Hemorrhagic Fever Renal Syndrome

Article Author:
Maria Romero
Article Editor:
Fatima Anjum
Updated:
7/25/2020 7:48:00 AM
PubMed Link:
Hemorrhagic Fever Renal Syndrome

Introduction

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.[1][2] 

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.[3] HFRS’s main characteristic is capillary leakage which is caused by both viral factors and our own immune factors.[4]

Etiology

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.[5][6][7]

Epidemiology

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.[4] HFRS is endemic to Asia and Europe; there are about 60,000 - 150,000 cases within the year worldwide.[8] 

The country with the highest incidence is China with ~90% of cases (50,000 annually and in epidemic years up to 100,000).[9] 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.[10] 

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.[11] We are certain that any exposure to rodents increases the risk of disease.

Pathophysiology

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:[10][12][13][5][6][14]

  • Viral factors: The virus attacks endothelial cells, the virus then gains access through beta-3 integrins receptors. Once inside, it seems to take over and induce cytoskeletal reorganization, decreasing the integrity of the endothelial cell barrier; this leads to dysfunction of glomerular filtration and capillary leakage. No cytopathic effects have been recorded, and overall the disease is thought to be immunopathologic
  • Immune factors: Activation of innate and adaptive immunity starts to clear the infection; however, in severe cases, it has been noted that overproduction of inflammatory cytokines causes most of the damage in this disease. This also suggests that a cytokine storm might play a vital role in disease pathogenesis. The concentrations of IL-6, IFN-gamma, TNF-alpha, IL-18, and others have been associated with disease severity. 
  • Host factors: Male gender has noted to be a factor in some studies and is associated mostly with males doing more outdoor activities. Age is also a factor as it has been reported that most deaths occur in older patients >70 yo. Genetics has also been noted to play a role; the HLA-B8-DR3 haplotype, along with others, has been associated with high mortality rates.

Histopathology

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.[1][5]

History and Physical

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.

Evaluation

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.

Treatment / Management

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]

Differential Diagnosis

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

Staging

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.

Prognosis

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.

Complications

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

Consultations from these departments should be obtained:

    • Infectious disease
    • Nephrology 
    • Intensive care

Deterrence and Patient Education

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.

Pearls and Other Issues

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.

Enhancing Healthcare Team Outcomes

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.


References

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