Expert Consensus on the Prevention and Treatment of Hemorrhagic Fever with Renal Syndrome : Infectious Diseases & Immunity

Secondary Logo

Journal Logo

Consensus and Guideline

Expert Consensus on the Prevention and Treatment of Hemorrhagic Fever with Renal Syndrome

Jiang, Hong; Huang, Changxing; Bai, Xuefan; Zhang, Fuchun; Lin, Bingliang; Wang, Shiwen; Jia, Zhansheng; Wang, Jingjun; Liu, Jing; Dang, Shuangsuo; Zhao, Yingren; Dou, Xiaoguang; Cui, Fuqiang; Zhang, Wenhong; Lian, Jianqi; Wang, Guiqiang; Gao, Zhiliang;  Infectious Disease Branch of the Chinese Preventive Medicine Association, Infectious Diseases Branch of the Chinese Medical Association

Author Information
Infectious Diseases & Immunity: October 2022 - Volume 2 - Issue 4 - p 224-232
doi: 10.1097/ID9.0000000000000054
  • Open

Abstract

Hemorrhagic fever with renal syndrome (HFRS), also known as epidemic hemorrhagic fever, is a zoonosis caused by a hantavirus, with rodents as the main source of infection. HFRS has a worldwide distribution and is endemic in many countries and regions in Asia and Europe, with a high mortality rate, making it a public health problem of global concern.[1–4] China is one of the countries with a heavy disease burden of HFRS.[5] This consensus was developed by basic, preventive, and clinical experts to standardize the prevention, diagnosis, and treatment of HFRS, based on the National Prevention and Control Program for Epidemic Hemorrhagic Fever (1997),[6] the Diagnostic Criteria for Epidemic Hemorrhagic Fever (WS278–2008),[7] and the Shaanxi Provincial Expert Consensus on the Diagnosis and Treatment of Hemorrhagic Fever with Renal Syndrome (2019),[8] combined with the latest research results.

This consensus was developed for adults as the main patient population. The management of special populations, such as children, the elderly, and pregnant women, should be individualized according to each patient’s specific situation. Moreover, this consensus mainly provides recommendations for common problems faced in HFRS and does not cover all the issues in the prevention and treatment of HFRS. Reasonable and feasible treatment plans for specific patient populations should be formulated on the basis of the relevant professional knowledge and medical resources.

Epidemiology and prevention

Epidemiology

The sources of HFRS infection are hosts of hantaviruses, mainly rodents.[3] The virus-carrying rodent urine, feces, and saliva contaminates the environment and can be inhaled by susceptible individuals in the form of dust or aerosols, which is the main route of transmission. Transmission routes could also include the gastrointestinal tract, direct contact, and insect bites. In addition, an infected pregnant woman can transmit the virus to the fetus via the placenta.[9]

According to data from the National Health Commission’s National Monthly Report on Statutory Infectious Diseases and the literature from 1950 to 2020, a total of 1,688,031 cases of HFRS, including 48,260 subsequent deaths, were reported in China, with an annual mortality rate fluctuating between 0.60% and 13.97% and an overall mortality rate of 2.86%.[10] HFRS is prevalent all around the year with two peaks. In the last 20years, the overall incidence of HFRS in China has decreased significantly; however, epidemics have repeatedly reoccurred in some areas. The rate of subclinical infection in endemic areas can range from 3.5% to 33%, depending on the local epidemic intensity.[11] HFRS patients are predominantly young adults with a male-to-female ratio of approximately 3:1. Farmers are the predominant population at risk in terms of occupation[12,13] and are susceptible to infection during fieldwork, weed and straw clearance, and other field activities. In addition, cases of infection have also been reported in laboratory researchers.[14] Moreover, in recent years, there has been an increase in the incidence of HFRS among people aged <15 and >60 years.[15]

High levels of serum antibodies can be maintained after hantavirus infection, allowing for durable immunity.[16] Although the immunoglobulin G (IgG) antibody titer in HFRS patients declines by 25% every 10years, it remains at a high level, more than twice than that of the vaccinated population after 30 years. However, this decline is not sufficient to affect the immune protection against hantavirus in humans.[11]

Prevention

In recent years, the rodent density/virus-carrier rate among rodents has remained high at some monitoring sites in China, and the possibility of HFRS outbreaks still exists. The appropriate prevention and elimination of rodents can reduce the risk of disease outbreaks. Personal protection should be strengthened while performing field activities during epidemics and experimental research. Bivalent inactivated vaccines containing the Hantaan and Seoul viruses have been used clinically in China since the 1990s, with the vaccinated population in the endemic areas being aged 16 to 60 years. The vaccination procedure is divided into basal and booster immunizations, with two doses of basal immunization at days 0 and 14, and a booster after 1 year.[15] The bivalent HFRS vaccine has good immunogenicity, with high positive conversion rates of neutralizing antibodies (100% for Hantaan virus and 84.21% for Seoul virus) and fluorescent antibodies (94.74%) after two doses of basal immunization.[17] High antibody titers can be obtained after completion of basal immunization; however, antibody titers decline significantly 5 years after vaccination, by 40% between 5 and 10 years after vaccination, and by more than 60% between 10 and 20 years after vaccination.[11] The protection rate decreases lower than 90% 7 to 8 years after HFRS vaccination according to the antibody titers, making it necessary to administer a booster every 7 to 8 years.[11,18,19] Vaccination is an effective measure to prevent HFRS, and increasing the vaccination rate in endemic areas can effectively control HFRS.[20]

Recommendation 1: Vaccination is an effective measure to prevent HFRS. Bivalent inactivated vaccine is recommended for populations aged 16 to 60 years in epidemic areas, especially for outdoor workers and those engaged in experimental research on hantavirus. Vaccines are given intramuscularly in the deltoid muscle of the upper arm, 1.0 mL each time on days 0 and 14, and a booster should be administered after 1 year.

Etiology and pathogenesis

Etiology

Hantaviruses belong to the genus Orthohantavirus of the family Hantaviridae, order Bunyavirales. Hantaviruses are round or ovoid in shape, with an average diameter of 120 nm, and a lipid outer membrane. The genome constitutes a single-negative stranded RNA divided into L, M, and S fragments, which encode the viral RNA polymerase, envelope glycoproteins, and nucleocapsid protein, respectively.[21,22] Hantaviruses are sensitive to common organic solvents and disinfectants, and exposure to a temperature of 60°C for 10 minutes, ultraviolet irradiation (50 cm for 1 h), or cobalt-60 irradiation can also inactivate the virus. Approximately 24 serotypes of hantaviruses have been identified,[3,23] with two main types of hantaviruses found to be prevalent in China, namely the Hantaan virus (HTNV) and Seoul virus (SEOV). HTNV, also known as type I virus, causes severe HFRS,[24] while SEOV, also known as type II virus, causes relatively mild HFRS.

