History: The history is non-specific, the patient will usually present with acute flu-like symptoms such as high fevers, headache, and vomiting. Depending on how severe the patient will have symptoms of hypotensive shock-like SOB, confusion, diaphoresis, and palpitations. If the patient has traveled to an endemic area, works in an occupation like farming or park ranger, has slept in a place infested with rodents, or was bitten by a rodent, then you can speculate you might be dealing with HFRS. 

Physical examination: It varies depending on which stage of the disease the patient is in when coming to you. The disease has five stages: during the febrile and hypotensive stage, which tend to overlap, the patient can have signs of shock and hemorrhage such as petechiae or conjunctival hemorrhage. During the oliguric stage, there will be a decreased urine output and might have costovertebral angle tenderness (CVAT). In the polyuric stage, the patient’s appearance should be improving and have an increase in urine output.

The presence of headache, high-grade fever, myalgias, and vomiting (might have hematemesis if in an acute state), which are very non-specific and seen in other diseases, are observed. Furthermore, the disease clinically varies from subclinical, mild, moderate to severe as it depends, which strain the patient acquired and how the host immune system reacts.

Severe HFRS is divided into 5 phases: febrile, hypotensive, oliguric, polyuric, and convalescent. Clinically it depends on which stage the patient is in. For example, in the febrile phase, some patients might have conjunctival hemorrhage and fine petechiae on the palate.[4] During the febrile and hypotensive stage, blood counts reveal leukocytosis, thrombocytopenia, and hemoconcentration due to fluid loss.

Thrombocytopenia is a key lab finding which is also associated with the increase in blood vessel permeability. Thrombocytopenia and high plasma IL-6 is also associated with the severity of the disease.[10] At the beginning of AKI, the patient might have only the presence of decreased urine output, proteinuria, and hematuria. Further, into the oliguric phase, there will be an elevated creatinine, as well as a decrease in GFR. If there is no urine output, then it can also lead to electrolyte imbalances such as hyperkalemia and hyperphosphatemia.

To confirm the diagnosis of HFRS, a serological test such as ELISA will detect antibodies against the virus, IgM on the 4th day, and IgG present on the 6th day. Western blot is another test that identifies the presence of viral antigens. PCR is not as reliable as the viral load is very short-lived. The most common serotypes in China are the hantavirus (HTNV) and Seoul virus (SEOV).[8] In Europe, the most commonly identified species are Dobrava and Puumala.

Some clinical trials have shown that ribavirin, when used early, decreases viral load. Other studies show Icatibant, which is a bradykinin inhibitor, to be effective in patients with Puumala infection. The presence of thrombocytopenia, oliguria, and elevated cytokines (such as TNF-beta or IL-18) are indicators of the severity of disease and suggest immediate ICU admission.[1] 

Overall, the most effective therapy has been supportive management. If the patient has signs of hemorrhage and severe thrombocytopenia, transfusion of RBCs and platelets will be suggested. If there is refractory fluid overload causing pulmonary edema, severe hyperkalemia, or uremic signs, then hemodialysis will be used. Always avoid drugs that will decrease GFR, such as NSAIDs and ACE inhibitors, as well as other nephrotoxic drugs.[10]

The differential diagnoses include other causes of hemorrhagic fever that have overlapping symptoms and evaluation with HFRS:

• Yellow fever
• Ebola
• Septicemia 
• Dengue
• Leptospirosis 
• Severe fever with thrombocytopenia syndrome

The disease is divided into five stages. Some phases overlap, and the five stages are only in severe cases whereas mild cases might not have all five:[2][10]

• Febrile: lasts for 1 to 7 days, the main symptom is acute high fever along with some flu-like symptoms like headache, nausea, vomiting, abdominal pain.
• Hypotensive: lasts for 1 to 3 days due to capillary leakage, will have signs of petechiae, conjunctival hemorrhage, hematemesis, and melena. 
• Oliguric: 2 to 6 days, decreased to no urine output, elevated BUN, creatinine, reduced GFR, and signs of fluid retention. The patient is at risk for hyperkalemia and other electrolyte abnormalities. Most deaths occur during this phase. 
• Polyuric: about two weeks, urine output is increased and is a sign that the patient's outcome is improving. The biggest risk will be hypokalemia. 
• Convalescent: lasts an average of 3 to 6 months but in some patients up to 1 year. The patient will still have mild symptoms, some proteinuria, and some fatigue.

Usually, the outcome of this viral infection is self-limited, and the patient will fully recover; however, the prognosis depends on which serotype of the virus the patient was infected with. The morbidity of HFRS is very low, and its mortality rate is from 0.43%-15%, depending on the strain of the virus.[1][2] The strains causing mild disease are Puumala and Saameraa mortality rates of <1%, moderate disease Seoul, and those causing severe disease are Dobrava, Amur, and Hantaan with mortality rates of 5% to 15%.[4] 

However, all strains can produce symptoms that range from asymptomatic to severe forms of the disease. Once a patient recuperates, very seldom do their kidneys have sequelae from the disease; however, it has been noted in the USA that 10% of patients with ESRD have hantavirus antibodies.

The disease can be fatal, and go into a multiorgan system failure and be complicated by: 

• Acute encephalomyelitis 
• Pulmonary edema
• Coagulation abnormalities like disseminated intravascular coagulation
• Acute respiratory distress syndrome
• Multiorgan failure
• End-stage renal disease (ESRD), in most patients HFRS is self-limiting however 10% of patients with ESRD have hantavirus specific antibodies in the USA

Consultations from these departments should be obtained:

• Infectious disease
• Nephrology 
• Intensive care

It is important to teach patients about the risks of exposing themselves to any type of rodents. The patients that are at higher risk such as those living/traveling to endemic areas or those working in occupations such as farming, forestry, or in the military. They need to be advised and educated on ways to eliminate and minimize contact with rodents.

Here are some important facts:

• The hallmark of hemorrhagic fever renal syndrome is noted to be fever, hemorrhage, and renal failure. 
• Hantavirus is transmitted through inhalation of aerosolized urine or feces of rodents.
• In a patient with a history of rodent exposure and flu-like symptoms consider a hantavirus infection even if it is not a common disease.
• Recent travel to an endemic country (China, Russia, Korea) is also important to consider
• HFRS pathophysiology is rather complicated, but studies note the hallmark of the disease to increase capillary permeability and excessive activation of the host immune system.
• Thrombocytopenia in HFRS is associated with disease severity and prompts ICU admission.
• Supportive care is the most helpful treatment and has been shown to decrease mortality. 
• Prevention is achieved by decreasing rodent populations and minimizing contact.

To enhance the outcome of hemorrhagic fever renal syndrome is first to educate the public about this zoonotic disease, and its transmission should be the main goal. Since rodents are the vectors, patients need to avoid contact, store food properly to prevent rats’ contamination, and avoid sleeping outside or in infested areas. In severe cases, HFRS has a 15% mortality rate, therefore in cases with severe disease management by an interprofessional team that includes intensivist, nephrologist, and infectious disease specialists will provide a better outcome.