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 [8].

• Febrile stage: Symptom onset is acute; non-specific symptoms like malaise, fever, chills, headaches, myalgia, nausea, and vomiting may last up to a week. Abdominal and lower back pain may already be present. Flushing and petechial rash may indicate vascular dysfunction.
• Hypotensive stage: Fever subsides. Patients develops hypotension and tachycardia. In severe cases, they may go into shock. This stage is much shorter than the previous one, and may only last a few hours or very few days.
• Oliguric stage: Kidney damage manifests in form of oliguria and uremia, whereby the latter aggravates the aforedeveloped bleeding diathesis. Hypertension may be noted, and lung edema may form. This stage typically lasts four or five days.
• Diuretic stage: Urine amounts rise again and for up to three weeks, patients may excrete up to five liters of urine per day. Dehydration and hypovolemic shock may occur if fluid resuscitation is not adequate.
• Convalescent stage: This stage is marked by gradual resolution of symptoms. It may take several months until complete recovery is achieved, if no irreversible kidney damage occurred.

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.

• Fever

  Isolation of the etiologic agent of Korean Hemorrhagic fever. J Infect Dis 1978;137:298–308. 10. Gajdusek DC. Virus hemorrhagic fevers. Special reference to hemorrhagic fever with renal syndrome (epidemic hemorrhagic fever). [synapse.koreamed.org]

  Kim and Choi: Hemorrhagic Fever with Renal Syndrome Complicated with Pregnancy: A Case Report Abstract Hantaviruses cause two forms of human disease: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome. [kjim.org]

  Abstract Hemorrhagic fever with renal syndrome (HFRS) and Crimean-Congo hemorrhagic fever (CCHF) are the 2 widespread viral hemorrhagic fevers occurring in Europe. [ncbi.nlm.nih.gov]

• Chills

  We report a case of HFRS in a 24-year-old soldier presenting with fever, chills, abdominal pain and generalized myalgia. His clinical course progressed through febrile, hypotensive, oliguria and polyuria phases. [ncbi.nlm.nih.gov]

  Initial symptoms begin suddenly and include intense headaches, back and abdominal pain, fever, chills, nausea, and blurred vision. Individuals may have flushing of the face, inflammation or redness of the eyes, or a rash. [en.wikipedia.org]

  Hemorrhagic fever with renal syndrome: A number of diseases, also known as hemorrhagic fever, characterized by an abrupt onset of high fever and chills, headache, cold and cough, and pain in the muscles, joints and abdomen with nausea and vomiting followed [medicinenet.com]

• Falling

  Peaks in spring and fall/winter were caused by Hantaan and Seoul viruses, respectively. Rodent hosts were the striped field mouse for Hantaan virus and the brown rat and house mouse for Seoul virus. [ncbi.nlm.nih.gov]

  They often invade homes and old buildings, especially in the fall. Hantavirus rarely, if ever, spreads from person to person. This has never been documented in North America. [gov.mb.ca]

• Asymptomatic

  Rodents and small mammals act as natural reservoirs for Hantaviruses but are asymptomatic upon infection. [thenativeantigencompany.com]

  In mild forms, infection is often asymptomatic. When symptoms of HFRS occur, onset is sudden, with high fever, headache, backache, and abdominal pain. [merckmanuals.com]

  The clinical features in patients with hantavirus disease are quite variable, from asymptomatic to severe. The incubation period is relatively long, mostly 2–3 weeks, but may be up to six weeks. [ecdc.europa.eu]

• Multiple Organ Dysfunction Syndrome

  The non-survivors were found to have higher frequencies of encephalopathy, refractory shock and multiple organ dysfunction syndrome (MODS), lower incidences of acute renal failure (ARF) and secondary hypertension (P CONCLUSION: The high mortality rate [ncbi.nlm.nih.gov]

• Pneumonia

  […] with Chlamydia Pneumoniae, Mycoplasma Pneumonia, Leptospirosis, Viral Hepatitis, Tuberculosis) and hematologic diseases (Idiopathic Thrombocytopenic Purpura, Thrombotic Thrombocytopenic Purpura, Hematological Hypersplenism). [alliedacademies.org]