Pathogenesis

Hantaviruses are ubiquitous and proliferate in tissues such as vascular endothelial cells, bone marrow, liver, spleen, lung, kidney, and lymph nodes after entering the body and are released into the blood, subsequently causing viremia. Hantavirus RNA can be detected in the blood of patients with HFRS in the febrile, hypotension, and shock phases, and the hantavirus RNA load correlates with disease severity.[25]

HFRS is characterized by a severe systemic inflammatory response, and inflammatory factor storms play an important role in its pathogenesis.[26,27] Hantaviruses have a weak direct cytopathic effect; however, they can cause structural and functional disorders in the infected cells.[28] Hantavirus infection can induce a strong innate and adaptive immune response, and various immune cells, cytokines, inflammatory factors, and complements are involved in the pathogenic process.[29,30]

Increased vascular permeability and hemorrhage due to endothelial damage are the most common pathological changes observed in this infection. Endothelial damage in small vessels leads to increased permeability of the vessel wall, and causes vascular leakage and plasma extravasation, subsequently producing pathophysiological changes such as tissue edema, hemoconcentration, hypovolemia, hypotension, disseminated intravascular coagulation (DIC), and shock.[2,31–33] Reduced circulating blood volume and inadequate renal blood flow result in a decreased glomerular filtration rate. Increased reninangiotensin levels, glomerular microthrombosis, basement membrane injury due to antigen-antibody complexes and tubular injury are also important causes of renal failure.

Clinical features

The incubation period is usually 4 to 45 days, and most commonly 7 to 14 days.

The course of the disease is typically divided into five phases: febrile, hypotension and shock, oliguric, polyuric, and recovery. The first three phases may overlap in severe cases, and the hypotension and shock or oliguric phases may be absent in mild cases.

Course of disease and clinical manifestations

  • (1) Febrile phase: Patients typically develop high-grade fever suddenly, with a body temperature from 38.0°C to 40.0°C. This acute febrile phase usually lasts 4 to 6days and is often accompanied by headache, backache, orbital pain, generalized body ache, and gastrointestinal symptoms such as nausea, vomiting, and abdominal pain. On the second to third day of illness, patients may experience congestion of the ocular conjunctiva, face, neck, and upper chest. Mild to severe hemorrhagic manifestations may occur, such as petechiae on the skin of the bilateral axillae, chest, shoulder, and needling sites. Mucosal membrane congestion and hemorrhage (eg, of the soft palate, palatal lobe, and posterior pharyngeal wall) are common. Ocular conjunctival and facial edema is often present, and exudative ascites, pleural effusion, and pericardial effusion may occur. Most patients experience pain on percussion of the renal region.
  • (2) Hypotension and shock phase: On days 3 to 7 of the illness, capillary permeability increases in parallel with an increase in hematocrit levels, resulting in hypotension and shock. The incidence of shock is approximately 5% to 20%, and the duration varies from several hours to several days. It is characterized by shortness of breath, dizziness and weakness, cold extremities, a rapid pulse, impaired consciousness, prominent exudative signs, and an obvious bleeding tendency, which may be complicated by DIC as well as respiratory failure in few patients. The earlier the shock appears, the longer it lasts and the more serious the condition. Few cases cannot be reversed after 24 hours of aggressive antishock treatment and manifest as refractory shock. The prognosis of refractory shock is extremely poor and is one of the major causes of death in patients with HFRS.
  • (3) Oliguric phase: This phase usually appears on days 5 to 8 of the illness and usually lasts for approximately 2 to 5 days and may last for 2 weeks or longer in a few cases. Oliguria or anuria is the most prominent manifestation in this phase. Few patients may develop hypervolemic syndrome, severe azotemia, metabolic acidosis, or electrolyte disturbances. Bleeding from the skin and mucous membranes is often aggravated and may be accompanied by vomiting, hemoptysis, hematochezia, hematuria, cerebral hemorrhage, and renal hemorrhage. Patients with severe azotemia may present with drowsiness, irritability, delirium, convulsions, and coma.
  • (4) Polyuric phase: This phase mostly appears on days 9 to 14 of the illness, mostly lasting 1 to 2 weeks but can last up to several months in a few patients. With the recovery of renal function, urine output gradually increases, and uremia and related complications are reduced. Patients with massive urination are prone to dehydration, hypokalemia, hyponatremia, and secondary kidney injury due to secondary shock, which can be life-threatening in severe cases.
  • (5) Recovery phase: Most patients begin to recover from the 3rd to 4th week of the illness. The recovery phase usually lasts 1 to 3 months, and a few patients with severe illness experience longer recovery times, although rarely more than 6 months. Renal function gradually improves, and the mental state, appetite, and physical strength are gradually restored. Very few patients experience hypertension or chronic renal insufficiency as a sequelae.

Disease characteristics in special populations

  • (1) HFRS in children: The incidence in children is low, and accounts for approximately 10% of all HFRS cases.[34] Moreover, the systemic toxic symptoms of HFRS in children are mild. The clinical presentation is usually atypical, and digestive, cardiac, and pulmonary injuries may occur.[35] Children with HFRS have a lower tendency toward hemorrhage, hypotension, and shock; they recover quickly, and have a better prognosis than adults.[36] The hantavirus IgM antibody test and renal ultrasonography in children with febrile symptoms from endemic areas can be beneficial for the early diagnosis of HFRS.
  • (2) HFRS in the elderly: Early clinical manifestations are atypical, and consist of mostly moderate or low fever; a few patients have no obvious febrile symptoms. In elderly patients, HFRS is often complicated by other underlying diseases, making these patients more prone to complications, with a high incidence of severe and critical illness, slow recovery, and high mortality rate.[37]
  • (3) HFRS in pregnancy: Women with HFRS during pregnancy are often severely ill and more prone to complications; few patients may die due to miscarriage, stillbirth, DIC, or vaginal hemorrhage.[38] Hantavirus can be transmitted vertically through the placenta and causes intrauterine infection in the fetus.[39,40]

