Continuing Education Activity

Hemorrhagic fever renal syndrome (HFRS) is an acute zoonotic disease transmitted through aerosolized excrement of rodents (mice, rats, shrews, and voles) and is the most common zoonosis in Asia. The infection is caused by various species of viruses under the hantavirus genera, which use rodents as hosts. The outcome of the disease is usually self-limited, and the severity of the disease depends on the viral strain. However, some patients develop HFRS, which is characterized by renal dysfunction, thrombocytopenia, and multi-organ failure. Severe disease classically presents in a 5-stage progression, which can result in death. Much of this presentation can be attributed to the immune response to the virus rather than cytotoxic virus effects. This activity reviews the epidemiology, pathophysiology, outcome, and treatment of HFRS. In addition, it highlights the role of the healthcare team in evaluating, preventing, and managing the disease.

Objectives:

• Identify the key clinical features and epidemiological factors associated with hemorrhagic fever renal syndrome.

• Differentiate between the various Hantavirus strains responsible and their respective clinical manifestations.

• Assess the severity and progression of HFRS using established clinical criteria and laboratory findings.

• Collaborate with infectious disease specialists, nephrologists, epidemiologists, and public health authorities to manage and control HFRS outbreaks. Outline the interprofessional team strategies to manage patients with hemorrhagic fever renal syndrome to achieve the best patient outcomes.

Introduction

Hemorrhagic fever with renal syndrome (HFRS) is a disease transmitted through aerosolized urine or feces of rodents (mice, rats, shrews, and voles). HFRS is the most common zoonosis in Asia and also common in parts of Europe.[1] Various serotypes cause the disease within the Orthohantavirus genus and are endemic in parts of Asia and Eastern Russia. The most common serotypes causing HFRS are Hantaan, Dobrava, Seoul, and Puumala. Rodents are asymptomatic reservoirs of the virus, which can spread to infect humans at a rate of over 100,000 cases per year.[1] The outcome of infection is usually self-limited, but mortality can exceed 15% with some infectious strains.[2] 

Recently, the taxonomical classification of these viruses has been updated. Due to a plethora of newly sequenced viral genomic data, classifications were expanded in 2016 to include Bunyavirales as an order, and the previous genus Hantavirus became the family classification Hantaviridae. The viruses causing hemorrhagic fever with renal syndrome are part of the Orthohantavirus genus and Hantaviridae family (previously referred to as Hantaviruses).[3] 

Two main disease processes result from Orthohantaviruses (which will be referred to as Hantaviruses from here on out): Hemorrhagic fever with renal syndrome (HFRS) and Hantavirus cardiopulmonary syndrome (HCPS). These two entities have distinct presentations and geographic predominance; the viruses causing HFRS circulate in Asia and Eastern Europe, while the viruses causing HCPS are found in the Americas.[2] Different Hantavirus strains cause HFRS and HCPS and have different clinical pictures, but both involve increased microvascular permeability, consumptive platelet coagulopathy, and hyperactivity of the host immune system. HCPS is associated with much higher mortality.  Please see our companion StatPearls topic "Hantvirus Cardiopulmonary Syndrome," for further information.

HFRS results from inhalation of Hantavirus, which spreads to other organ systems through the immune system and targets the renal vasculature. In patients who develop HFRS, a variety of clinical presentations exist, from mildly symptomatic to death. No known cure exists for Hantavirus infection other than supportive care.[1][2]

Etiology

HFRS results from inhalation of Hantavirus, which spreads primarily through macrophages and targets the renal vasculature. Many residents of endemic areas show antibodies to these environmental viruses, suggesting that most people exposed to the virus are asymptomatic or have subclinical infections.[1][2] 