  "She didn't test positive for pneumonia, the flu, hepatitis — nothing she tested for was coming back," Barron said. [ 10 Bizarre Diseases You Can Get Outdoors ] But finally, Lane was given a test for hantavirus, which came back positive. [livescience.com]

  There were subtle pleural effusions bilaterally, but no pneumonia. His respiratory status prompted an evaluation of his acid-base status which revealed a combined disorder. [wehrmed.de]

  […] direct test for respiratory viruses (e.g., influenza, RSV, etc) or group A Streptococcus in a person with an illness compatible with streptococcal pharyngitis, a positive culture from a normally sterile site, or a presentation consistent with bacterial pneumonia [clinicaltrials.gov]

  Although the diagnosis at the time of admission was pneumonia in 7 patients (41 percent), 10 patients (59 percent) had other diagnoses: abdominal pain in 3 (18 percent); adult respiratory distress syndrome in 2 (12 percent); cardiopulmonary arrest in [nejm.org]

• Pharyngitis

  On examination, she had a normal body temperature, flushing of the face, conjunctive congestion, pharyngeal congestion, bulbar conjunctive edema, severe jaundice, petechiae and ecchymosis at sites of venipuncture, deranged liver and renal function tests [ncbi.nlm.nih.gov]

  […] criteria: subjects with a likely diagnosis other than hantavirus infection, including any positive culture or direct test for respiratory viruses (e.g., influenza, RSV, etc) or group A Streptococcus in a person with an illness compatible with streptococcal pharyngitis [clinicaltrials.gov]

• Respiratory Insufficiency

  Later symptoms (4 to 10 days after initial phase) include coughing and shortness of breath, respiratory insufficiency, low blood pressure, which can possibly lead to death. [1] Historical information – The hantaviruses are named after the Hantaan river [austincc.edu]

  Insufficiency Respiration Disorders Respiratory Tract Diseases Methylprednisolone Methylprednisolone Acetate Methylprednisolone Hemisuccinate Prednisolone Prednisolone acetate Prednisolone hemisuccinate Prednisolone phosphate Anti-Inflammatory Agents [clinicaltrials.gov]

• Nausea

  The HFRS put these women at increased risk for severe illness, despite the patients' symptomologies in the onset phase were similar to those observed in non-pregnant HFRS patients, such as fever, headache, nausea, and thrombocytopenia. [ncbi.nlm.nih.gov]

  Initial symptoms begin suddenly and include intense headaches, back and abdominal pain, fever, chills, nausea, and blurred vision. Individuals may have flushing of the face, inflammation or redness of the eyes, or a rash. [en.wikipedia.org]

  These illnesses typically develop within 1 to 2 weeks of exposure (sometimes later) and are characterized by acute fever, severe headache, blurred vision, and nausea. [britannica.com]

• Abdominal Pain

  Clinicians should be alert to the possibility of HFRS when examining patients who have been in endemic areas and complain of fever associated with renal dysfunction, hemorrhage or abdominal pain or both. [ncbi.nlm.nih.gov]

• Hypotension

  His clinical course progressed through febrile, hypotensive, oliguria and polyuria phases. Hantavirus infection was proven by serology at the second hospital week. The patient was successfully treated with supportive management. [ncbi.nlm.nih.gov]

  Hypotensive stage: Fever subsides. Patients develops hypotension and tachycardia. In severe cases, they may go into shock. This stage is much shorter than the previous one, and may only last a few hours or very few days. [symptoma.com]

   Thirst, edema, hemoconcentration, postural hypotension 11. [slideshare.net]

• Hypertension

  Follow-up of 2 patients identified persistent hypertension and renal disease providing further evidence of an association between past hantaviral infection and hypertensive renal disease. [ncbi.nlm.nih.gov]

  The hypotonic stage, a couple of hours-2 days: facial hyperemia, sinus bradycardia, slight hypertension. 3. The oliguric stage, 4-7 days: hypertension, oligo-anuria. 4. [alliedacademies.org]

  Oliguric Phase • 3-7 days • Marked by decreased urine production due to renal (kidney) dysfunction • Hypervolemia (high blood volume) leading to hypertension • Blood electrolyte imbalance • Continuation of hemorrhagic symptoms • Severe complications: [slideshare.net]

  Longer-lasting complications are rare, and include glomerulonephritis, Guillain-Barré syndrome, hypopituitarism, and hypertension. [ecdc.europa.eu]