Diagnosis

Laboratory diagnosis

  • (1) Routine blood tests: The total white blood cell count is normal or low during the early stage and increases significantly after 3 to 4 days of illness. The neutrophil ratio is elevated and the heterogeneous lymphocyte count is increased. The platelet count starts to decrease on day 2 of illness. There is mostly hemoconcentration and an obvious increase in the red blood cell count and hemoglobin concentration.
  • (2) Routine urine tests: Urine protein can appear on days 2 to 4 of illness, with the levels increasing rapidly. Early urine protein levels are “+ to ++,” and patients with severe illness can indicate levels of “+++ to ++++,” reaching a peak in the oliguric phase and subsequently resolving negative in the polyuric and recovery phases. In severe cases, there may be a large number of red blood cells and clear or granular tubular patterns in the urine, with visible meatus hematuria and rarely membranous material.
  • (3) Blood biochemistry examination: Blood urea nitrogen and creatinine levels can rise in the febrile, hypotension, and shock phases, peaking in the oliguric phase, while the estimated glomerular filtration rate significantly reduces in this phase. Changes in myocardial enzyme profiles are common, with mild-to-moderate elevations in alanine aminotransferase and total bilirubin levels and a decrease in serum albumin levels. The procalcitonin levels may be mildly elevated.
  • (4) Coagulation and bleeding tests: HFRS complicated by DIC is mainly observed in the hypotensive shock and oliguric phases. The diagnostic criteria are the Chinese DIC scoring system.[41] DIC is a complex dynamic pathological process, and the test results depict only a part of this process. Furthermore, dynamic testing and scoring are beneficial for DIC diagnosis.
  • (5) Serological tests: Positive hantavirus-specific IgM antibodies can confirm the diagnosis of a current or recent infection. However, a negative result does not exclude the possibility of HFRS. For suspected cases with negative results, testing can be repeated daily or every other day. As the disease progresses, the positive IgM detection rate increases significantly, with the positivity rate exceeding 90% on days 4 to 6 and approaching 100% on day 7. A small proportion of clinical cases have atypical symptoms and are positive for specific IgM antibodies. Antibody detection methods include enzyme-linked immunosorbent assays, immunofluorescence, and immunochromatography. Currently, only colloidal gold immunochromatography is approved for clinical testing in China.
  • (6) Etiological examination: Serum hantavirus RNA detection is of clinical importance.[42] The positive detection rate of serum hantavirus RNA in patients with HFRS within 1week of onset is nearly 100%.[43] The viral load in patients with HFRS is significantly higher in the febrile, hypotension, and shock phases than in the oliguric phase, and most test results are negative in the polyuric or recovery phase. Real-time quantitative reverse transcription polymerase chain reaction assays are highly sensitive for detecting hantavirus, with good linearity, specificity, and reproducibility.[44,45] However, there is a lack of commercial clinical testing kits in China.

Diagnostic imaging

  • (1) Ultrasonography: Observation of renal changes can be beneficial for the early diagnosis of HFRS. Ultrasonography is mainly able to image enlarged and fully shaped kidneys. Parenchymal echogenicity is obviously thickened and enhanced, with a hypoechoic renal medullary cone. Moreover, the renal peritoneum is easily separated from the renal parenchyma, and subperitoneal fluid may be present in severe cases. Ultrasonography is beneficial for detecting renal rupture, ascites, pleural effusion, and pulmonary edema.
  • (2) Radiological imaging: Although computed tomography (CT) is accurate, it is not easy to implement in critically ill patients, and chest X-ray is more convenient to implement beside the bed. Pulmonary edema is common, with an incidence of 47% in the hypotension and shock phases, and up to 68% in the oliguric phase.[46] Cranial CT is feasible in patients with neuropsychiatric symptoms and can be beneficial for the diagnosis of cerebral hemorrhage.

Electrocardiography

Abnormalities on electrocardiography are common in patients with HFRS, with sinus arrhythmias and ST-T alterations being the most common. There is a predisposition to sinus bradycardia during the oliguric and polyuric phases.

Clinical diagnosis

Based on epidemiological history, clinical presentation, and laboratory tests, cases can be classified as suspected, clinically diagnosed, or confirmed.[7]

Recommendation 2: Suspected cases can be diagnosed if they have the following characteristics: (1) history of travel to an endemic area within 2months before the onset of the disease or a history of exposure to rodents or their excreta or secretions; (2) symptoms such as fever, malaise, nausea; (3) flushing of the face, neck, and chest symptoms such as headache, lumbago and orbital pain; bulbar conjunctiva congestion and edema; petechia on skin and mucosa, and signs such as pain on percussion of the renal area; (4) other febrile diseases should be ruled out.

Recommendation 3: Clinical cases can be diagnosed if at least one of the following criteria is met: (1) increased white blood cell count and decreased platelet count on routine blood tests, with the presence of heterogeneous lymphocytes and hemoconcentration; (2) manifestations of kidney injury such as proteinuria, membranous material in the urine, hematuria, elevated blood creatinine, and oliguria or polyuria; (3) hypotension or shock; and (4) typical course including fever phase, hypotension and shock phase, oliguric phase, polyuric phase, and recovery phase.

Recommendation 4: Based on the suspected or clinical diagnosis, the confirmed case should meet at least one of the following conditions: (1) a positive serum-specific IgM antibody test; (2) detection of hantavirus RNA in the patient’s blood specimen; (3) a 4-fold or higher increase in serum-specific IgG antibody titer during the convalescent stage compared to the acute stage; and (4) isolation of hantavirus from the patient’s blood specimen.

Early warning indications for identifying severe cases

Few of the early clinical manifestations and laboratory findings of patients with HFRS can be early warning indications to identify severe cases.[8,38,47–49] These include (1) persistent high fever for more than 1week; (2) severe nausea, vomiting, and other gastrointestinal symptoms; (3) mental abnormalities such as irritability, delirium, or disturbance of consciousness; (4) severe bulbar conjunctival edema; and (5) white blood cell count >30 × 109/L, platelet count <20 × 109/L, and a serum albumin level <15 g/L. When the aforementioned warning signs of severe illness appear, the patient’s vital signs should be closely monitored to detect hypotensive shock, respiratory failure, and hemorrhage as early as possible, and should be managed in a timely manner. Laboratory indicators, such as complete blood count and serum albumin, should be monitored dynamically. The severity and duration of shock, organ bleeding, coma, and acute respiratory distress syndrome (ARDS) are independent factors that influence the prognosis of patients with severe HFRS.[50-52]

Recommendation 5: Early warning indications for severe cases include a temperature of ≥40°C or fever lasting for more than 1 week, frequent and severe nausea and vomiting, irritability, delirium, disturbance of consciousness, severe bulbar conjunctival edema, obvious bleeding tendency, white blood cell count >30 × 109/L, platelet count <20 × 109/L, and serum albumin level <15g/L.

