| disease | Epidemic Hemorrhagic Fever |
| alias | HFRS, EHF, Hemorrhagic Fever with Renal Syndrome |
Epidemic hemorrhagic fever (EHF) is a natural focal disease caused by viruses. In 1982, the World Health Organization (WHO) named it hemorrhagic fever with renal syndromes (HFRS). The main pathological changes of this disease are widespread damage to small blood vessels and capillaries throughout the body, and it is clinically characterized by fever, hypotension, bleeding, and kidney damage.
bubble_chart Epidemiology
(1) Epidemic Distribution This disease is widely prevalent, mainly distributed across Europe and Asia, including China, North Korea, Japan, the former Soviet Union, Finland, Denmark, Sweden, Norway, the Netherlands, Poland, Czechoslovakia, Hungary, Romania, Bulgaria, Yugoslavia, Greece, Switzerland, Belgium, the United Kingdom, and other countries. In China, it began to spread along the lower reaches of the Heilongjiang River in the early 1930s and gradually expanded southward and westward. In recent years, it has become widespread across the country.
(2) Source of Pestilence Rodents are the primary source of pestilence. The striped field mouse is the main source in Asia, while the European bank vole is the primary source in Europe. In rural areas of China, the main sources are the striped field mouse and the brown rat. In the forested regions of Northeast China, the large woodland mouse is the primary source. In urban areas, the brown rat is the main source, and in laboratory animal facilities, the albino rat is the primary source. Additionally, the Asian house rat, house mouse, harvest mouse, and common vole can also serve as sources of pestilence for this disease.
In recent years, the virus or its antigens have been detected in animals such as cats, dogs, pigs, rabbits, and Asian house shrews. Furthermore, EHFV has also been found in frogs, snakes, and birds, indicating a wide range of host animals for this virus. Attention should be paid to the potential long-distance transmission of the virus by birds. Since animals like the Asian house shrew and cats naturally carry the virus, keeping cats is not advisable in epidemic areas.
(3) Transmission Routes The transmission routes of this disease have not yet been fully elucidated. The following two possibilities are proposed:1. Vector-borne Transmission Japanese researchers in the 1940s observed that the dominant mite species on striped field mice, Chinese Taxillus Herb, had the ability to bite and suck blood. When a suspension of these mites was injected into humans, it produced typical clinical symptoms of epidemic hemorrhagic fever. Thus, it was suggested that mites are one of the vectors transmitting this disease. In recent years, the virus has been isolated from mites, and it has been confirmed that the virus can be passed transovarially in mites, making them one of the reservoir hosts. Mites can transmit the disease among mice through biting and blood-sucking and are also one of the routes of transmission from mice to humans. Korean researcher Lee Ho-wang and others studied the role of mites in transmission but could not confirm the above results. Some have proposed that chiggers are the transmission vector, and the virus has been isolated from Leptotrombidium scutellare.
2. Animal-source Transmission Recent studies abroad have confirmed that the disease can be transmitted through virus-carrying rodent excreta, which has drawn significant attention.
(1) Respiratory Transmission: By the 10th day after infection, striped field mice begin to excrete the virus in their saliva, urine, and feces, with viral shedding in urine lasting for over a year. Virus-carrying excreta can contaminate dust, and humans can contract the disease by inhaling it.
(2) Digestive Tract Transmission: There have been reports of people contracting the disease by consuming food or water contaminated with rodent excreta, as well as instances where the same food caused outbreaks in large groups. The virus can enter the body through damaged oral mucosa, leading to infection.
Additionally, the virus has been isolated from the liver, kidneys, lungs, and other organs of stillborn fetuses from infected pregnant women, as well as from fetal mice of striped field mice and brown rats in epidemic areas. This indicates that the virus can be transmitted vertically via the placenta. Vertical transmission among mice plays a role in maintaining natural foci, but its epidemiological significance in humans is limited.
In summary, this disease can be transmitted through multiple routes, but further research is needed to determine which is the primary mode of transmission.
(4) Susceptibility Humans are not universally susceptible to this virus, and whether infection leads to illness depends on the type of virus involved. The disease is more common in young and middle-aged adults, while cases in children are extremely rare. Recent studies have observed that after infection with Rebing hemorrhagic fever virus of the wild rodent type or the domestic rodent type, only a minority of people develop the disease, with the majority showing a latent infection state. The latent infection rate of the domestic rodent type is higher than that of the wild rodent type. After the onset of the disease, serum antibodies can peak within 2 weeks and persist for a long time, providing lifelong immunity after infection.
(5) Epidemiological Characteristics and Typing of Endemic Areas The disease exhibits certain regional characteristics but can expand to form new endemic areas. Cases are mostly sporadic, though localized outbreaks may occur, particularly in collective living environments such as work sheds and camping tents. Domestic endemic areas include low-lying river and lake regions, damp forest grasslands, and paddy fields, with the former being the most common. Infection is associated with human activities, occupations, and other factors.
Both wild rodent-type and domestic rodent-type hemorrhagic fever exhibit epidemic periodicity, with peak outbreaks occurring every few years. These peaks are associated with increased viral carriage rates in the primary host animals.
Typing of Endemic Areas: - **Apodemus-type**: Predominantly found in Asia, with epidemics in autumn and winter. - **Domestic rodent-type**: Widely distributed, with epidemics in spring and summer. - **Vole-type**: Mainly distributed in Europe, with epidemics in autumn and winter. - **Field mouse-type**: Found in North America.