• Petechiae

  The patient was a 38-year-old man, living in Tainan, Taiwan, who had been visiting Mainland China for 3 months when he suddenly developed fever and chills, generalized myalgia, abdominal pain and petechiae on his chest. [ncbi.nlm.nih.gov]

  Febrile Phase  3-5 days  Characterized by fever, chills  Headache, severe myalgia (muscle pain), nausea  Blurred vision, photophobia, eye pain caused by movement  Flushing of face, V-area of the neck and back  Petechiae (small red spots on skin) [slideshare.net]

  The hemorrhagic part of the disease name comes from petechiae, hematuria, and melena that may develop in more severe cases. [microbewiki.kenyon.edu]

  The skin and mucous membranes were dry without petechiae, rash or edema. There was no jaundice. His heart and lungs were clear to auscultation without wheezing, rales or rhonchi. [wehrmed.de]

• Eczema

  Forest disease A98.3 Marburg virus disease A98.4 Ebola virus disease A98.5 Hemorrhagic fever with renal syndrome A98.8 Other specified viral hemorrhagic fevers A99 Unspecified viral hemorrhagic fever B00 Herpesviral [herpes simplex] infections B00.0 Eczema [icd10data.com]

• Back Pain

  Abstract Hantavirus hemorrhagic fever with renal syndrome (HFRS) is a zoonotic disease characterized by acute onset, fever, malaise, and back pain. As the disease progresses, hemorrhagic disturbances and kidney dysfunctions predominate. [ncbi.nlm.nih.gov]

  Symptoms include abrupt onset of fever, headache, orbit pain, back pain, erythema of face, neck and chest. Later it may proceed to exhibit bleeding signs, little urine output, renal failure, shock. Death could occur in as high as 15% of cases. [travelhealth.gov.hk]

   Abdominal pain and back pain.  Thirst, edema, hemoconcentration, postural hypotension 11. [slideshare.net]

  Initial symptoms begin suddenly and include intense headaches, back and abdominal pain, fever, chills, nausea, and blurred vision. Individuals may have flushing of the face, inflammation or redness of the eyes, or a rash. [en.wikipedia.org]

  Haemorrhagic Fever with Renal Syndrome (HFRS) An acute zoonotic disease caused by the Old World Hantaviruses and is characterised by abrupt onset of fever, headache, severe abdominal or lower back pain, hypotension and renal failure. [chp.gov.hk]

• Arthralgia

  A 30-yr-old man was admitted to hospital with a 5-d history of flu-like symptoms: Headache, shivers, nausea, vomiting, backache, arthralgias, myalgias, and blurred vision. [jasn.asnjournals.org]

• Kidney Failure

  Later symptoms can include low blood pressure, acute shock, vascular leakage, and acute kidney failure, which can cause severe fluid overload. The severity of the disease varies depending upon the virus causing the infection. [en.wikipedia.org]

  […] disease with renal manifestations ( A98.5 ) hemorrhagic fever with renal manifestations ( A98.5 ) Use Additional code to identify any associated acute kidney failure ( N17.9 ) Disease, diseased - see also Syndrome Hantavirus, with pulmonary manifestations [icd10data.com]

  Symptoms: Fever, Bleeding, Kidney damage. [slideplayer.com]

  The virus can cause severe infections of the lungs (with cough and shortness of breath) or kidneys (with rash, abdominal pain, and sometimes kidney failure). Hantavirus is spread through contact with infected rodents or their droppings. [merckmanuals.com]

• Hematuria

  The patient's condition quickly deteriorated, with frank hematuria, oliguria and finally anuria, together with shock. [ncbi.nlm.nih.gov]

  Proteinuria, hematuria, and pyuria may develop; renal failure may occur. [merckmanuals.com]

• Polyuria

  His clinical course progressed through febrile, hypotensive, oliguria and polyuria phases. Hantavirus infection was proven by serology at the second hospital week. The patient was successfully treated with supportive management. [ncbi.nlm.nih.gov]

  The rash subsides; patients develop polyuria and recover over several weeks. Proteinuria, hematuria, and pyuria may develop; renal failure may occur. [merckmanuals.com]