Recommendation 6: When early warning indications for severe cases appear, the patient’s vital signs should be observed, and the white blood cell count, platelet count, serum albumin level, and hemoglobin level should be monitored closely.

Clinical classification

There are four types according to the severity of the disease.

  • (1) Mild-type: Body temperature below 39°C, skin and mucous membrane petechiae, urine protein of “+ to + +,” and no oliguria and hypotensive shock.
  • (2) Moderate-type: Body temperature of 39°C to 40°C, marked bulbar conjunctival edema, obvious petechiae on the skin and mucous membranes, systolic blood pressure <90 mmHg (1 mmHg = 0.133 kPa) or pulse pressure difference <30 mmHg, oliguria, and urine protein of “++ to ++++” during the course of the disease.
  • (3) Severe-type: Temperature above 40°C, neurological symptoms, shock, and oliguria lasting for 5 days or anuria lasting for ≤2 days.
  • (4) Critical-type: At least one of the following conditions: refractory shock, bleeding from vital organs, anuria lasting for more than 2days, and other serious comorbidities such as heart failure, pulmonary edema, respiratory failure, coma, and severe secondary infection.

Treatment

Principles of treatment

Early detection, diagnosis, and treatment are recommended at the nearest secondary or tertiary hospital, taking into account the capacity of the healthcare facilities. Fluid therapy and symptomatic supportive therapy are the main lines of treatments, and the prevention and treatment of shock, oliguria, bleeding, and other organ damage are the keys to successful management. It is advisable to organize resuscitation in situ for hypotensive shock in order to reduce transport. Severely ill patients with complex conditions and high mortality rates can be better treated by referral to centers for infectious diseases or comprehensive intensive care units (ICUs). Special populations such as children, the elderly, and pregnant women should be managed individually according to their characteristics.

Treatment points

  • (1) General treatment: Patients should be on bed rest, eat easily digestible food, and consume no less than 150 to 200 g of sugar daily to ensure daily calories. Patients with a high fever in the febrile phase are mainly treated with physical cooling. Antipyretic drugs such as acetaminophen should be used with caution as they can cause patients to sweat, potentially aggravating the lack of effective circulating blood volume. Furthermore, aspirin and ibuprofen have specific antiplatelet effects that can increase the risk of bleeding and should be avoided.[53,54] Active prevention, early diagnosis, and treatment can be beneficial in controlling secondary infections. The rational selection of antimicrobial drugs based on pathogenic findings and antimicrobial therapy should follow the general principles of antimicrobial drug therapy, and nephrotoxic drugs such as aminoglycosides should be avoided.

Recommendation 7: Physical cooling is the main antipyretic measure used during the febrile phase. Patients taking aspirin and ibuprofen were excluded in treatment. Acetaminophen and other antipyretic drugs should be used carefully.

  • (2) Fluid therapy: Fluid therapy is essential to maintain blood pressure stability as well as water, electrolyte, and acid-base balance in patients with HFRS. Excessive fluid infusion during the course of antishock treatment can increase the cardiopulmonary load, and lead to acute kidney injury (AKI). In patients with AKI, excessive fluid restriction and rapid or early excess removal of fluids may also lead to hypovolemia and recurrent kidney injury.[55] Therefore, fluid volume should be adjusted according to the patient’s cardiopulmonary load and renal function to maintain fluid balance.[56] The type and volume of rehydration fluid should be selected according to the phase of the disease. Crystalloid fluids, such as balanced salt solutions and 0.9% NaCl solution, are the mainstays in the febrile, hypotension, and shock phases. In the febrile phase, 1000 to 2000 mL of fluids should be infused daily to maintain the balance of intake and output, and reduce and prevent the occurrence of shock. In hypotension and shock phases, the amount of rehydration fluid should be adjusted according to the status of the shock treatment. In the oliguric phase, the amount of rehydration fluid should be limited, with a balance of intake and output, to prevent and control complications such as hypervolemia, heart failure, and pulmonary edema. In the polyuric phase, the amount of rehydration fluid should be less than that of the output.

Recommendation 8: Fluid therapy is the basic treatment for HFRS. Fluid type, volume, and duration should be adjusted according to the course of the disease.

  • (3) Fluid resuscitation: Fluid resuscitation is the primary measure for resuscitation in shock patients with HFRS. A rapid infusion of 1000 mL of fluid should be administered within 1 hour, followed by 1000 mL of fluid within 2hours if blood pressure returns to normal. The amount and speed of fluid infusion should be adjusted dynamically according to changes in blood pressure, mean arterial pressure (MAP), hemoglobin volume, peripheral circulation, tissue perfusion, and urine volume. After the blood pressure is stable, it is still necessary to maintain the infusion at approximately 200 to 300 mL per hour, until the blood pressure is stable for more than 6 hours. International multicenter randomized controlled clinical trials have demonstrated that the choice of crystalloids or colloids for fluid resuscitation in patients with septic shock had no effect on mortality.[57] An analysis of several multicenter randomized controlled studies performed by Bansal et al.[58–63] showed that the choice of crystalloids or colloids for initial fluid resuscitation had no effect on the mortality rate of septic patients at 28 to 30 days. Colloid fluids play an important role in the antishock treatment of HFRS, as this disorder is often associated with severe vascular leaking symptoms. The recommended antishock treatment primarily comprises crystalloid fluids, such as balanced salt solutions; however, the infusion of colloid fluids, such as albumin, plasma, and low-molecular dextrose solution is also required.[64]

The major objectives of fluid resuscitation are (1) systolic blood pressure of 90 to 100 mmHg; (2) MAP of 65 mmHg or more; (3) heart rate <100 beats/min; (4) correction of microcirculatory disorders, with an arterial blood lactate level <2 mmol/ L; and (5) hemoglobin and hematocrit levels close to normal. Treatment units should perform dynamic monitoring of central venous pressure and continuous cardiac output (CCO) and also conduct passive leg raising tests, bedside cardiopulmonary ultrasound, and non-invasive CCO monitoring to assess the volume status.

Recommendation 9: Fluid resuscitation is the primary antishock measure. Crystal liquids such as compounded sodium acetate Ringer’s solution, and sodium lactate Ringer’s solution, and colloid liquids such as human albumin and fresh plasma can be used for fluid resuscitation. Crystal liquid is the fluid of choice. Approximately 3000 mL of fluid should be infused in adults within 2 to 3 hours, initially at a rapid pace and then at a slow pace. The volume and infusion speed should be adjusted according to blood pressure, MAP, hemoglobin and lactate levels, peripheral circulation, and urine output.