In China, endemic areas can be classified as: - **Wild rodent-type**: Primarily distributed in rural areas. - **Domestic rodent-type**: Found in both urban and rural areas. - **Mixed-type**: Refers to areas where both wild rodent-type and domestic rodent-type hemorrhagic fever coexist. In recent years, domestic rodent-type cases have increased annually, and endemic areas are gradually shifting toward the mixed-type.
Epidemic Hemorrhagic Rebing Fever Virus (EHFV) belongs to the Bunyaviridae family and the Hantavirus genus (Hantavirus, HV), now collectively referred to as Hantavirus (HV). This virus is an enveloped RNA virus with three morphological forms: round, oval, and elongated. The viral core consists of genomic RNA and nucleocapsid, surrounded by a lipid bilayer envelope with surface glycoproteins, measuring 70–210 nm in diameter.
The genome and structural proteins of the virus and their functions: The Hantavirus genome consists of three segments: L, M, and S. The S segment encodes the viral nucleoprotein, which can induce the production of non-neutralizing antibodies and plays a role in immune protection. The M segment encodes the viral envelope glycoproteins, including G1 and G2. The G1 region contains the main antigenic determinants, and virulence genes may also be located in this region. Glycoproteins are likely the primary functional sites for generating neutralizing antibodies, hemagglutination-inhibiting antibodies, cell fusion, and cellular immunity. Differences in glycoproteins among different serotypes, as well as variations in virulence between serotypes and strains within the same serotype, form the basis for differences in etiology, epidemiology, and clinical manifestations among serotypes. The L segment encodes the L protein, which primarily functions as the viral polymerase (or transcriptase) and plays a major role in viral replication.
Serotypes of Hantavirus: Type I is Hantaan virus (HTNV), isolated from the striped field mouse in Korea, with the primary host being Apodemus agrarius, also known as the wild mouse type. The disease is severe. Type II is Seoul virus (SEOV), isolated from the brown rat in Seoul, Korea, and laboratory rats in Japan, with the primary host being Rattus norvegicus, also known as the domestic rat type. The disease is moderate. Type III is Puumala virus (PUUV), isolated from the bank vole in Finland, with the primary host being Myodes glareolus, also known as the vole type, prevalent in Northern Europe. The disease is mild. Type IV is Prospect Hill virus (PHV), isolated from the meadow vole in the United States, with the primary host being Microtus pennsylvanicus, also known as the meadow vole type, but no pathogenicity has been observed so far. These four serotypes have been recognized by WHO.
In recent years, new serotypes of Hantavirus have been discovered, including Belgrade-Dobrava Virus, prevalent in the Balkan Peninsula and Yugoslavia, causing severe disease. Thai virus (Thaiv), isolated from the bandicoot rat in Thailand. Thottapatayam virus (TPMV), isolated from the shrew in India. Muerto-Canyon virus, isolated from the deer mouse in the United States, with the primary host being Peromyscus maniculatus. Since 1993, outbreaks in the southwestern United States have primarily caused lung damage, with clinical manifestations resembling adult respiratory distress syndrome, known as Hantavirus pulmonary syndrome (HPS), with a fatality rate exceeding 60%. Also referred to as HPS virus.
The latter four serotypes have not yet been recognized by WHO.
This virus is sensitive to lipid solvents. Ether, chloroform, acetone, benzene, fluorocarbon, and deoxycholate can inactivate it. Common disinfectants and glutaraldehyde can also inactivate it. It can be inactivated at pH below 5.0, at 60°C for 1 hour, or by ultraviolet irradiation for 30 minutes.
The pathogenesis of this disease has not been fully elucidated. Recent studies suggest that the onset of the disease may be related to viral effects and the involvement of the body's immune response.
After the virus invades the human body, it spreads throughout the body via the bloodstream, proliferates in the cells of various organs and tissues, particularly in vascular endothelial cells, and is released into the blood, causing viremia, leading to fever and toxic symptoms. When small blood vessels and capillaries are damaged, vascular permeability increases, plasma extravasation occurs, and effective circulating blood volume decreases, resulting in hypotensive shock. On the basis of vascular damage, platelet damage, aggregation, destruction, and dysfunction, coupled with coagulation mechanism disorders and the formation of DIC, lead to widespread systemic bleeding. Renal vascular damage and increased vascular permeability cause renal interstitial edema. Glomerular basement membrane injury, degeneration, necrosis, shedding of renal tubular epithelial cells, and tubular obstruction result in a series of pathophysiological changes such as proteinuria, oliguria, and renal failure. The reasons for these changes may be
viral effects: Recent studies have observed structural and functional changes in cells infected with EHFV. Human vascular endothelial cells are susceptible to EHFV. The virus replicates in vascular endothelial cells, causing cell swelling, exposed basement membrane, loosening and interruption, and separation of continuous structures. It has also been observed that EHFV-infected endothelial cells exhibit cell retraction, intercellular gap formation, and increased permeability. Infected endothelial cells synthesize and release prostacyclin, which is significantly increased in the early stages of the disease, promoting vasodilation, increased vascular permeability, and plasma extravasation. However, some have not observed significant cytopathic effects in infected vascular endothelial cells. Some have observed virus-infected megakaryocytes in the bone marrow of patients, noting maturation disorders in these cells. Biopsies of the liver, gastric mucosa, and kidneys reveal severe degeneration, necrosis, hemorrhage, and ultrastructural changes in hepatocytes and gastric mucosal epithelial cells. The glomeruli and renal tubules show varying degrees of damage, and EHFV has been detected in these biopsy specimens. EHFV can cross the blood-brain barrier, causing central nervous system lesions, and has been detected in neural cells.
