AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Hemorrhagic fever with renal failure syndrome (HFRS) occurs mainly in Europe and Asia and is characterized by fever and renal failure associated with hemorrhagic manifestations. HFRS is caused by an airborne contact with secretions from rodent hosts infected with the group of viruses belonging to the genus Hantavirus of the family Bunyaviridae. In Europe, HFRS is caused by 3 hantaviruses: Puumala virus (PUUV), carried by the bank vole (Myodes glareolus); Dobrava virus (DOBV), carried by the mouse (Apodemus flavicollis); and Saaremaa virus (SAAV), carried by the striped field mouse (Apodemus agrarius). 

HFRS was initially recognized between 1913 and 1930 by Soviet scientists, who described sporadic outbreaks of fever with renal failure in the eastern Soviet Union. The disease came to the attention of the Western world in 1950, when the North American soldiers serving with the United Nations forces in Korea developed a febrile illness associated with shock, hemorrhage, and renal failure.

In 1993, in the southwestern United States, an outbreak of respiratory illness caused by the Sin Nombre virus, which belongs to the genus Hantavirus, occurred and was described as the Hantavirus pulmonary syndrome (HPS).

Pathophysiology

The pathogenesis is largely unknown, but findings from several studies have suggested that immune mechanisms play an important role. After the infection, marked cytokine production, kallikrein-kinin activation, complement pathway activation, or increased levels of circulating immune complexes occur. These components play an important role during the febrile and hypotensive stages. Damage to the vascular endothelium, capillary dilatation, and leakage are clinically significant features of the disease.

Antibody specific to the viral antigen can be detected close to the onset of HFRS symptoms. A vigorous response is often a marker of severe disease. T-cell activation occurs very early in the course of HFRS and is associated with an absolute increase in the number of neutrophils, monocytes, B cells, and CD8+ (suppressor) T cells. The number of helper (CD4+) T cells does not increase, resulting in a decrease in the ratio of helper-to-suppressor T cells. Virus has been cultured from B cells and monocytes but not from T cells. Therefore, T-cell activation is a response to infection of other cell types rather than a consequence of direct viral infection.

A possible role for immune complexes has also been suggested following the demonstration of immune complexes in serum, on the surface of red cells and platelets, in glomeruli, in renal tubules, and in urine. Activation of both classic and alternative complement pathways also occurs in HFRS. By activating complement and by triggering mediator release from platelets and inflammatory cells, immune complexes can produce the vascular injury that is the hallmark of the disease.

Some investigators have suggested that HFRS is primarily an allergic disease. This is based on the finding of early appearance of specific immunoglobulin E (IgE), the presence of IgE immune complexes, and the beneficial effects of therapy aimed at inhibiting allergic pathways.

Frequency

United States

The rodent reservoir of Seoul virus (Rattus norvegicus) are present in many port cities of the eastern United States and were introduced from Europe by cargo ships. Observations from enhanced surveillance for Hantavirus infection in humans eventually suggested the presence of HFRS caused by the pathogen in the Seoul infections in few reported cases.

International

The severe form of HFRS occurs in China, Japan, and Singapore. The number of cases reported in China is approximately 100,000-250,000 per year. The mild form of HFRS (nephropathic epidemica) occurs in the Scandinavian countries of Sweden, Finland, Norway, and Denmark.¹ The disease is observed throughout the year, but the prevalence depends on the population dynamics of the carrier rodents.

Mortality/Morbidity

Mortality and morbidity rates vary from 5-15%, depending on the strain of the virus.

Race

No apparent racial predilection is known.

Sex

The increased incidence in male individuals is caused by their probable increased frequency of outdoor activities, which leads to contact with infected rodents.

Age

HFRS is commonly reported in persons older than 15 years. In children and adolescents younger than 15 years, the disease is mild and often subclinical.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The clinical features consist of a triad of fever, hemorrhage, and renal insufficiency. Other common symptoms during the initial phase of the illness include headache, myalgia, abdominal and back pain, nausea, vomiting, and diarrhea. The disease may range from mild to severe. Subclinical infections are especially common in children. The average incubation period varies from 4-42 days. The disease is characterized by fever, hemorrhagic manifestations, and (if severe) hypovolemic shock.