  • (4) Vasoactive drugs: Vasoactive drugs should be administered promptly in shock patients with HFRS where blood pressure cannot be restored by rapid and adequate fluid resuscitation (3000 mL fluid infusion within 2–3 h in adults), or cases where blood pressure falls again after restoration, in order to maintain blood pressure, secure blood supply to vital organs, and avoid aggravating tissue edema. Moreover, both norepinephrine and dopamine can elevate the MAP. Dopamine has a greater effect than norepinephrine on heart rate and stroke volume, and is less effective in improving the hypotensive state of patients with septic shock.[65] Using the principles of septic shock treatment as a reference, norepinephrine is recommended as the first choice for treating shock patients with HFRS, with dobutamine as an alternative for patients with a low risk of tachyarrhythmia or bradycardia.[66] The usual adult dose of norepinephrine is started at a drip rate of 8 to 12 mg/min, which can be adjusted according to the presenting blood pressure. The maintenance dose is 2 to 4 mg/min, and is increased if necessary.

Recommendation 10: Vasoactive drugs should be used when fluid resuscitation is ineffective in shock patients with HFRS, especially in adult patients with blood pressure that cannot be restored by infusion of more than 3000 mL of fluid within 2 to 3 hours, or cases where blood pressure falls again after restoration. Norepinephrine is recommended as the first choice, with a starting dose of 8 to 12 µg/min. The dripping speed should be adjusted according to blood pressure, with a maintenance dose of 2 to 4 µg/min.

  • (5) Glucocorticoids: Although glucocorticoids have powerful anti-inflammatory effects, they can also cause adverse effects such as immunosuppression. Therefore, they should be used with caution after weighing their pros and cons. Glucocorticoids can be used in patients with significant exudative symptoms during the febrile phase to resist inflammation and reduce exudation. There was no significant difference in the reduction of the mortality rate between HFRS patients who used glucocorticoids early and those who did not, although the mortality rate due to shock might have been reduced.[67] Randomized controlled studies have revealed a significant effect of glucocorticoids in the treatment of septic shock.[68,69] Due to the lack of relevant randomized controlled studies on shock in HFRS, the treatment of septic shock can be used as a reference, and in cases where hemodynamic goals cannot be achieved, glucocorticoids can be administered in the following manner: hydrocortisone 100 mg intravenously once or twice per day, dexamethasone 5 to 10 mg intramuscularly or intravenously once or twice per day, or methylprednisolone 20 to 40 mg intravenously once or twice per day. The duration of treatment depends on the patient’s condition, and usually ranges from 3 to 5 days, and generally no more than 7 days.

Recommendation 11: Glucocorticoids should be usedly. Glucocorticoids, such as hydrocortisone, can be used in shock or in patients with early warning indications for severe disease in the form of hydrocortisone injection (100 mg intravenous drip once or twice a day). The course is usually 3 to 5 days and generally no more than 7 days.

  • (6) Antiviral agents: There are no specific antiviral drugs available for hantavirus infection. Ribavirin can be used for antiviral treatment during the early stages of the disease, and is administered intravenously at 10 to 15 mg/kg daily, with two divided doses in 250 mL of 10% dextrose solution. The total daily dose does not exceed 1500 mg, and the duration of treatment generally does not exceed 7 days. A prospective, randomized, double-blind, placebo-controlled clinical trial demonstrated that the treatment of HFRS with intravenous ribavirin significantly reduced the risk of entering the oliguric phase and significantly reduced the rate of morbidity and mortality.[70] A Korean retrospective study concluded that early use of ribavirin could reduce the incidence of oliguria and the need for dialysis.[71] A meta-analysis indicated that application of ribavirin during the early course of HFRS improved patient survival; however, its use in patients with hantavirus pulmonary syndrome did not reduce the mortality rate.[72]

Recommendation 12: Ribavirin can be used as an antiviral measure during the early stages of HFRS. Ribavirin is injected at 10 to 15 mg/kg intravenous drip daily with two divided doses in 250 mL of 10% dextrose solution. The total daily dose should not exceed 1500 mg, and the course of treatment should not exceed 7days.

  • (7) Diuretic therapy: Diuretics are widely used in patients with severe AKI, and do not increase the mortality rate of patients with renal failure.[73] Diuretics can reduce the volume load in AKI patients and delay the use of renal replacement therapy.[74] Diuretics can be used in the oliguric phase of HFRS, and furosemide is the preferred drug of choice. It is advisable to start with a small dose of 20 to 40 mg intravenously. If there is no urination for 2 to 4 hours, the dosage of furosemide can be increased to 100 to 200 mg/dose, 2 to 4 times daily. The diuretic dosage for the day should be determined by the urine output on the previous day to ensure approximately 2000 mL of urine output daily, and the total amount of furosemide usually does not exceed 800 mg/day. Diuretic drugs such as torasemide may also be used. For patients who have experienced shock, it is advisable to start diuresis after 12 to 24 hours of blood pressure stabilization. Premature diuresis may result in a drop in blood pressure and even shock.

Recommendation 13: Patients with oliguria should be treated with diuretics. Diuresis should be started after 12 to 24 hours of blood pressure stabilization in patients with shock. The first choice is furosemide, and is to be administered in a 20 to 200 mg/dose, once every 4 to 24 hours, starting with the smallest recommended dose, with a total daily dose of no more than 800 mg.

  • (8) Blood purification: Blood purification therapy includes intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT). Peritoneal dialysis can be used in hospitals that do not have these modalities. Blood purification therapy can be used in patients with increased serum creatinine levels of more than 300% of the basal value or ≥353.6 mmol/L, urine output of <0.3 mL/kg/h lasting for more than 24 hours, or anuria lasting for >12 hours (ie, AKI grade 3) as well as the patients with AKI complicated by hypercatabolism (daily rise in blood urea nitrogen level ≥10.5 mmol/L and rise in serum creatinine level ≥76.8 mmol/L).[75] Hemodialysis can be used for HFRS in patients who also have (1) oliguria lasting for more than 3days or anuria lasting for 1day that is ineffectively treated with diuretic therapy; (2) a slow increase in urine output, increasing azotemia, and blood urea nitrogen level >30 mmol/L; (3) hypervolemic syndrome with pulmonary edema, cerebral edema, and uremic encephalopathy, which can be treated simultaneously with pharmacological therapy; or (4) severe electrolyte disturbance (blood potassium level >6.5 mmol/L, blood sodium level >160 mmol/L, or blood sodium level <125 mmol/L). There are no absolute contraindications for hemodialysis; however, relative contraindications include shock or systolic blood pressure of <80 mmHg, severe bleeding or bleeding tendency, severe cardiopulmonary insufficiency, and extreme weakness. The decision to start blood purification therapy should be made after weighing its advantages and disadvantages. Common complications include bleeding, coagulation, hemolysis, hypotensive shock, imbalance syndrome, and fever.
  • The IHD is the most commonly used modality for blood purification. Depending on the degree of azotemia, blood potassium level, blood volume, and catabolism, dialysis is administered once daily or every other day for 3 to 4 hours. CRRT has a low hemodynamic influence and a high solute clearance. Furthermore, it can remove inflammatory mediators, which is suitable for critically ill HFRS patients who are hemodynamically unstable. However, CRRT can cause a loss of nutrients and removal of therapeutic agents. Heparin or lowmolecular heparin anticoagulation can be used in patients in the oliguric phase without a severe coagulation disorder. For patients with a severe coagulation disorder, either citrate anticoagulation in vitro or no anticoagulant regimen is recommended.[76] Arterial blood gas, complete blood count, renal function, electrolytes, and coagulation parameters should be monitored regularly during CRRT.