These changes all suggest the role and involvement of the virus in pathogenesis, with the virus also acting as a trigger to stimulate the body's immune response.
Immune response of the body: Early in EHF patients, serum IgE and histamine levels are significantly elevated, mast cells show degranulation, and IgE-IC is present in the blood, indicating the involvement of type I hypersensitivity in pathogenesis. Researchers have observed the deposition of specific immune complexes in the walls of small blood vessels and capillaries, as well as in the glomerular and renal tubular basement membranes. Plasma and blood components extravasate, and the complement alternative and classical pathways are sequentially activated. Immune complex-mediated release of vasoactive substances damages vascular endothelial cells, leading to hypotensive shock and renal damage. The deposition of specific immune complexes on platelet surfaces causes massive platelet aggregation and destruction, leading to a sharp decline in platelet count and dysfunction, which is one of the main causes of widespread bleeding, indicating the involvement of type III hypersensitivity in pathogenesis.
Additionally, significant increases in interleukin, interleukin receptors, tumor necrosis factor, prostaglandin E2, endothelin, and other factors in patient serum suggest the massive release of cytokines and inflammatory mediators, which participate in endothelial cell damage and exacerbate vascular injury.
Researchers have also observed that non-specific cellular immunity in EHF patients is suppressed, while specific cellular immunity is significantly enhanced, with the latter participating in viral clearance. The CD4/CD8 ratio in peripheral blood is decreased or inverted. Spontaneous suppressor T-cell function is impaired, while cytotoxic T-cell and B-cell functions are relatively increased. The latter two cell types participate in anti-infection immunity and also in hypersensitivity reactions, indicating that cellular immunity is also involved in the pathogenesis of this disease.
ADE phenomenon (Antibody-Dependent Enhancement) refers to the antibody-dependent infection enhancement phenomenon. In recent years, it has been discovered that this virus exhibits the ADE phenomenon. The mechanism involves viral antigens binding to pre-existing specific antibodies in the body, which then bind to Fc receptors on target cells via the Fc region of the antibodies, facilitating viral entry into cells and subsequent proliferation. Viral proliferation can reach 50 to 200 times that of the normal serum control group. When monoclonal antibodies of this virus are Dongshu into animals, followed by inoculation with Hantaan virus, it can lead to earlier death in the animals. The viral load in the brains of these early-death animals is 10 times higher than that of the control group. The relationship between the ADE phenomenon and disease onset, as well as its severity (grade III), still requires further research for confirmation.
bubble_chart Pathological Changes
The basic pathological changes of this disease involve widespread damage to small blood vessels throughout the body (including small arteries, small veins, and capillaries). The vascular endothelial cells swell and degenerate, and in severe cases, the vessel walls may undergo fibrinoid necrosis and rupture. The visceral capillaries are highly dilated, with stagnant blood, and thrombus formation can be observed in the lumen, leading to congestion, hemorrhage, degeneration, and even necrosis in various tissues and organs. The lesions are particularly prominent in the kidneys, anterior pituitary, adrenal cortex, right atrial endocardium, and skin. Although inflammatory cells are present, they are not prominent, primarily consisting of lymphocytes, monocytes, and plasma cells.
**Heart**: The right atrium exhibits characteristic large subendocardial hemorrhages, while hemorrhages in the left atrium and left ventricle are much milder than those in the right atrium. This may be related to the lower pressure in the right atrium, making small vessels in the atrial wall more prone to bleeding. Microscopically, focal myolysis and fatty degeneration are observed in cardiac cells, with interstitial edema accompanied by infiltration of lymphocytes and monocytes.
**Kidneys**: The kidneys are enlarged, with edema and hemorrhage in the adipose capsule, particularly severe at the corticomedullary junction. The clear demarcation between the cortex and medulla is one of the pathological features. Due to widespread damage to small vessels, plasma extravasation, and hemoconcentration, the afferent arterioles spasm, promoting the opening of arteriovenous shunts between the cortex and medulla. This leads to extreme dilation and congestion of medullary vessels, especially the vasa recta at the corticomedullary junction. Microscopically, the glomerular basement membrane is thickened, and the renal tubules are markedly swollen, degenerated, and necrotic, with narrowed or occluded lumens.
**Pituitary gland**: The characteristic feature is hemorrhage and necrosis in the anterior lobe.
**Adrenal glands**: The main manifestation is lipid depletion in the cells of the zona fasciculata, occasionally with scattered focal necrosis.
**Trachea and lungs**: The tracheal and bronchial mucosa exhibit scattered hemorrhagic spots. Microscopically, the alveolar wall capillaries are extremely dilated with stagnant blood, and some show microthrombus formation. The alveolar spaces contain large amounts of exudate, including plasma cells and red blood cells.
**Gastrointestinal tract**: The gastric mucosa shows diffuse hemorrhage, and scattered hemorrhagic spots are also present in the duodenum and upper jejunum. Hemorrhagic spots are significantly reduced in the lower small intestine and colon.
**Liver**: Some hepatocytes exhibit fatty degeneration, along with scattered focal necrosis.
**Retroperitoneal gelatinous edema** is a characteristic feature of this disease, caused by increased venous pressure in capillaries and heightened vascular permeability, leading to massive plasma extravasation.
bubble_chart Clinical Manifestations
The incubation period ranges from 8 to 39 days, typically around 2 weeks. About 10–20% of patients experience prodromal symptoms, manifesting as upper respiratory catarrhal symptoms or gastrointestinal dysfunction.