Each viral strain is closely associated with a specific rodent host, and transmission between rodent hosts and humans usually occurs via aerosolizing virus particles. The host rodents are largely asymptomatic, and human-to-human contact is extremely rare. At least 24 species of Hantaviruses can cause human disease, but a few serotypes are clinically predominant. Hantaan and Dobreva viruses are associated with more severe disease; Seoul virus is associated with moderate disease; and Puumala virus is linked to a milder form of HFRS called nephropathia epidemica.[4] Nephropathica epidemic is the most common Hantavirus disease in Europe and is characterized by milder symptoms and less progressive disease.[5]

The 3 main factors causing pathology in HFRS are the following:

1. Viral infection causes loss of the endothelial barrier and increases vascular permeability.
2. The coagulation cascade is activated due to viral infection.
3. A cytokine storm causes an immune response, induces inflammation, and damages tissue.

Delayed symptoms demonstrate the importance of the immune response in the pathology of HFRS after the onset of viremia and lack of apoptosis or cytotoxic destruction in infected cells.[1]

Once the virus is inhaled into the lungs, its primary target is the kidney. Through vascular permeability, the glomerulus loses its barrier function, resulting in proteinuria and decreased glomerular filtration rate. Direct tubular injury and tubulointerstitial nephritis are also seen. Concurrently, activation of the coagulation cascade causes a consumptive coagulopathy, resulting in thrombocytopenia and hemorrhage.

Epidemiology

Transmission of the virus has been most notably from rodent host to human host; however, the Andes virus, which causes Hantavirus cardiopulmonary syndrome (HCPS), is noted to have rare human-to-human infection.[4] HFRS is endemic to Asia and Europe; although many countries do not report these statistics, worldwide incidence is estimated at 60,000 to 150,000 cases yearly.[6]

China has the highest incidence rate, with 40% to 50% of known cases globally.[1] Russia has the second-most number of cases, followed by Korea. Variability in yearly case burden correlates with environmental variations (such as temperature and rainfall), causing variations in rodent populations. In some areas, a male predominance exists, attributed to males doing more outdoor activities. In other countries like Sweden, males and females have a 1:1 ratio. The mild form of HFRS (nephropathia epidemica) is found in the Scandinavian countries of Finland, Sweden, Denmark, and Norway.[7] The disease is seen throughout the year, and prevalence varies with the population dynamics of rodents.[8] Hantavirus strains causing HFRS are rare in Africa but have been reported; in addition, the virus has been found in non-rodent African vectors, such as shrews and bats.[9]

The most common serotypes in China are the Hantaan and the Seoul viruses. In Europe, the most commonly identified species are Dobrava and Puumala.[6] 

The disease has a generally low morbidity; however, the mortality for HFRS can be anywhere from less than 1% up to 15%, depending on the viral strain (in contrast, the mortality for HCPS is up to 40%.) Risk factors have not been widely studied; however, a study of Puumala virus infections noted smoking as a risk factor.[10] Age is also a factor, as it has been reported that most deaths occur in older patients above 70. Genetics has also been noted to play a role; the HLA-B8-DR3 haplotype and others have been associated with high mortality rates. This is likely due to significant mortality attributed to differences in immune response.[11][12][13] Any rodent exposure increases the risk of contracting the disease.

Pathophysiology

Hantaviruses contain negative-sense single-stranded RNA composed of 3 segments encoding for RNA-dependent RNA polymerase, nucleocapsid protein, and glycoprotein precursor. The virions are spherical and enveloped with a lipid bilayer containing two types of surface glycoproteins.[2] The glycoproteins on the surface of Hantaviruses attach to integrin and complement receptors and infect endothelial, epithelial, dendritic, and lymphocytic cells.[4][14] Attachment to endothelial cells in the microvasculature is a causative factor in disease pathology, causing capillary leakage in renal glomeruli and tubular cells. The Hantaviruses causing HFRS have been shown to attach to microvasculature in the lungs, heart, liver, and spleen; however, the primary clinical symptoms are associated with renal dysfunction.[14]

