Hemorrhagic fever with renal syndrome (HFRS) is a zoonotic disease transmitted through aerosolized feces from rodents. The disease is caused by various serotypes within the Hantavirus genus in the Bunyaviridae family. It is endemic to Asia and Europe; the most common serotypes causing HFRS are Dobrava, Hantaan, Seoul, and Puumala. Annual cases range from 60,000-150,000 and correlate with rodent populations. The outcome of the disease is usually self-limited with a very low morbidity rate. The mortality rate varies from 0.43% to 15% depending on the strain of the virus.
In North America, the most common serotype is SNV-Sin Nombre Virus, and in South America, the Andes virus; these strains are associated with a different outcome of a disease called hantavirus pulmonary syndrome. HFRS’s main characteristic is capillary leakage which is caused by both viral factors and our own immune factors.
Moderate and severe infections with hantavirus serotypes lead to Hemorrhagic fever with renal syndrome. The incubation period of the virus varies from 2-4 weeks. The main cause of the disease is acute kidney injury (AKI), capillary leakage, and thrombocytopenia. The overall etiology is broad and has been identified to have viral factors, immune factors, and host genetic factors. Tubulointerstitial nephritis leads to acute kidney injury, cytokines and thrombocytopenia lead to capillary leakage and coagulation abnormalities. The virus itself has been noted not to be cytopathic and the disease is thought to be immunopathologic.
Transmission of the virus has been most notably from rodent host to human host, however, the Andes virus which causes hemorrhagic fever renal syndrome has been the only strain noted to have human to human infection. HFRS is endemic to Asia and Europe; there are about 60,000 - 150,000 cases within the year worldwide.
The country with the highest incidence is China with ~90% of cases (50,000 annually and in epidemic years up to 100,000). Russia is in second place followed by Korea. The increase in cases during different years was shown to be correlated by an increase in temperature and favorable conditions which lead to an increased rodent population. The disease seems to affect mostly males but this has been attributed to males doing more outdoor activities. In countries like Sweden, males and females tend to have a 1 to 1 ratio.
The disease has very low morbidity however the mortality for HFRS can be anywhere from <1% to 15% (depending on the viral strain); in contrast, the mortality for HPS is up to 40%. Risk factors have not been widely studied however a study of Puumala infections noted smoking as a risk factor. We are certain that any exposure to rodents increases the risk of disease.
The incubation of hantavirus has an average of 3 weeks. The main abnormality caused by hantavirus is vascular endothelial damage. This is associated with vascular permeability leading to loss of plasma, hypotension, hemoconcentration, and eventually coagulation abnormalities. There is also an aggressive activation of the immune system, which can lead to a cytokine storm and further complications. Overall, the pathogenesis is due to viral, immune, and host genetic factors:
In one study post mortem organs were evaluated, and it was found that the most affected organs were the lungs and the kidney. This was identified by the finding of immune complex deposits in their tissues. In another study, all of the kidney biopsies showed diffuse interstitial infiltrates of mononuclear cells.
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. 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. 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). 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.
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.
The differential diagnoses include other causes of hemorrhagic fever that have overlapping symptoms and evaluation with HFRS:
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. 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%.
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:
Consultations from these departments should be obtained:
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:
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.
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