Clinically, it can be divided into five stages: the febrile stage, hypotensive stage, oliguric stage, polyuric stage, and stage of convalescence, though these stages may overlap.
(1) **Febrile Stage**: The onset is abrupt, with symptoms such as fear of cold, fever, headache, lumbago, orbital pain, photophobia, blurred vision, thirst, nausea, vomiting, lumbago, and diarrhea. Body temperature rises sharply after onset, usually between 39–40°C, with a remittent fever pattern being the most common, though some may exhibit a sustained or irregular pattern. The face and orbital area show marked congestion, resembling a flushed appearance. The upper chest is erythematous, with conjunctival edema, congestion, and petechiae or ecchymoses. Scattered pinhead-sized hemorrhagic spots may be seen on the soft palate and axilla, sometimes appearing linear or scratch-like. Costovertebral angle tenderness is present, and the tourniquet test is positive.
**Laboratory Findings**: Peripheral white blood cell count is typically around 15,000/mm3, with some patients exhibiting a leukemoid reaction. Lymphocytosis with atypical lymphocytes is observed, along with thrombocytopenia. Urinalysis reveals proteinuria, red blood cells, white blood cells, and casts.
This stage generally lasts 5–6 days.
(2) **Hypotensive Stage**: This usually occurs on days 4–6 of the illness but may overlap with the febrile stage. In mild cases, blood pressure fluctuates slightly and lasts briefly. In severe cases, blood pressure drops abruptly, sometimes becoming unmeasurable. During shock (except in advanced stages), the patient's skin is typically flushed, warm, and sweaty, with worsening thirst and vomiting, and reduced urine output. Symptoms may include dysphoria, restlessness, delirious speech, and carphology; severe cases may present with agitation and mental confusion. The pulse becomes thready and rapid, and gallop rhythm or heart failure may occur.
**Laboratory Findings**: Peripheral white blood cell count shows an increase in total leukocytes and atypical lymphocytes, while red blood cell count and hemoglobin levels rise. Platelet count decreases significantly. Urinary changes are pronounced. Blood urea nitrogen shows grade I retention. Abnormalities may be observed in fibrinogen, prothrombin time, thrombin time, kaolin partial thromboplastin time, protamine paracoagulation test, and fibrin(ogen) degradation products.
This stage generally lasts 1–3 days.
(3) **Oliguric Stage**: This typically occurs on days 5–7 of the illness. Gastrointestinal symptoms, neurological symptoms, and bleeding become prominent. Patients experience thirst, hiccups, intractable vomiting, abdominal pain, delirious speech, hallucinations, spasms, epistaxis, hematemesis, hematochezia, hemoptysis, and hematuria. Petechiae on the skin and mucous membranes increase. Blood pressure is mostly elevated, with widened pulse pressure. Costovertebral angle tenderness is significant. Urine output markedly decreases, with less than 400ml in 24 hours or even anuria (less than 50ml in 24 hours). Severe cases may develop uremia, acidosis, and hyperkalemia. Due to oliguria or anuria, coupled with massive reabsorption of plasma and other fluids, hypervolemic syndrome may occur, leading to heart failure and pulmonary edema.
**Laboratory Findings**: Urine appears dark brown or red, with significant proteinuria, red blood cells, and casts; membranous tissue may be excreted. Blood urea nitrogen rises markedly, CO2 combining power decreases, serum potassium increases, and calcium and sodium decrease. Fibrinogen levels drop, the protamine paracoagulation test is positive, and fibrin(ogen) degradation products increase.
This stage generally lasts 1–4 days.
(4) Polyuria Phase This phase usually occurs around days 10–12 of the disease course. As the circulating blood volume increases, glomerular filtration function improves, and renal tubular epithelial cells gradually recover, but reabsorption function remains impaired. Additionally, the excretion of metabolic products such as urea retained in the body during the oliguria phase creates the material basis for osmotic diuresis, leading to polyuria and nocturia. Daily urine output can reach 3,000–6,000 ml of low-specific-gravity urine, or even exceed 10,000 ml. Systemic symptoms significantly improve. However, due to the massive excretion of urine, dehydration and electrolyte imbalances, particularly hypokalemia, may occur. In the initial stage of polyuria, metabolic disturbances and azotemia can be very pronounced.
Laboratory tests: Various test results gradually return to normal, but urine specific gravity remains low, and blood potassium is still below normal.
This phase generally lasts from several days to several weeks.
(5) Stage of convalescence: Recovery usually begins in the fourth week of the disease course, with urine output gradually returning to normal, nocturia disappearing, and urine concentration function recovering. General condition improves, and aside from weakness, there are no significant subjective symptoms. Laboratory tests all return to normal.
The entire disease course lasts about 1 to 2 months.
Not all patients experience every stage mentioned above. Mild or atypical cases may lack the hypotensive phase or oliguric phase.
In China, there are two types of epidemic hemorrhagic fever: the field mouse type and the domestic mouse type. The field mouse type has more typical clinical manifestations, a more severe course, and is more likely to present with shock, hemorrhage, and kidney damage, with a higher fatality rate. The domestic mouse type often has atypical clinical manifestations, a milder course, less frequent shock, hemorrhage, and kidney damage, and a shorter disease duration. Most patients directly enter the polyuric phase or stage of convalescence after the fever phase, with a lower fatality rate.