The other defining clinical symptom of HFRS is abnormal coagulation. It is thought that the viral particles adhering to endothelial cells cause platelet aggregation, leading to consumptive coagulopathy and complement activation. More severe presentations of HFRS can result in disseminated intravascular coagulation and thrombosis.[14]

Most of the morbidity and mortality associated with HFRS are attributed to a hyper-reactive immune response to the viral pathogens.[15] The concentrations of cytokines IL-6, IFN-γ, TNF-α, IL-18, and others have been associated with disease severity. Vascular endothelial growth factors (VEGFs) are also considered an essential mediator of endothelial cell permeability.[5] T-cells are activated very early during HFRS, resulting in an absolute rise in monocytes, B-cells, neutrophils, and CD8+ (cytotoxic) T-cells.[8] Complement pathway activation plays a role in the pathogenesis of HFRS, as shown by lower C3 and higher MAC levels during active disease.[16] Immune complexes can also cause vascular injury by activating complement and triggering inflammatory cytokines.

An important defensive mechanism against Hantaviruses is thought to be the production of neutralizing antibodies. Patients who died of HFRS had significantly lower numbers of neutralizing antibodies, suggesting an association with mortality.[17]

Histopathology

Primary histological changes in HFRS include tubulointerstitial nephritis, acute tubular necrosis, necrotic glomerulonephritis, IgA nephropathy, and hemorrhagic necrosis.[1][18] One study of renal biopsies from patients with HFRS showed disruption of intercellular tight junctions, which correlated with disease severity; this could be a mechanism for increased capillary permeability. Of note, the glomerular endothelium in this study did not show structural damage despite the increased permeability, supporting an immunologic mechanism of injury rather than direct cellular toxicity from the virus itself.[19] Evidence further supporting intercellular junction disruption in HFRS is in vitro studies demonstrating redistribution of tight junction proteins and cytoskeletal rearrangements affecting podocyte mobility.[14]

History and Physical

History

The history of hemorrhagic fever with renal failure syndrome is non-specific. The patient usually presents with acute flu-like symptoms, such as high-grade fever, myalgias, headache, backache, diarrhea, and vomiting. Depending on the severity of the illness, patients can have symptoms of hypotensive shock, such as dyspnea, confusion, diaphoresis, and palpitations. Other symptoms include dizziness, chills, increased thirst, flank pain, and costovertebral tenderness. The incubation period is between 12 and 16 days. Subclinical cases are prevalent in children. If the patient has traveled to an endemic area, works in an occupation with rodent exposure (such as farming or park ranger), has slept in a place infested with rodents, or was bitten by a rodent, then the likelihood of HFRS is increased.

Although patients do not always follow a typical clinical course, the disease often has the following five progressive stages:

1. Febrile
2. Hypotensive
3. Oliguric
4. Diuretic
5. Convalescent

HFRS in children and adults exhibits these same 5 phases, but children often have less severe presentations associated with abdominal pain. Patients can occasionally present with HFRS-associated orchitis or pancreatitis.[20][21]

Physical Examination

Findings vary depending on the stage of the disease. The disease generally has 5 stages, as mentioned above, and each has different specific findings, as described below:[1][4]

The febrile stage lasts for around 3 to 7 days and is characterized by the following:

• Flushing of the face, neck, and chest
• Subconjunctival hemorrhage
• Bradycardia
• Acute kidney injury (AKI) appears toward the end of this phase
• Petechia in the axilla and soft palate also can appear towards the end of this phase

The hypotensive stage lasts from several hours to two days. Hypotensive shock during this stage is associated with one-third of HFRS deaths. Bleeding complications can also occur during this stage. Clinical presentations include the following:

• Hypotension and tachycardia
• Bleeding diatheses, including bruising, hematemesis, epistaxis, melena, hematuria, and intracranial hemorrhage 
• Acute abdomen due to paralytic ileus
• Convulsions or purposeless movements