Recommendation 14: Patients with renal failure and severe internal environmental disturbances should be treated with blood purification, usually IHD. CRRT is preferred for patients with severe hemodynamic instability. Patients with severe coagulation disorder should receive either citrate extracorporeal anticoagulation or no anticoagulant regimen.

  • (9) Prevention and treatment of bleeding: Bleeding may occur in several vital organs during the course of HFRS, which is one of the causes of death. Gastrointestinal hemorrhage is common and can be treated according to the Guidelines for the Diagnosis and Treatment of Acute Non-variceal Upper Gastrointestinal Hemorrhage.[77] Renal rupture complicated by subperitoneal hemorrhage mostly occurs in severely or critically ill patients, and ultrasound and CT examinations can clarify the site, type, and extent of renal rupture hemorrhage. Moreover, these patients often have a low platelet count, poor coagulation function, and tissue and organ edema, and conservative medical treatment or interventional hemostatic treatment is commonly chosen. A combination of two to three hemostatic drugs can be used and gradually discontinued when bleeding stops. Absolute bed rest is usually required for 2 to 4 weeks, and prematurely getting out of bed and moving around can induce rebleeding. Intracranial hemorrhage in patients with HFRS mainly includes cerebral parenchymal hemorrhage and subarachnoid hemorrhage, which are dangerous conditions with a poor prognosis. Cranial CT should be performed as soon as possible for suspected intracranial hemorrhage. For patients with subarachnoid hemorrhage, a lumbar puncture may reveal bloody cerebrospinal fluid. A few patients may have cerebral hemorrhage combined with cerebral hernia. Pulmonary hemorrhage can be treated with vasopressin, and bronchoscopy is feasible, if necessary. Thrombocytopenia in patients with HFRS is often accompanied by bleeding. With reference to the principles of platelet transfusion of the American Society for Blood Transfusion,[78] transfusion of a platelet suspension is recommended for platelet counts ≤20 × 109/L to prevent further bleeding. In cases of massive hemorrhage, a platelet suspension should be transfused, even if the platelet count ranges from 20 × 109/L to 50 × 109/L.

Recommendation 15: Cases involving bleeding such as renal rupture, intracranial hemorrhage, gastrointestinal hemorrhage, pulmonary hemorrhage, and vaginal bleeding generally require internal medicine treatment to stop bleeding. Interventional hemostasis is feasible when internal medicine treatment is ineffective and there are indications for interventional treatment.

Recommendation 16: A platelet suspension transfusion is recommended when the patient has a platelet count ≤20 × 109/L with a bleeding tendency. In the presence of active bleeding, platelet suspensions should be transfused even if the platelet count ranges from 20 × 109/L to 50 × 109/L.

  • (10) Comprehensive treatment: Control of the total fluid volume and sodium-containing fluid input can prevent secondary pulmonary edema. Hemodialysis and diuresis are effective for treating pulmonary edema. For patients with shortness of breath, respiratory rate ≥30 breaths/min, resting oxygen saturation ≤93%, and oxygenation index ≤300 mmHg, a probable diagnosis of respiratory failure and/or ARDS should be suspected. Oxygenation, high-flow oxygen therapy, or ventilator- assisted breathing should be administered according to the condition and treatment effect. For patients with an oxygenation index of ≤200 mmHg, non-invasive or invasive mechanical ventilation should be used as soon as possible. In few patients, ARDS, disturbance of consciousness, heart failure, and multiple organ dysfunction syndrome (MODS) may occur due to renal failure, shock, and hemorrhage. These patients are in critical condition, with rapid changes and a high mortality rate. The treatment process is complicated and difficult, and requires advanced treatment facilities, equipment, and a highly specialized medical care team. Treatment in the ICU of a secondary or tertiary hospital is recommended.

Recommendation 17: Patients with severe manifestations such as ARDS, disturbance of consciousness, and MODS should be treated in the ICU of a secondary or tertiary hospital.

Discharge criteria

  1. The main symptoms have disappeared, the patient can move about with no signs of hypoxia, and has a normal urine output.
  2. Normal complete blood count or only mild anemia, normal urine routine tests, minimal levels of urine protein, basically normal biochemical indicators, and an approximately normal electrocardiogram.

Issues to be addressed

  1. Vaccination of people under 16 and over 60years of age.
  2. A clinical rapid test for hantavirus.
  3. Elucidating the mechanisms of vascular injury and vascular leakage.
  4. Treatment of refractory shock in HFRS.
  5. Therapeutic approaches to repair kidney injury.
  6. Mechanisms of lung injury in HFRS and how to improve the cure rate of respiratory failure.
  7. Mechanisms of coagulation disorders in HFRS and methods to reduce the incidence of visceral bleeding.

Author Contributions

Experts involved in the drafting of the consensus (in alphabetical order by last name): Hong Jiang (Department of Infectious Diseases, Tangdu Hospital, The Air Force Medical University), Changxing Huang (Department of Infectious Diseases, Tangdu Hospital, The Air Force Medical University), Xuefan Bai (Department of Infectious Diseases, Tangdu Hospital, The Air Force Medical University), Fuchun Zhang (Center of Infectious Diseases, The Eighth People’s Hospital, Guangzhou Medical University), Bingliang Lin (Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University), Shiwen Wang (National Institute for Viral Disease Control and Prevention, China CDC), Zhansheng Jia (Infection and Liver Disease Center, Xi’an International Medical Center Hospital), Jingjun Wang (Shaanxi Provincial Center for Disease Control and Prevention), Jing Liu (Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University), Shuangsuo Dang (Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University), Yingren Zhao (Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University), Xiaoguang Dou (Department of Infectious Diseases, Shengjing Hospital of China Medical University), Fuqiang Cui (School of Public Health, Peking University), Wenhong Zhang (Department of Infectious Diseases, Huashan Hospital, Fudan University), Jianqi Lian (Department of Infectious Diseases, Tangdu Hospital, The Air Force Medical University), Guiqiang Wang (Department of Infectious Diseases, The First Hospital of Peking University), Zhiliang Gao (Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University).