Clinical classification: Based on severity, the disease can be divided into four types. (1) Mild type: ① Body temperature around 38°C, mild toxic symptoms; ② Blood pressure mostly within the normal range; ③ Aside from skin and/or mucosal petechiae, no significant bleeding elsewhere; ④ Mild kidney damage, urine protein + to ++, no obvious oliguric phase. (2) Moderate type: ① Body temperature 39–40°C, severe systemic toxic symptoms, significant conjunctival edema; ② Systolic pressure below 12 kPa (90 mmHg) or pulse pressure less than 3.45 kPa (26 mmHg) during the course; ③ Obvious bleeding in skin, mucosa, or other areas; ④ Significant kidney damage, urine protein may reach "+++," with a clear oliguric phase. (3) Severe type: ① Body temperature ≥40°C, severe systemic toxic symptoms and extravasation, or toxic psychiatric symptoms; ② Systolic pressure below 9.3 kPa (70 mmHg) or pulse pressure below 2.6 kPa (20 mmHg) during the course, with clinical shock; ③ Severe bleeding, such as skin ecchymosis or cavity bleeding; ④ Severe kidney damage, oliguria lasting up to 5 days, or anuria for up to 2 days. (4) Critical type: On the basis of the severe type, any of the following serious conditions: ① Refractory shock; ② Severe bleeding, with critical organ hemorrhage; ③ Extremely severe kidney damage, oliguric phase exceeding 5 days, or anuria for over 2 days, or blood urea nitrogen exceeding 120 mg%; ④ Heart failure, pulmonary edema; ⑤ Central nervous system complications; ⑥ Severe secondary infections; ⑦ Other serious complications.
The diagnosis can be made based on epidemiological data, clinical manifestations, and laboratory test results.
(1) Epidemiology: Includes endemic areas, epidemic seasons, history of direct or indirect contact with rodents, entry into an epidemic area, or residence in an epidemic area within the past two months.
(2) Clinical Manifestations: Sudden onset, fever, headache, orbital pain, lumbago, thirst, vomiting, flushed face resembling drunkenness, conjunctival edema, congestion, and hemorrhage, petechiae on the soft palate and underarms, and tenderness upon percussion of the costovertebral angle.
(3) Laboratory Tests
1. General Laboratory Tests: Elevated total white blood cell count with increased lymphocytes and atypical lymphocytes, decreased platelet count. Urinalysis may show protein, red blood cells, white blood cells, and casts.
2. Specific Laboratory Diagnostics: In recent years, serological methods have been applied to aid in early diagnosis, particularly for atypical clinical cases. Detection methods include indirect immunofluorescence assay, enzyme-linked immunosorbent assay (ELISA), enzyme-labeled SPA histochemical test, hemagglutination inhibition test, immune adherence hemagglutination test, solid-phase immune hemadsorption test, and solid-phase radioimmunoassay. A positive specific IgM or a fourfold or greater increase in specific IgG antibody titers between the early stage of illness and the convalescent stage has definitive diagnostic value. Isolation of the virus or detection of viral antigens from the patient's blood or urine can also confirm the diagnosis. Recently, polymerase chain reaction (PCR) has been used to directly detect viral antigens, aiding in etiological diagnosis.
bubble_chart Treatment Measures
Treatment during the fever phase
(1) General treatment: Patients should rest in bed and receive treatment on-site. Provide a high-calorie, high-vitamin semi-liquid diet. Ensure adequate fluid intake.
(2) Fluid therapy: Due to vascular damage leading to plasma extravasation and electrolyte loss, combined with symptoms such as high fever, loss of appetite, vomiting, and diarrhea, patients often experience insufficient intake. This results in reduced effective circulating blood volume, electrolyte imbalance, and a decline in blood osmotic pressure, leading to internal environmental disturbances. During this phase, sufficient fluids and electrolytes should be replenished. Intravenous fluids should primarily consist of isotonic and saline solutions, commonly including balanced salt solutions and glucose saline, administered at 1000–2000 ml per day via intravenous drip. The treatment course lasts 3–4 days.
(3) Adrenocortical hormone (steroid) therapy: Steroids have anti-inflammatory and vascular wall-protective effects, stabilize lysosomal membranes, and reduce the sensitivity of the thermoregulatory center to endogenous pyrogens. Early application can help reduce fever, alleviate toxic symptoms, and shorten the disease course.
Dosage: Hydrocortisone 100–200 mg dissolved in glucose solution for intravenous drip, once daily. Dexamethasone may also be used. The treatment course lasts 3–4 days.
(4) Immunomodulatory therapy: Used to regulate the patient's immune function.
1. Cyclophosphamide: An immunosuppressant that primarily inhibits humoral immune responses. Early use can reduce antibody production and immune complex formation, thereby alleviating symptoms. Its effectiveness is diminished in the advanced stage.
Dosage: Cyclophosphamide 300 mg dissolved in 30 ml of normal saline for intravenous injection, once daily. The treatment course lasts 3–4 days.
2. Phytohemagglutinin (PHA): An immunostimulant that enhances T-cell function and promotes lymphocyte transformation.
Dosage: PHA 20 mg dissolved in glucose solution for intravenous drip, once daily. The treatment course lasts 3–4 days.
Other immunomodulatory drugs, such as cytarabine, transfer factor, calf thymosin, and polyinosinic-polycytidylic acid, also show certain efficacy.
(5) Antiviral therapy: Ribavirin is a broad-spectrum antiviral drug effective against both RNA and DNA viruses, with particular sensitivity to this virus.