The disease has 5 progressive stages: febrile, hypotensive, oliguric, diuretic, and convalescent.² Physicians should be aware of the various presentations during each stage. Individual patients can completely skip stages.

Physical

Physical examination of the patient is based on the stage of the illness.

• The febrile stage occurs in all patients and lasts about 4-6 days. The disease is characterized by an abrupt onset of fever with a temperature in the range of 40°C.
• • Patients may complain of headache, chills, abdominal pain, and malaise.
  • Flushing of the face, neck, and chest due to probable vascular dysregulation may be observed.
  • Petechia may occur in the axilla and soft palate.
  • Subconjunctival hemorrhage is noted in one third of patients.
  • Absolute bradycardia may be noted.
  • A normal or mildly elevated hematocrit level caused by hemoconcentration may be observed. Leucocytosis with atypical lymphocytes. The disease is characterized by thrombocytopenia, which also defines prognosis and severity of renal failure.
  • The onset of proteinuria and microhematuria can be observed. Proteinuria due to Hantavirus nephritis is transient and usually resolves within 2 weeks.
• The hypotensive stage lasts approximately a few hours to 2 days. It occurs in 11% of patients and coincides with defervescence.
• • Patients may have tachycardia, which may indicate impending shock.
  • Patients may have acute abdomen caused by a paralytic ileus.
  • Patients may have convulsions or purposeless movements.
  • The coagulation profile may reveal a prolonged bleeding time, prothrombin time (PT), and activated partial thromboplastin time (aPTT).
• The oliguric stage occurs in 65% of the patients and lasts about 3-6 days.
• • Oliguria, hypertension, bleeding tendency (caused by uremia), and edema are characteristic of this stage.
  • Patients may develop pulmonary edema.
  • Thrombocytopenia usually resolves in the oliguric stage.
• The diuretic stage lasts 2-3 weeks.
• • Diuresis in the range of 3-6 L/d occurs after symptoms from the previous stage disappear. Responsiveness of the collecting duct to vasopressin is reduced.
  • Rapid signs of dehydration and severe shock can occur during this stage if fluid replacement is inadequate. The patient's volume status should be closely monitored.
• The convalescent stage may last for as long as 3-6 months.
• • Clinical recovery usually begins in the middle of the second week, with a gradual resolution of symptoms and azotemia.
  • The concentrating capacity of the renal tubules recovers over many months.

Causes

The viruses of the genus Hantavirus cause different forms of hemorrhagic fever with renal failure syndrome (HFRS). The severity of the illness depends on the infecting virus and on the geographic distribution.

• Korean hemorrhagic fever, a severe type of HFRS observed in Asia, is caused by a Hantavirus and is transmitted by the infected A agrarius mouse (striped field mouse).³
• Balkan hemorrhagic fever, a severe type of HFRS observed in Balkan countries, is caused by the Dobrava virus and is transmitted by the infected A flavicollis mouse (yellow-necked field mouse).
• A mild-to-moderate form of HFRS is caused by the Seoul virus and is transmitted by the infected Rattus rattus rat (black rat) or the Rattus novergicus rat (urban rat).
• Nephropathia epidemica, a mild form of HFRS observed in Europe, is caused by the Puumala virus and is transmitted by the infected Clethrionomys glariolus vole (European bank vole).

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

In high-risk geographic areas, hemorrhagic fever with renal failure syndrome (HFRS) should be included in the differential diagnosis of acute renal failure of uncertain cause associated with febrile illness, hemorrhagic phenomenon, or renal or hepatic dysfunction.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

The geographic distribution of the disease, an exposure to rodents, the patient's clinical picture, and the laboratory data suggest the diagnosis.