Experts involved in the development of the consensus (in alphabetical order by last name): Dewei Du (Department of Nephrology, TangduHospital, The Air ForceMedical University), Hong Du (Department of Infectious Diseases, Tangdu Hospital, The Air Force Medical University), Wanhu Fan (Department of Infectious Diseases, The First AffiliatedHospital of Xi’an Jiaotong University), Enqing Fu (Department of Respiratory and Critical Care Medicine, Tangdu Hospital, The Air Force Medical University), Chunqiu Hao (Department of Infectious Diseases, Tangdu Hospital, The Air Force Medical University), Miaowang Hao(Department ofHematology, TangduHospital,TheAir Force Medical University), Yuxian Huang (Department of Infectious Diseases, Huashan Hospital, Fudan University), Hongbing Li (Department of Infectious Diseases, Weinan Central Hospital), Jin Li (HospitalOffice, The Third People’s Hospital, Shenzhen), Pei Li (Department of Infectious Diseases, Tangdu Hospital, The Air ForceMedicalUniversity), Xingwang Li (Department of Infectious Diseases, Ditan Hospital, Capital Medical University), Yarong Li (Department of Infectious Diseases, Xi’an Children’s Hospital), Yanping Li (Department of Infectious Diseases, Shaanxi Provincial Infectious Disease Hospital), Yongguo Li (Department of Infectious Diseases, The First Affiliated Hospital of ChongqingMedical University), Zhiwei Li (Department of Infectious Diseases, Shengjing Hospital of China Medical University), Hailing Liu (Department of Infectious Diseases, Xianyang Central Hospital), Hongyan Liu (Department of Infectious Diseases, The Sixth People’s Hospital, Shenyang), Layang Liu (Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University), Xiaoying Liu (Department of Infectious Diseases, Xianyang Central Hospital), Zhengwen Liu (Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University), Lixian Ma (Department of Infectious Diseases, Qilu Hospital of Shandong University), Bo Ning (Department of Infectious Diseases, Baoji Central Hospital), Feng Wang (Department of Infectious Diseases, The First Hospital of Jilin University), JiupingWang (Department of Infectious Diseases, Xijing Hospital, The Air Force Medical University), Kai Wang (Department of Hepatology, QiluHospital of Shandong University), Linxu Wang (Department of Infectious Diseases, Tangdu Hospital, The Air Force Medical University), Pingzhong Wang (Department of Infectious Diseases, Tangdu Hospital, The Air Force Medical University), Xuelian Wang (Department of Infectious Diseases, Shengjing Hospital of China Medical University), Zhikai Xu (Department of Microbiology and Pathogen Biology, School of Basic Medical Sciences, The Air Force Medical University), Jianhua Yi (Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology), Hong Zhang (Department of Infectious Diseases, People’s Hospital of Shaanxi Province), Ying Zhang (Department of Infectious Diseases, Tangdu Hospital, The Air Force Medical University).

Haifeng Hu, Xuyang Zheng, and Jiayi Zhan approved the English writing.

Conflicts for Interest

None.