Dosage: Ribavirin 1000 mg dissolved in glucose solution for intravenous drip, once daily. The treatment course lasts 3–4 days.
(6) Traditional Chinese medicine (TCM) therapy: Commonly used medications include:
1. Salvia: A blood-activating and stasis-resolving herb. Its effects include: ① Increasing the surface charge of red blood cell membranes to prevent aggregation, reducing blood viscosity, and preventing DIC and fibrinolysis inhibition; ② Relieving vascular spasms, improving microcirculatory perfusion, and alleviating microcirculatory disorders.
Dosage: Salvia injection 24 g in glucose solution for intravenous drip, 1–2 times daily. The treatment course lasts 3–4 days.
2. Astragalus Root: A qi-tonifying herb that enhances cellular immune function.
Dosage: Astragalus Root injection 24 g dissolved in glucose solution for intravenous drip, once daily. The treatment course lasts 3–4 days.
Apart from fluid therapy as the foundational treatment, any one of the other therapies may be selected.
Treatment during the hypotensive phase
Once shock occurs, active measures should be taken to replenish blood volume, adjust plasma colloid osmotic pressure, correct acidosis, regulate vasomotor function, prevent DIC formation, and improve cardiac output.
(1) Replenishing blood volume: Early replenishment is a critical measure for treating hypotensive shock. A commonly used solution is 10% low-molecular-weight dextran, which expands blood volume, increases plasma osmotic pressure, counteracts plasma extravasation, reduces red blood cell and platelet aggregation, improves microcirculation, enhances tissue perfusion, and promotes osmotic diuresis.
Usage: Initially, administer 200–300 ml by rapid drip to maintain systolic blood pressure at approximately 13.3 kPa (100 mmHg). Then, adjust the drip rate and dosage based on dynamic changes in blood pressure, pulse pressure, hemoglobin levels, peripheral circulation, and tissue perfusion. Generally, a daily infusion of 500–1000 ml is recommended. If exceeding this amount, balanced salt solutions, 5% glucose saline, or glucose solutions may be used in combination. The total daily fluid replacement should generally not exceed 2500–3000 ml.
(II) Adjusting Plasma Colloid Osmotic Pressure During shock, the plasma colloid osmotic pressure significantly decreases, causing a large amount of intravascular fluid to flow into the interstitial spaces. This results in a sharp drop in intravascular blood volume and a rapid increase in interstitial tissue fluid. In cases of severe shock or particularly pronounced vascular exudation, if only crystalloid solutions are administered, the plasma colloid osmotic pressure will further decrease, leading to a large amount of fluid rapidly leaking out of the blood vessels. This can create a vicious cycle of unstable blood pressure and progressive edema in internal organs and serous cavities, and may also easily induce pulmonary edema. Fresh blood or plasma (300–400 ml per dose) should be promptly transfused to adjust the plasma colloid osmotic pressure, stabilize blood pressure, and reduce tissue edema, which will facilitate the reversal of shock.
(III) Correcting Acidosis Shock is often accompanied by metabolic acidosis, which can reduce myocardial contractility and vascular tension, and may also affect vascular sensitivity to Black Catechu phenols. Therefore, correcting acidosis is an important measure in treating shock. The first choice is generally 5% sodium bicarbonate, but the dosage should not be excessive (no more than 800 ml within 24 hours) to prevent sodium retention, which could worsen tissue edema and increase cardiac burden.
(IV) Application of Vasoactive Drugs If shock is not corrected, vasoactive drugs should be promptly administered to adjust vascular constriction and dilation functions, restoring smooth blood flow and thereby interrupting the vicious cycle of shock. Vasoactive drugs fall into two categories: vasoconstrictors and vasodilators, which can be selected based on the type of shock.
1. Vasoconstrictor Drugs: Suitable for patients with reduced vascular tension. Hemorrhagic fever shock often presents as warm shock primarily characterized by small vessel dilation, and vasoconstrictors such as norepinephrine, metaraminol, and ephedrine are generally used.
(1) Norepinephrine: Stimulates the α-receptors of blood vessels, causing vasoconstriction (mainly in small arteries and veins), with the most pronounced effect on cutaneous mucous membrane vessels, followed by those in the kidneys, brain, liver, mesenteric membrane, and even skeletal muscles. Coronary vessels, however, dilate. This drug also stimulates the β-receptors of the heart, enhancing myocardial contractility and increasing cardiac output. The usual dose is 0.5–1 mg diluted in 100 ml of fluid for intravenous drip.
(2) Metaraminol (Aramine): Primarily acts on α-receptors, similar to norepinephrine. This drug can be taken up by adrenergic nerve endings, entering vesicles near the presynaptic membrane, where it promotes the release of stored norepinephrine through displacement. Continuous use can deplete norepinephrine in the vesicles, leading to reduced or lost efficacy. The usual dose is 10 mg diluted in 100 ml of fluid for intravenous drip.
(3) Ephedrine: Its effects resemble those of adrenaline, stimulating both α- and β-receptors to directly mimic adrenergic effects. It also promotes the release of neurotransmitters from adrenergic nerve endings, indirectly mimicking adrenergic effects.
This drug can constrict cutaneous mucous membrane and visceral blood vessels, with a weak dilating effect on skeletal muscle vessels. It stimulates the heart, increasing cardiac output. Ephedrine notably raises systolic blood pressure with minimal changes in diastolic pressure, and its effects last 3–6 hours. Repeated use in a short period may gradually weaken its effects, leading to rapid tolerance, which subsides after several hours of discontinuation. The dosage is 10–20 mg diluted in 100 ml of fluid for intravenous drip.