• Enzyme-linked immunosorbent assay (ELISA) is useful in detecting antihantaviral-specific immunoglobulin M (IgM) early in the course of the illness.
• Antihantaviral immunoglobulin G (IgG) titers may be elevated for prolonged periods (as long as 10 y).
• Blood findings usually reveals clinically significant leukocytosis, an elevated or normal hematocrit level, and thrombocytopenia.
• Elevated levels of liver enzymes, BUN, and serum creatinine can be observed.
• Hyponatremia, hyperphosphatemia, and hyperkalemia may occur during the oliguric phase.
• Complement (C3) levels may be decreased; therefore, hemorrhagic fever with renal failure syndrome (HFRS) should be included in the differential diagnosis of hypocomplementemic acute nephritic syndrome.
• The coagulation profile can be altered with a prolonged PT, aPTT, or bleeding time. Levels of fibrin-degradation products also may be elevated.
• Urinalysis consistently shows hematuria and proteinuria. Proteinuria may last for few years after the attack.
• Increased levels of nitric oxide (NO) during the acute phase of the HFRS illness are correlated with disease activity.

Imaging Studies

• No specific radiologic studies are indicated.

Other Tests

• Hantavirus antigen can be detected in various tissues, predominately in the microvasculature, by using immunohistochemical (IHC) methods.

Procedures

• Performing a kidney biopsy is not essential for diagnosis.
• As discussed earlier, the diagnosis of HFRS is based on a history of exposure to infected rodents, clinical symptoms and signs, and laboratory findings.
• If the diagnosis cannot be clearly made during the course of the illness and if the patient's hemodynamic and coagulation status is stable, a renal biopsy is indicated.

Histologic Findings

• Upon histologic evaluation, renal alterations in HFRS include features of acute interstitial nephritis, such as acute tubular necrosis with evidence of glomerular and endothelial damage.
• Hemorrhagic necrosis has been identified in the renal medulla.
• Hemorrhage is observed in different organs, especially the right atrium of the heart, the anterior pituitary gland, the pancreas, and the skin.
• Pulmonary infiltrates may be observed, and, pulmonary edema is occasionally present.
• Infiltration of large, atypical mononuclear cells in the spleen, lymph node, and hepatic portal triad has been reported.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Treatment depends on the stage of the disease and on the patient's hydration status and hemodynamic condition. The most essential step in managing hemorrhagic fever with renal failure syndrome (HFRS) is maintaining the patient's circulatory and hemodynamic status.

• During active illness, maintaining fluid and electrolyte balance is mandatory.
• • Early and effective fluid therapy is the cornerstone of managing renal failure.
  • Most patients recover with supportive care.
  • The indications for various medications are based on the patient's specific requirements during the different stages of the disease process.
• The use of vasoactive agents and intravenous albumin during periods of shock is helpful. Excessive administration of fluids can lead to extravasation caused by capillary leak, especially during the febrile and hypotensive stages.
• Consider the use of diuretics, such as furosemide, when the patient has volume overload and oliguria. Consider renal replacement therapy if the patient has no response to diuretics and if he or she has other features, such as fluid overload, hyperkalemia, and acidosis that increases azotemia and is associated with oliguria or anuria.
• The possibility of the sudden appearance of life-threatening GI bleeding is always present. In that case, blood transfusions and the use of H₂ receptor antagonists are indicated as general emergency procedures. In the case of DIC, fresh plasma infusions, plasma exchange treatment, or both are administered but are not always effective.
• Results of one prospective placebo-controlled trial suggested that intravenous ribavirin decreased the severity and mortality of HFRS in China.⁴
• • In contrast, 30 patients with HPS who received investigational open-label intravenous ribavirin tolerated it well.
  • Furthermore, treatment was accompanied by drug-induced anemia, which required transfusion, and no clear evidence of benefit was obtained.
  • Differences in dosing schedules did not account for the contrasting responses, and the rapidity with which the disease progressed may have cause the lack of response in the patients with HPS.
  • Ribavirin is not approved for intravenous use in the United States, pending further ongoing studies.
  • If ribavirin is used during the early part (febrile phase) of the illness, it reduces viremia and the severity of the illness.
• Antihypertensives are indicated in patients with hypertension, which is usually present during the oliguric phase of the illness.
• Dialysis is indicated if the patient has prolonged oliguria with no response to medical treatment and if renal failure is rapid deteriorating with worsening fluid and electrolyte abnormalities.

