eMedicine Specialties > Pediatrics: General Medicine > Nephrology

Hemorrhagic Fever With Renal Failure Syndrome

Author: Rajendra Bhimma, MB, ChB, Associate Professor of Pediatrics, Principal Specialist, Department of Pediatrics and Child Health, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, South Africa
Coauthor(s): Vellore K Sairam, MBBS, Assistant Professor, Department of Nephrology, Sri Ramachandra Medical College and Research Institute, India; Luther Travis, MD, William W Glauser Professor of Pediatrics and Pediatric Nephrology, Department of Pediatrics, Divisions of Nephrology and Diabetes, University of Texas Medical Branch and Children's Hospital
Contributor Information and Disclosures

Updated: May 14, 2008

Introduction

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

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).

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