2. Vasodilator Drugs Suitable for cases of cold shock and should be administered after adequate blood volume replenishment. Commonly used drugs include:
(1) β-adrenergic agonists: Commonly used agents include dopamine. Dopamine is a precursor of norepinephrine, exerting β-adrenergic agonist effects on the heart and causing grade I vasoconstriction in peripheral blood vessels. However, it dilates small stirred pulses in visceral organs such as the liver, gastrointestinal tract, mesentery, and kidneys, as well as coronary stirred pulses. Its administration enhances myocardial contractility, increases cardiac output, improves renal blood flow and urine output, elevates stirred pulse pressure by grade I, and exhibits antiarrhythmic effects. The usual dosage is 10–20 mg diluted in 100 ml of intravenous fluid, infused at a rate of 2–5 μg/kg per minute.
(2) α-receptor blockers: Phentolamine can relieve microvascular spasms and microcirculatory block caused by endogenous norepinephrine, as well as pulmonary microcirculatory block induced by high concentrations of norepinephrine, thereby redirecting pulmonary circulation blood to systemic circulation. Thus, it can prevent pulmonary edema and renal complications caused by norepinephrine. The usual dosage is 0.1–0.2 mg/kg administered via intravenous drip in 100 ml of fluid.
3. Combined Use of Vasoactive Drugs When the effect of a single vasoactive drug is insufficient, combination therapy may be considered. Combining vasoconstrictors and vasodilators—such as norepinephrine + phentolamine, metaraminol + dopamine, or norepinephrine + dopamine—can help improve microcirculation and enhance the pressor effect.
(5) Use of Cardiotonic Drugs Applicable for patients with persistent shock due to cardiac insufficiency. Cardiotonic drugs can strengthen myocardial contractility, increase cardiac output, improve microcirculation, and promote diuresis. A commonly used agent is lanatoside C (0.2–0.4 mg), diluted in 40 ml of glucose solution and administered via slow intravenous push.
Treatment for the Oliguric Phase
When oliguria occurs, it is crucial to differentiate between prerenal and renal oliguria. Once renal oliguria is confirmed, it should be managed as acute renal failure.
(1) General Treatment During the oliguric phase, patients often have low plasma colloid osmotic pressure and may present with hypervolemic syndrome and cellular dehydration. For patients with central nervous system symptoms, blood osmotic pressure should be monitored to distinguish between hyperosmolar encephalopathy and hypo-osmolar cerebral edema. Patients with hypervolemic syndrome and low colloid osmotic pressure are at high risk of pulmonary edema if fluid administration is inappropriate.
A high-calorie, high-vitamin semi-liquid diet is typically provided, with fluid intake restricted based on the patient's output. The intake should equal the previous day's urine output, stool volume, and vomiting volume plus 400 ml. In cases of oliguria or anuria, fluid intake must be strictly controlled, not exceeding 1000 ml in 24 hours, with oral intake preferred.
(2) Treatment for Functional Renal Damage Stage
1. Use of Diuretics
(1) Diuretics for Relieving Renal Vascular Spasms: Diuretic cocktail (0.25–0.5 g caffeine, 0.25 g aminophylline, 1–2 g vitamin C, 0.25–0.5 g procaine, and 25 mg hydrocortisone in 300 ml of 25% glucose solution) administered via intravenous drip once daily.
(2) Diuretics Acting on Renal Tubules: Furosemide and ethacrynate sodium inhibit sodium and water reabsorption in the renal tubules, exerting a potent diuretic effect. Furosemide has fewer side effects and can be used at higher doses (20–200 mg per intravenous push). Ethacrynate sodium is administered at 25 mg per dose, either intramuscularly or intravenously.
2. Anticoagulation Therapy Salvia can mitigate renal intravascular coagulation and improve renal blood circulation. Its administration and dosage are as described in the Chinese herbal medicine treatment during the febrile phase.
(3) Treatment for Organic Renal Damage Stage
1. Cathartic Therapy This method facilitates the excretion of body fluids, electrolytes, and urea nitrogen through the intestines, effectively alleviating uremia and hypervolemic syndrome. It is simple to use, has few side effects, and is a common approach for managing oliguria.
(1) 250–350 ml of 20% mannitol taken orally once. If ineffective, 40 ml of 50% magnesium sulfate may be added.
(2) Rhubarb Rhizoma 30 g and Mirabilite 15 g. The former is steeped in water and taken with the latter, or it may be combined with mannitol.
2. Dialysis Therapy Helps to remove urea nitrogen and excess water from the blood, correct electrolyte and acid-base imbalances, alleviate uremia, and buy time for kidney repair and regeneration. Indications for use: ① No urine output for 1 day, with no diuretic response after intravenous injection of furosemide or rapid intravenous drip of mannitol; ② Hyperkalemia; ③ Hypervolemic syndrome; ④ Severe bleeding tendency.
(1) Peritoneal dialysis: Strict adherence to disinfection and isolation protocols should be maintained during the procedure to prevent secondary infections and ensure the patency of the tubing. Due to significant protein loss during dialysis, appropriate supplementation with albumin, plasma, etc., should be provided to prevent hypoproteinemia.