Surgical Care

• If the clinical presentation involves extravasation of plasma in the abdomen (suggestive of acute abdomen and subsequent development of paralytic ileus), the patient probably needs surgical evaluation and, occasionally, exploratory laparotomy.
• Renal rupture, which rarely occurs, requires surgical management.
• A pediatric nephrologist should perform renal biopsy, if indicated, after taking all precautions. The patient's hemodynamic status and coagulation status should be stable before the biopsy is performed.

Consultations

Consultation with the following specialists are indicated as needed:

• Pediatric nephrologist
• Pediatric infectious disease specialist
• Pediatric critical care specialist
• Pediatric surgeon

Diet

A low-sodium diet with restriction of fluid during the oliguric phase, followed by liberal intake of fluid in the diuretic phase, is recommended.

Activity

Bed rest during the acute phase of the illness is recommended.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Antihypertensive agents, vasoactive drugs, colloids, or diuretics may be needed to control hypertension, to treat shock, or to induce diuresis, respectively. Antibiotics have not had any benefit during the course of illness. Although intravenous ribavirin initiated within 4 days of illness reduces the morbidity and mortality associated with the disease, in the setting of adequate supportive measures and dialysis, ribavirin is not needed; at present, it is not approved for use in United States.

Drug Category: Antihypertensive agents

These agents are used to treat hypertension. Pharmacotherapy may include numerous drug classes that have antihypertensive effects, such as beta-blockers, calcium-channel blockers, ACE inhibitors, alpha-blockers, and angiotensin II–receptor antagonists. The antihypertensive regimen is customized to the population, with attention on ways to enhance compliance and to improve the patient's ability to tolerate treatment. For additional information see the eMedicine pediatric topic Hypertension.

Drug Category: Diuretic agents

These agents are used for the treatment of hypertension, oliguria, or edema. They promote the excretion of water and electrolytes by the kidneys. Diuretics are also used to treat heart failure or hepatic, renal, or pulmonary disease when sodium and water retention has resulted in edema or ascites. They may be used as monotherapy or combination to treat hypertension.

Drug Category: Colloids

These agents are used for volume expansion to treat shock. They are preferred over crystalloids because the excessive administration of fluids can lead to extravasation caused by vascular leak, especially during the febrile and hypotensive stages.

Drug Category: Vasopressors

Vasopressors are used for the treatment of hypotension. Dopamine is unique among other catecholamines; unlike norepinephrine, epinephrine, and isoproterenol, low doses of dopamine increase renal blood flow without increasing the patient's heart rate or systemic arterial pressure. It is an effective vasopressor for treating shock and hypotension in persons unresponsive to plasma volume expansion (ie, crystalloids or colloids). It also dilates the mesenteric and renal blood vessels, which improves renal blood flow and increases the glomerular filtration rate, sodium excretion, and urine output. However, dosages of more than 20 mcg/kg/min may decrease renal blood flow secondary to a reversal of the dopaminergic vasodilation.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients with established oliguric renal failure must be carefully monitored for water, electrolyte, and acid-base imbalance, which must be promptly corrected.  
• Vasoactive agents should be used in patients with shock after correction of volume deficit.
• In cases with pulmonary edema, the use of forced diuresis by administration of furosemide, vigorous ultrafiltration, or continuous arteriovenous hemofiltration can be lifesaving.

Further Outpatient Care

• Recovery takes 0-3 months from the acute phase of the illness, usually beginning in the middle of the second week.
• • The diuretic phase may last from a few days to weeks, and close monitoring for electrolyte imbalances and signs of dehydration is needed.
  • Patient education regarding electrolyte imbalances and signs of dehydration is imperative.
  • Follow-up care is needed as often as warranted.
• The convalescent phase lasts for 3-6 months.
• • Glomerular clearances usually normalize, and the concentration ability of the renal tubules steadily improves.
  • Follow-up should be conducted on a weekly basis, until the clearance normalizes, and then on a monthly basis.
• Long-term follow-up care is important, especially because hypertension and proteinuria have been reported on long-term follow-up.
• Patients with hypertension, residual neurologic defects, concentration defects in the renal tubules, or persistent proteinuria should be followed on a regular basis.

Transfer

• Early referral to a tertiary center is essential to prevent complications and decrease morbidity and mortality. 

