Hemorrhagic Fever With Renal Failure Syndrome

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 hemorrhagic fever with renal failure syndrome symptoms. A vigorous response is often a marker of severe disease. T-cell activation occurs very early in the course of hemorrhagic fever with renal failure syndrome 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. Interferon-gamma–producing T cells may help reduce the risk of progression to acute renal failure.

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 hemorrhagic fever with renal failure syndrome. 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 hemorrhagic fever with renal failure syndrome 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.

The viruses of the genus Hantavirus (family Bunyaviridae) cause different forms of hemorrhagic fever with renal failure syndrome. The severity of the illness depends on the infecting virus and on the geographic distribution. The Hantaviruses associated with HFRS include inter alia: Hantaan virus (HTNV), Dobrava/Belgrade virus (DOBV), Seoul virus (SEOV), Puumala virus (PUUV), and Saaremaa virus (SAAV), while HPS is caused by Sin Nombre (SNV) and related viruses.

• Korean hemorrhagic fever, a severe type of hemorrhagic fever with renal failure syndrome observed in Asia, is caused by a Hantavirus and is transmitted by the infected A agrarius mouse (striped field mouse). ^[4]

• Balkan hemorrhagic fever, a severe type of hemorrhagic fever with renal failure syndrome 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 hemorrhagic fever with renal failure syndrome is caused by the Seoul virus and is transmitted by the infected Rattusrattus rat (black rat) or the Rattusnovergicus rat (urban rat).

• Nephropathiaepidemica, a mild form of hemorrhagic fever with renal failure syndrome observed in Europe, is caused by the Puumala virus and is transmitted by the infected Clethrionomysglariolus vole (European bank vole).

• The virus is usually transmitted to humans through inhalation of infected animal excreta (ie, urine, feces, saliva). Transmission by bite occurs among rodents and may also result in human infection. Although reports from Chile and Argentina have claimed that the hantavirus strain Andes virus can cause human-to-human transmission, ^[5] no evidence from comparative studies is available to support this claim. ^[6]

• Epidemiological investigations have linked viral exposure to activities such as heavy farm work, threshing, sleeping on the ground, military exercises, and lower socioeconomic status. Military personnel are at greater risk for hantavirus infections because maneuvers often involve soil removal, digging with accompanied dust, and living in the field, which can expose soldiers to rodents and their excreta. ^[7]

United States statistics

The rodent reservoir of Seoul virus (Rattusnorvegicus) 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 hemorrhagic fever with renal failure syndrome caused by the pathogen in the Seoul infections in few reported cases (see the image below).

International statistics

The severe form of hemorrhagic fever with renal failure syndrome 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 hemorrhagic fever with renal failure syndrome (nephropathicepidemica) occurs in the Scandinavian countries of Sweden, Finland, Norway, and Denmark. ^[8] The disease is observed throughout the year, but the prevalence depends on the population dynamics of the carrier rodents.

Seasonal peaks of HFRS in spring and fall are due to rodent breeding seasons, with increased rodent contact due to human planting and harvesting in these periods. The most severe form of HFRS is caused by Hantaan virus (HTNV) in Asia. Puumala is the most prevalent Hantavirus and causes a less severe from of HFRS through central and northern Europe, the Russian Federation and the Balkans. Dobrava virus causes a more severe form of HFRS. The causes of the differences in clinical severity are unknown; it may involve differences in the strain of the virus, the infective dose, or various host factors.

Race-, sex-, and age-related demographics

No apparent racial predilection is known.

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

Hemorrhagic fever with renal failure syndrome is commonly reported in persons older than 15 years, with a peak incidence of 20-60 years. In children and adolescents younger than 15 years, the disease is mild and often subclinical.

Morbidity/mortality

Mortality and morbidity rates vary from 5-15%, depending on the strain of the virus. In Dobrava virus–induced HFRS, mortality rates range from 3-12%, whilst that due to Puumala virus carries a mortality of 0.1-0.4%.

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. Atrophy of the anterior pituitary lobe with diminution of gland function may occur during the late stages of the disease. ^[9]

• Hemorrhagic fever with renal failure syndrome 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 hemorrhagic fever with renal failure syndrome 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.

• Pancreatitis and orchitis may complicate hemorrhagic fever with renal failure syndrome.

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).