• Oliguria

  His clinical course progressed through febrile, hypotensive, oliguria and polyuria phases. Hantavirus infection was proven by serology at the second hospital week. The patient was successfully treated with supportive management. [ncbi.nlm.nih.gov]

• Headache

  The initial presentation of HFRS is extremely variable, but generally includes fever, malaise, headache and abdominal pain. [ncbi.nlm.nih.gov]

  His review of symptoms was remarkable for mild headache fatigue and paresthesia in both hands. [wehrmed.de]

  Initial symptoms begin suddenly and include intense headaches, back and abdominal pain, fever, chills, nausea, and blurred vision. Individuals may have flushing of the face, inflammation or redness of the eyes, or a rash. [en.wikipedia.org]

• Dizziness

  Early symptoms of HPS include Fatigue Fever Muscle aches, especially in the thighs, hips and back Headaches Chills Dizziness Nausea, vomiting, diarrhea or abdominal pain Later symptoms include coughing and shortness of breath. [medlineplus.gov]

  They can include: tiredness dizziness fever and chills muscle aches and headaches nausea and vomiting stomach pain coughing More severe symptoms may include: shortness of breath severe difficulty breathing Symptoms of haemorrhagic fever with renal syndrome [canada.ca]

  There may also be headaches, dizziness, chills and gastrointestinal symptoms such as nausea, vomiting, diarrhoea and abdominal pain. [chp.gov.hk]

  Symptoms Symptoms first appear between a few days to six weeks after contact with the virus and include a flu-like illness with any of the following signs: Fever Muscle and body aches Chills Cough Headaches Nausea Vomiting Diarrhea Dizziness Fatigue The [idph.iowa.gov]

  Fever Chills Headaches Nausea Vomiting Diarrhea Dizziness Fatigue Muscle aches in the large muscle groups (ie, back, thighs, shoulders) After the first few days, respiratory difficulties begin abruptly and can progress rapidly. [healthychildren.org]

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 [7]. 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 [9]. If renal biopsies are taken, immunohistochemical methods may be applied.

• Decreased Platelet Count

  Relevant thrombocytopenia occurs in the majority of patients and thrombocyte levels below 50.000/µl develop in more than half of the cases, but the extent of decrease in platelet count as in our case (lowest platelet count 9.000/µl) has not been described [wehrmed.de]

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:

• Transfusion of blood products in case of severe hemorrhages.
• Diuretics to compensate for oliguria; a symptoms shown by the majority of patients at some point in time.
• Drug therapy to relieve specific symptoms, e.g., alterations of blood pressure.
• In case of renal insufficiency, dialysis.

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 [1] [4]. 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:

• Hantaan virus provokes Korean hemorrhagic fever, i.e., the most severe form of HFRS. It's endemic in East Asian countries like China and South Korea. The main reservoir of this virus is Apodemus Agrarius, the striped field mouse.
• Dobrava-Belgrade virus is distributed in Balkan countries, Eastern Europe, and Russia. People who suffer from HFRS due to an infection with this pathogen are often diagnosed with Balkan hemorrhagic fever, a severe disease. The virus is transmitted by Apodemus Flavicollis, the yellow-necked mouse.
• Seoul virus originates from Eurasia but can now be found in America too, relating to its main carriers Rattus Norvegicus and Rattus Rattus, the Norway and black rats [2]. The virus is of intermediate virulence.
• Puumala virus causes nephropathia epidemica, a mild form of HFRS that is most commonly diagnosed in Northern Europe. Cases have been reported from other European countries, too. The virus' host is Myodes Glareolus, the European bank vole.
• Saaremaa virus is a European virus that may provoke mild HFRS. It is transmitted by the striped field mouse.
• Amur virus has been isolated from Apodemus Peninsulae, the Korean field mouse, in Far East Russia. It is a rare cause of HFRS and little is known about its virulence [3].

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 [2].

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 [4]. The Puumala virus causes about 10,000 annual cases of nephropathia epidemica in Europe [5]. In Far East Russia, 100 to 200 patients contract Amur virus-induced HFRS every year [3]. Seasonal variations have been observed and presumably depend on the population dynamics of carriers [5].

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 [6].

Hantaviruses are known to infect endothelial cells, lymphocytes, and macrophages, among other cells [1]. 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 [7]. 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 [7] [10].

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 [1].

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.

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