The oliguric stage lasts between 3 and 7 days and is associated and often requires hemodialysis. It is associated with about half of  HFRS mortality and has the following findings:

• Oliguria or anuria
• Azotemia
• Abdominal or back pain
• Normotension or hypertension
• Hemorrhagia
• Peripheral edema
• Pulmonary edema

The diuretic stage persists for 2-3 weeks and can be associated with several liters of daily urine output. It is characterized by the following:

• Excessive diuresis leading to hypotension
• Signs of dehydration

The convalescent stage may continue for as long as 3-6 months. The patients have the following features:

• Fatigue and myalgias
• Slowly resolving tubular concentrating defects 

Evaluation

HFRS can be diagnosed with the help of lab investigations, imaging studies, and other tests. The following are lab findings that can aid in diagnosis:[22]

• Significant leukocytosis, thrombocytopenia, and high or normal hematocrit level
• Elevated liver enzymes, blood urea nitrogen, and serum creatinine
• Hyponatremia, hyperkalemia, and hyperphosphatemia during the oliguric phase
• Reduced complement (especially C3) levels
• Prolonged prothrombin, activated partial thromboplastin, and bleeding times
• Elevated fibrin degradation products
• Urinalysis with hematuria and proteinuria
• Elevated serum amylase and lipase in the setting of pancreatitis

Thrombocytopenia is a crucial lab finding associated with increased blood vessel permeability and disease severity.[1][8] In early AKI, signs may be decreased urine output, proteinuria, and hematuria. Further, into the oliguric phase, there will be elevated creatinine and decreased glomerular filtration rate. Anuria leads to electrolyte imbalances, such as hyperkalemia and hyperphosphatemia.

The humoral immune response can be used to help track disease progression. IgM levels are prevalent early in the disease and reach maximal levels around days 7  to 11 after the initial start of symptoms. The recovery phase shows declining IgM levels and increased IgG levels. Western blot can also identify viral antigens. PCR is not as reliable since increased viral load is short-lived.[8]

Imaging Studies

Renal ultrasounds, CT scans, and MRIs are often used to image kidney anatomy. Imaging can show hydronephrosis, chronic changes, and the presence of blood products resulting from intramedullary bleeding (a possible consequence of HFRS).

Treatment / Management

Treatment of hemorrhagic fever with renal failure syndrome depends on the stage of the illness and the patient's hemodynamic status. The most crucial step in managing HFRS is maintaining the patient's circulatory status. Early and efficient fluid therapy is the mainstay of management. Most patients will recover with supportive care. In cases of shock, intravenous albumin and vasoactive agents can be helpful. Fluid administration must be closely monitored as it can cause extravasation caused by capillary leak, particularly during the febrile and hypotensive stages. Excess fluid can also cause pulmonary edema during the oliguric phase. Diuretics are helpful in patients with volume overload and oliguria. However, if diuretics fail, renal replacement therapy may be needed, particularly in patients with volume overload, acidosis, and hyperkalemia.[8][23]

Some clinical trials show that when used early, ribavirin and other antivirals can decrease viral load by inhibiting viral replication. Antivirals have not been proven effective in later stages of the disease. Other studies show Icatibant, a bradykinin inhibitor, to be effective in patients with Puumala infection (bradykinin is associated with vascular permeability).[1][17] Theoretically, corticosteroids should improve HFRS since much of the systemic damage results from an overactive immune response. Steroids can be used case-by-case; however, no randomized or large clinical trials have proven effectiveness.[1]

Prevention is critical to reducing Hantavirus morbidity and mortality. Improved public health measures like reducing rodent entry into human dwellings and removing rodent feces and urine are essential to prevent outbreaks. Officials often monitor rodent populations, and removal of rodent feces and urine should involve proper ventilation and protective equipment.[1]

