrhagic fever. In contrast, in Europe, severe forms of HFRS are provoked by the Dobrava-Belgrade virus, which is distributed throughout the Balkan countries and Eastern Europe. Other forms of HFRS are less severe.
Infected rodents excrete virus particles with urine, feces, and saliva. People who live, work, or stay in close proximity to those animals may be exposed to their excretions. Airborne pathogens may be inhaled and cause fever, hemorrhages and renal failure. In order to avoid this, appropriate preventive measures should be taken to reduce the exposure to rodents.