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Hemorrhagic Fever With Renal SyndromeAutor: Marcelo Moraes Gazola, MD |
Hemorrhagic fever with renal disease (HFRD) is an infectious viral disease characterized by fever, capillary dilatation, and blood leakage leading to hemorrhagic manifestations and, in severe cases, associated with shock and renal impairment.
It is caused by viruses of the genus Hantavirus, a genus of single-stranded RNA viruses belonging to the Bunyaviridae family. The genus consists of at least five species: Seoul virus, Puumala virus, Porogia virus, Prospect Hill virus, and Hantaan virus (the prototype of the genus).
The disease is typically found in Asia (Korea, Japan, and China mainly) and Europe (principally Scandinavia). It usually occurs as outbreaks in an isolated event. This might explain the reason for its appearance on different regions of the globe, such as its last occurring outbreak in the southeast of Brazil.
The human transmission is from rodents, and there is no evidence for person-to-person transmission. The contaminated rodent excretes the virus in urine, feces, and saliva for weeks or months after infection. Transmission is by the respiratory route or by direct contact with fomites contaminated by rodent's excretion. The urban reservoir appears to be the house rat. The group with the greatest risk of acquiring HFRD are soldiers at field operations, campers, farmers, woodsmen, and family groups who live in houses harboring rodents. However, outbreaks have also occurred in laboratories housing field rodents or laboratory rats that carried the virus as an inapparent infection.
At autopsy petechial hemorrhages are found in the skin and in multiple organs, indicating widespread capillary fragility. Macroscopic hemorrhages in the pituitary and the right atrium, as well as a great gelatinous retroperitonial hemorrhage, are also found. If the patient died during the earlier stages of the disease, the renal medulla may be congested and hyperemic. If death occurred at a later onset, there may be marked tubular necrosis.
The incubation period lasts from 2 to 42 days, but is usually about 2 weeks. The illness is mild (with only fever, facial flush, backache, and muscle aches) or moderate (presenting the fever plus proteinuria and petechial hemorrhages) in 80% of the cases. The remaining 20% are severe, and these progress through five characteristic phases: febrile, hypotensive, oliguric, diuretic, and convalescent.
The febrile phase lasts approximately five days. The onset may be preceded by prodromal symptoms resembling an upper respiratory infection, but it is usually abrupt, often initiated by a chill and accompanied by fever(between 38.0 and 41.1°C), frontal or retroorbital headache, backache, abdominal pain, and generalized myalgia. Anorexia and thirst are present in almost every patient, and nausea and vomiting are common. One of the most typical early findings is a diffuse reddening of the skin most marked over the face and V area of the neck, that may resemble a severe sunburn. The erythema disappears with pressure, and dermatographism is common at the same time as the flush. Bulbar and palpebral conjunctivae show injection. Conjunctival petechiae may develop by the third to fifth day of illness, and subconjunctival hemorrhages may be important. The first location to form petechiae is usually the palate, and with 12 to 24 hours of evolution petechiae appear at pessure areas such as the axillary folds, lateral chest wall, belt line, hips, and thighs. Generalized nontenders linfadenomegaly occur. The degree of flush, fever, conjunctival infection and number of petechiae correlate quite well with the severity of the illness. Albuminuria, which is an almost universal finding, and the most important laboratory abnormality, appears abruptly between the second and fifth days of illness. The other laboratory studies do not show striking abnormalities.
On the fourth to seventh day of presentation, fever ends by lysis. This is the beginning of the hypotensive phase. In the beginning of this phase the patient has warm, dry skin and extremities. As systolic pressure starts to decrease and pulse pressure narrows. Tachycardia replaces the relative bradycardia of the febrile phase. As this occurs the skin becomes cold and moist, and hypotension, or even shock, take place. Patients manifest nausea, vomiting, and abdominal pain, associated with loss of plasma through damaged capillaries. There is a rise of the hematocrit associated with leukocytosis (10,000 to 56,000 leukocytes per microliter), thrombocytopenia (less than 70,000 platelets per microliter), heavy proteinuria, and a decreased renal clearance. The hypotensive phase lasts about 4 days.
The oliguric phase follows next beginning approximately on the eighth day of illness. In this phase the blood pressure returns to normal levels, rising up to hypertensive levels. This new shift in the pressure levels is due to the reabsorbance of the extracelular fluid, which leads to hypervolemia and hypertension. Oliguria is an important feature of this phase. The patient continues to be weak and thirsty, and headaches and backaches persist and may worsen. Blood urea nitrogen rises rapidly, and, in severe cases, is accompanied by hyperkalemia, hyperphosphatemia, hypocalcemia, and metabolic acidosis. Hemorrhagic manifestations become more important and include petechiae, hematemesis, melena, hemoptysis, gross hematuria, and intracranial hemorrhages.
With the onset of diuresis on about the seventh to eleventh day of illness, the diuretic phase begins. There is a return of the renal clearance, although symptoms of fluid and electrolyte abnormalities and central nervous system or pulmonary complications may appear in this phase. Progressive improvement is generally the rule, since patients restart drinking and eating and regain strength. The diuresis may be extremely bulky, leading to a worsening of the fluid and electrolyte abnormalities, which may take the patient's life if not adequately treated.
The convalescent phase is characterized by the slow return of the renal function to normal levels. The phase may last 1 to 3 months, and complaints such as muscular weakness, intention tremor, and lack of stamina, may remain present until total recovery.
The clinical diagnosis may be reliable during an outbreak if the patient has classic severe symptoms, but not if the symptoms are only mild. The diagnosis is based, on the majority of cases, on the serologic confirmation. This confirmation is made by demonstrating the presence of specific IgM antibodies by immunofluorescence, ELISA, or neutralizing tests, which become positive by the end of the first week of illness; or by the rising of fourfold of the immune adherence hemagglutination titers in paired sera. Because of the similarity in epidemiology and clinical presentation and the potential for dual infections, it has been recommended that blood be submitted from Hantavirus serology in all cases of suspected leptospirosis.
Management of the ill patient includes careful monitoring of electrolytes and fluid intake and output with correction of any fluid and electrolyte imbalances, especially during the oliguric and diuretic phases. Plasma expanders should be used for shock, and hemodialysis in cases of renal failure with hyperkalemia. Ribavirin improves survival of the patient if it is given within five days of disease onset.
The prognosis of the disease depends on its severity. The milder the cases, the better the prognosis. If the patient develops shock, or any other complication, the prognosis is worse. Lethality ranges from 5 to 32% of the cases treated with hospital management in different countries of Asia.
Rodent control should be done where it is feasible-especially in urban settings-for disease prevention.
1.SANFORD, Jay P. Arbovirus Infections. In: ISSELBACHER, Kurt J, BRAUNWALD, Eugene, et al. Harrison's Principles of Internal Medicine. Mc-Graw Hill Inc. 13th edition, 1994.
2.SHOPE, Robert E. Introduction to Hemorrhagic Fever Viruses. In: BENNET, J Claude, and PLUM, Fred. Cecil Textbook of Medicine. W.B. Saunders Company. 20th edition, 1996.
Co., 1996.
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