Official FDA- or WHO-approved vaccines are not currently available, but inactivated Orthohantavirus vaccines have been used in China and Korea and appear safe and effective (although large cohort data is lacking). DNA vaccines and vaccines using the virus subunit components are also being studied.[1][2] Since early neutralizing antibodies are considered a key component of resisting infection, this may be clinically important. Convalescent plasma containing neutralizing antibodies has shown effectiveness when administered in the early stages of HFRS.[1]

Differential Diagnosis

Hemorrhagic fever with renal failure syndrome should be considered in the differential when dealing with acute renal failure in high-risk geographic areas. The differential diagnoses include other causes of hemorrhagic fever that have overlapping symptoms and evaluation with HFRS. These conditions include Yellow fever, Ebola, Dengue, Leptospirosis, Malaria, Murine typhus, septicemia, disseminated intravascular coagulation, and thrombotic thrombocytopenic purpura.

Prognosis

Usually, the course of HFRS is self-limiting, and the patient will fully recover; however, the prognosis depends on which serotype of the virus the patient was infected with. The mortality of HFRS is overall low but ranges from 0.43% to 15%, depending on the infecting virus strain.[17][24] The Puumala strain has mortality rates of less than 1%; the Seoul virus causes moderate disease; and species causing severe disease are Dobrava and Hantaan, with mortality rates of 5% to 15%.[4]

All strains can produce symptoms that range from asymptomatic to severe forms of the disease. Once a patient recuperates, kidney parameters usually return to pre-illness values.

Complications

Hemorrhagic fever with renal failure syndrome can be fatal, and patients can have multiorgan system failure with the following complications:

• Acute encephalomyelitis 
• Pulmonary edema
• Coagulation abnormalities like disseminated intravascular coagulation
• Acute respiratory distress syndrome[25]
• Multiorgan failure
• End-stage renal disease
• Acute pancreatitis[26][27]

Deterrence and Patient Education

Teaching patients about the risks of exposure to rodent urine and feces is essential. Patients at higher risk are those living and traveling to endemic areas or working in occupations such as farming, forestry, or in the military. They should be advised and educated on minimizing contact with rodents.

A low-sodium diet and fluid restriction are recommended during the oliguric stage, followed by a liberal fluid intake in the diuretic stage. Bed rest in the acute phase of the disease is recommended.

Pearls and Other Issues

Here are some essential facts about hemorrhagic fever with renal failure syndrome:

• Hantavirus is transmitted through inhalation of aerosolized urine or feces of rodents.
• Hantavirus strains causing HCPS are found in the Americas, while Hantavirus strains causing HFRS are found in Asia, Europe, and more recently in Africa.
• HFRS pathophysiology involves 3 main processes: 1) increased vascular permeability, 2) consumptive coagulopathy causing thrombocytopenia and bleeding diathesis, and 3) a hyperactive immune response with cytokine storm.
• There are generally 5 distinct phases to the clinical presentation with associated symptomology. These phases are 1) febrile, 2) hypotensive, 3) oliguric, 4) diuretic, and 5) convalescent.
• Most of the mortality is seen in the hypotensive and oliguric phases.
• Patients in the diuretic phase are prone to complications of dehydration.
• Thrombocytopenia in HFRS is associated with disease severity and should prompt a critical care evaluation.
• Supportive care is the most helpful treatment and has been shown to decrease mortality.
• Prevention is achieved by decreasing rodent populations and minimizing associated contact.
• Vaccines are being studied and inactivated Hantavirus vaccines are available in China and Korea.

Enhancing Healthcare Team Outcomes

To enhance the outcome of hemorrhagic fever with renal failure syndrome, educating the public about this zoonotic disease and its transmission is of prime importance. Since rodents are the vectors of infection, patients should avoid contact when possible, store food properly to prevent rodent exposure, and avoid sleeping outside or in infested areas. Management by an interprofessional team, including primary care providers, intensivists, nephrologists, and infectious disease specialists, should be utilized. Local public health officials can be involved in monitoring rodent exposure and current disease trends to minimize the risk of outbreaks.