(2) Hemodialysis: This method acts faster and is more effective than peritoneal dialysis, rapidly removing urea nitrogen and other waste products, thereby quickly improving uremia. A drawback is the increased risk of bleeding due to heparinization. During dialysis, attention must be paid to the osmotic pressure of the dialysate. If it is lower than that of the blood, the dialysate may flow into the bloodstream, potentially causing pulmonary edema and heart failure. Patients undergoing rapid dehydration, those in shock, or those with insufficient blood volume are prone to shock; dehydration should be promptly halted, and intravenous fluids or blood transfusions administered as needed.
(4) Treatment of bleeding: The causes of bleeding in this condition are complex but are related to significant platelet reduction, impaired platelet function, depletion of clotting factors, and vascular injury. Patients with obvious bleeding should receive fresh blood transfusions to supply functional platelets and clotting factors. Those with markedly low platelet counts should receive platelet transfusions. For epistaxis, acupuncture at Hegu (LI4) and Yingxiang (LI20) points with strong stimulation, retaining the needles for 30 minutes, may be applied. Treatment for gastrointestinal bleeding is similar to that for ulcer-related bleeding. If repeated massive bleeding does not respond to medical therapy, surgical intervention may be considered.
(5) Treatment of spasms: Common causes of spasms include uremia and central nervous system complications. In addition to treating the underlying cause, administer 10mg of diazepam intravenously by slow injection and 5ml of 5% phenytoin sodium intramuscularly. For recurrent spasms, a combination of 25mg each of chlorpromazine, promethazine (Phenergan), and pethidine in glucose solution may be administered via intravenous drip.
(6) Treatment of secondary infections: Secondary infections, such as pneumonia and pyelonephritis, are common. The choice of antibiotics should be based on the patient’s condition, the type of pathogen, and its drug sensitivity. For patients with acute renal failure, antibiotics with low or no nephrotoxicity should be selected, and the dose should be adjusted appropriately.
Treatment during the diuretic phase
The primary concerns during the diuretic phase are dehydration and electrolyte imbalances, such as hypokalemia. Adequate fluids and potassium supplements should be provided, primarily orally, with intravenous supplementation as a secondary measure. Excessive intravenous fluids may prolong the diuretic phase.
After recovery, patients should continue resting for 1–3 months, with longer rest periods recommended for severe cases. Physical activity should be gradually increased.
The case fatality rate of this disease is generally around 5-10%, with a higher rate observed in severe cases. The main causes of death include shock, uremia, pulmonary edema, and hemorrhage (primarily cerebral and pulmonary hemorrhage). In recent years, due to improvements in treatment methods, deaths caused by shock, uremia, and pulmonary edema have gradually decreased, while cases of death due to hemorrhage have relatively increased.
(1) Rodent Elimination and Prevention Rodent elimination is the key to preventing the spread of this disease. In epidemic areas, the public should be mobilized to carry out synchronized rodent elimination within a specified timeframe. The timing of rodent elimination should be before the peak periods of the disease (May–June and October–December). In spring, the focus should be on eliminating house mice, while in early winter, the emphasis should be on eliminating field rodents.
Currently, common methods include mechanical and baiting techniques. Mechanical methods involve using tools like mouse traps and cages to capture and kill rodents. Baiting methods primarily use food attractive to rodents as bait, mixed with rodenticides in specific proportions to create poison bait, which is then placed near rodent burrows or frequented areas. Common rodenticides for house mice include diphacinone sodium and warfarin, while zinc phosphide, phosacetim, diphacinone sodium, and chlorophacinone are used for field rodents. Baiting is highly effective but carries the risk of accidental poisoning to humans and livestock if mishandled. Therefore, in fields, poison bait should be monitored for three days after placement, and any remaining bait should be collected and destroyed afterward. At home, poison bait should be placed before bedtime and retrieved during the day. Due to rodents' high reproductive capacity, elimination efforts must be persistent; any lapse could undo previous progress.
While prioritizing rodent elimination, preventive measures should also be implemented. Beds should not be placed against walls, and elevated sleeping arrangements are recommended. Digging rodent-proof trenches outside homes can prevent rodents from entering buildings or courtyards. New or renovated residences should include rodent-proof installations.
(2) Mite Elimination and Prevention Maintain clean, ventilated, and dry indoor environments. Regularly spray mite-killing agents like organophosphates (e.g., dichlorvos). Remove haystacks indoors and outdoors.
(3) Strengthening Food Hygiene Ensure food hygiene, utensil disinfection, and proper food storage to prevent contamination by rodent excreta. Leftover food must be reheated or boiled before consumption.
(4) Disinfection Measures Disinfect the blood, urine, and carcasses of host animals, as well as their excreta, to prevent environmental contamination.
(5) Personal Protection In epidemic areas, avoid direct hand contact with rodents or their excreta. Do not sit or lie on haystacks. Protect skin from injuries during labor, and disinfect and bandage any wounds. When working outdoors, wear socks and secure pant legs and sleeves to prevent mite bites.
Mainly include acute heart failure, bronchopneumonia, adult respiratory distress syndrome, kidney rupture, and other secondary infections.
In the early stages, the disease should be differentiated from upper respiratory tract infections, common cold, sepsis, cold-damage disease, and leptospirosis. Cases with skin hemorrhagic spots should be distinguished from thrombocytopenic purpura, while proteinuria should be differentiated from acute pyelonephritis and acute glomerulonephritis. Abdominal pain must be distinguished from acute appendicitis and acute cholecystitis. Gastrointestinal bleeding should be differentiated from ulcer bleeding, and hemoptysis should be distinguished from bronchiectasis and pulmonary subcutaneous nodule hemoptysis. The disease's typical clinical manifestations, unique disease progression, and serological testing all contribute to differential diagnosis.