Deterrence/Prevention

Human habits can increase incidence of the disease; hence, basic preventive measures are required, including the following:

• Proper storing of food and avoiding contamination by rats
• Taking precautions during work or travel in farms contaminated with rodents
• Avoiding camping in grain fields
• Avoiding stocking straw stacks outside houses
• Avoiding sleeping outside homes

Complications

• Complications that develop during the illness are rare.
• Abdominal pain and back pain occurs because of retroperitoneal hemorrhage.
• During the oliguric or early diuretic phase, renal rupture occurs, but it responds to conservative management and only occasionally requires surgical intervention.
• Pulmonary edema and intraventricular hemorrhage occur.
• Transient hypopituitarism occurs, causing an abnormal anterior pituitary hormonal response and leading to delayed diuresis and the late appearance of Sheehan syndrome.
• Hemorrhagic fever with renal failure syndrome (HFRS) is a self-limiting disease, and most patients recover without any sequelae; however, in few patients, neurologic and renal tubular defects may persist.
• • Defective sodium reabsorption is observed to occur in patients one year after the illness, causing increased sodium excretion.
  • Long-term monitoring of proteinuria and hypertension is essential.
• Some patients may develop hypercalciuria and hyperphosphaturia due to tubular defects.
• Although recovery from hantaviral disease is complete, chronic renal insufficiency and hypertensive renal disease have been reported.
• Approximately 10% of adults with end-stage renal disease (ESRD) have Hantavirus-specific antibodies.
• The Dobrava virus causes severe form of HFRS in Balkan regions of eastern Europe. It is associated with an increased mortality rate; patients develop hepatomegaly, with dysfunction observed more commonly than hemorrhagic manifestations.

Patient Education

• The prevalence of the disease largely depends on human habits; therefore, patient health education is essential to prevent the disease.
• Educate patients regarding the following issues:
• • Avoidance of living in barracks and sleeping in open areas outside homes
  • Eradication of rodents
  • Effective storage of food items
  • Early reporting of illness and obtaining medical advise
  • Avoidance of person-to-person transmission or nosocomial transmission
  • Need for a liberal intake of fluid during the diuretic phase of the illness to avoid dehydration and shock
• For additional advice or information regarding the disease, patients are advised to contact the Centers for Disease Control and Prevention (CDC) (Tel: 800-CDC-INFO, email: cdcinfo@cdc.gov).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider hemorrhagic fever with renal failure syndrome (HFRS) in differential diagnosis of fever with hemorrhagic manifestation and renal failure
• Failure to suspect HFRS if the patient has a history of travel to an endemic area and if symptoms appear within 3 weeks of their return home

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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2. Ko KW. Haemorrhagic fever with renal syndrome: clinical aspects. Pediatr Nephrol. Mar 1992;6(2):197-200. [Medline].
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18. Mustonen J, Vaheri A, Clement J. Third International Conference on Haemorrhagic Fever with Renal Syndrome (HFRS) and Hantaviruses. Nephrol Dial Transplant. Apr 1996;11(4):730-3. [Medline].
19. Niklasson BS. Haemorrhagic fever with renal syndrome, virological and epidemiological aspects. Pediatr Nephrol. Mar 1992;6(2):201-4. [Medline].
20. Papadimitriou M. Hantavirus nephropathy. Kidney Int. Sep 1995;48(3):887-902. [Medline].
21. Papadimitriou MG, Antoniadis A. Hantavirus nephropathy in Greece. Lancet. Apr 23 1994;343(8904):1038. [Medline].
22. Peco-Antic A, Popovic-Rolovic M, Gligic A, et al. Clinical characteristics of haemorrhagic fever with renal syndrome in children. Pediatr Nephrol. Jul 1992;6(4):335-8. [Medline].
23. Peters CJ, Simpson GL, Levy H. Spectrum of hantavirus infection: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Annu Rev Med. 1999;50:531-45. [Medline].
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25. Yoo KH, Choi Y. Haemorrhagic fever with renal syndrome in Korean children. Korean Society of Pediatric Nephrology. Pediatr Nephrol. Oct 1994;8(5):540-4. [Medline].
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Article Last Updated: May 14, 2008