References

1. Wu J, Wang DD, Li XL, et al. Increasing incidence of hemorrhagic fever with renal syndrome could be associated with livestock husbandry in Changchun, northeastern China. BMC Infect Dis 2014;14:301. doi:10.1186/1471-2334-14-301.
2. Jiang H, Du H, Wang LM, et al. Hemorrhagic fever with renal syndrome: pathogenesis and clinical picture. Front Cell Infect Microbiol 2016;6:1. doi:10.3389/fcimb.2016.00001.
3. Jiang H, Zheng X, Wang L, et al. Hantavirus infection: a global zoonotic challenge. Virol Sin 2017;32(1):32–43. doi:10.1007/s12250-016-3899-x.
4. Schmaljohn C, Hjelle B. Hantaviruses: a global disease problem. Emerg Infect Dis 1997;3(2):95–104. doi:10.3201/eid0302.970202.
5. Sun L, Zou LX. Spatiotemporal analysis and forecasting model of hemorrhagic fever with renal syndrome in mainland China. Epidemiol Infect 2018;146(13):1680–1688. doi:10.1017/S0950268818002030.
6. Ministry of Health of the People’s Republic of China. National epidemic hemorrhagic fever control program [EB/OL]. (1997-02-04). Available from: https://law.lawtime.cn/d490579495673.html. Accessed December 1, 2020.
7. Ministry of Health of the People’s Republic of China. WS278-2008 Diagnostic Standard for Epidemic Hemorrhagic Fever. Beijing: China Standard Press; 2008:1–11.
8. Shaanxi Provincial Health Committee, Tangdu Hospital of The Air Force Medical University. Shaanxi provincial expert consensus on the diagnosis and treatment of hemorrhagic fever with renal syndrome. Shaanxi Med J 2019;48(3):275–288. doi:10.3969/j.issn.1000-7377.2019.03.001.
9. Yang WS, Zhang WB, Bai XF, et al. Study on the distribution of epidemic hemorrhagic fever virus antigen in infected fetal organs. Chin J Infect Dis 1988;6(2):128–129.
10. Chen HX. Achievements and prospects of hemorrhagic fever with renal syndrome in China in the 20th century. Chin J Vector Biol Control 2001;12(5):388–396. doi:10.3969/j.issn.1003-4692.2001.05.025.
11. Wang JJ, Wei J, Ma CA, et al. Antibody formation after natural infection and artificial immunization in hemorrhagic fever with renal syndrome. Chin J Dis Control Prev 2014;18(5):387–390.
12. Huang LY, Zhou H, Yin WW, et al. Surveillance and epidemiological analysis of hemorrhagic fever with renal syndrome in China in 2010. Chin J Epidemiol 2012;33(7):685–691. doi:10.3760/cma.j.issn.0254-6450.2012.07.010.
13. Zhang S, Wang S, Yin W, et al. Epidemic characteristics of hemorrhagic fever with renal syndrome in China, 2006–2012. BMC Infect Dis 2014;14:384. doi:10.1186/1471-2334-14-384.
14. Yin P, Li ZJ. Nine cases of laboratory personnel infected with epidemic hemorrhagic fever due to animal experiments. Zhonghua lao dong wei sheng zhi ye bing za zhi 2007;25(7):428–429. doi:10.3760/cma.j.issn.1001-9391.2007.07.019.
15. Ma CF, Yu PB, Li HX, et al. Current status of epidemic and immunization strategy in hemorrhagic fever with renal syndrome in China. Chin J Prev Med 2014;48(12):1039–1042. doi:10.3760/cma.j.issn.0253-9624.2014.12.004.
16. Chen GX, Liu SF. Investigation of specific antibodies against hemorrhagic fever in renal syndrome. Chin J Vector Biol Control 2002;13(3):210–211. doi:10.3969/j.issn.1003-4692.2002.03.018.
17. Xing YF, Li DX, Wang SW. Progress of research on hemorrhagic fever with renal syndrome vaccine and evaluation of immunization effect. Chin J Exp Clin Virol 2008;22(1):68–70. doi:10.3760/cma.j.issn.1003-9279.2008.01.024.
18. Yu PB, Tian HY, Ma CF, et al. Hantavirus infection in rodents and haemorrhagic fever with renal syndrome in Shaanxi province, China, 1984–2012. Epidemiol Infect 2015;143(2):405–411. doi:10.1017/S0950268814001009.
19. Wang JJ, Wei ZZ, Wei J, et al. Long term epidemiological effects of vaccination on hemorrhagical fever with renal syndrome (HFRS) in Shaanxi provincial HFRS epidemic areas. Chin J Epidemiol 2012;33(3):309–312. doi:10.1017/S0950268814001009.
20. Hang CS, Xie YX, Xi Y, et al. Clinical study on vaccine of hemorrhagic fever with renal syndrome. Chin J Exp Clin Virol 2006;20(4):423–425. doi:10.3760/cma.j.issn.1003-9279.2006.04.043.
21. Hall PR, Leitão A, Ye C, et al. Small molecule inhibitors of hantavirus infection. Bioorg Med Chem Lett 2010;20(23):7085–7091. doi:10.1016/j.bmcl.2010.09.092.
22. Avsič-Županc T, Saksida A, Korva M. Hantavirus infections. Clin Microbiol Infect 2019;21S:e6–e16. doi:10.1111/1469-0691.12291.
23. Lee HW, Lee PW, Johnson KM. Isolation of the etiologic agent of Korean hemorrhagic fever. J Infect Dis 1978;137(3):298–308. doi:10.1093/infdis/137.3.298.
24. Song G. Epidemiological progresses of hemorrhagic fever with renal syndrome in China. Chin Med J 1999;112(5):472–477.
25. Yi J, Xu Z, Zhuang R, et al. Hantaan virus RNA load in patients having hemorrhagic fever with renal syndrome: correlation with disease severity. J Infect Dis 2013;207(9):1457–1461. doi:10.1093/infdis/jis475.
26. Garanina E, Martynova E, Davidyuk Y, et al. Cytokine storm combined with humoralimmune response defect in fatal hemorrhagic fever with renal syndrome case, Tatarstan, Russia. Viruses 2019;11(7):601. doi:10.3390/v11070601.
27. Khaiboullina SF, Levis S, Morzunov SP, et al. Serum cytokine profiles differentiating hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Front Immunol 2017;8:567. doi:10.3389/fimmu.2017.00567.
28. Luo DD, Zeng LL, Cai SQ, et al. Pathogenic effect of epidemic hemorrhagic fever virus on normal human bone marrow cells. Chin J Infect Dis 1994;12(3):131–133. doi:10.1007/BF02007173.
29. Jiang H, Wang PZ, Zhang Y, et al. Hantaan virus induces toll-like receptor 4 expression, leading to enhanced production of beta interferon, interleukin-6 and tumor necrosis factor-alpha. Virology 2008;380(1):52–59. doi:10.1016/j.virol.2008.07.002.
30. Wang PZ, Li ZD, Yu HT, et al. Elevated serum concentrations of inflammatory cytokines and chemokines in patients with haemorrhagic fever with renal syndrome. J Int Med Res 2012;40(2):648–656. doi:10.1177/147323001204000227.
31. Gavrilovskaya IN, Gorbunova EE, Mackow NA, et al. Hantaviruses direct endothelial cell permeability by sensitizing cells to the vascular permeability factor VEGF, while angiopoietin 1 and sphingosine 1-phosphate inhibit hantavirus-directed permeability. J Virol 2008;82(12):5797–5806. doi:10.1128/JVI.02397-07.
32. Gorbunova EE, Gavrilovskaya IN, Pepini T, et al. VEGFR2 and Src kinase inhibitors suppress Andes virus-induced endothelial cell permeability. J Virol 2011;85(5):2296–2303. doi:10.1128/JVI.02319-10.
33. Hayasaka D, Maeda K, Ennis FA, et al. Increased permeability of human endothelial cell line EA.hy926 induced by hantavirus specific cytotoxic Tlymphocytes. Virus Res 2007;123(2):120–127. doi:10.1016/j.virusres.2006.08.006.
34. Dzagurova TK, Tkachenko EA, Ishmukhametov AA, et al. Severe hantavirus disease in children. J Clin Virol 2018;101:66–68. doi:10.1016/j.jcv.2018.01.018.
35. Ma HW, Xuan TJ, Ma YT, et al. Clinical characteristics of pediatric hemorrhagic fever with renal syndrome. Chin J Contemp Pediatr 2014;16(11):1091–1095. doi:10.7499/j.issn.1008-8830.2014.11.003.
36. Echterdiek F, Kitterer D, Alscher MD, et al. Clinical course of hantavirus-induced nephropathia epidemica in children compared to adults in Germany-analysis of 317 patients. Pediatr Nephrol 2019;34(7):1247–1252. doi:10.1007/s00467-019-04215-9.
37. Li CC, He CJ, Zhou ZL, et al. 89 cases of elderly hemorrhagic fever with renal syndrome. Chin J Infect Dis 2005;23(3):208–209. doi:10.3760/j.issn:1000-6680.2005.03.021.
38. Bai XF, Xu ZK. Hemorrhagic Fever with Renal Syndrome. Beijing: People’s Health Publishing House; 2013:192–193.
39. Yang WS, Bai XG, Zhang WB, et al. Study on the transmission of epidemic hemorrhagic fever virus through human placenta and its localization in some organs of human fetus. Chin J Public Health 1987;6(2):85–89. doi:CNKI:SUN:ZGGW.0.1987-02-011.
40. Lu DH, Jiang H, Lian JQ. Hantavirus infection during pregnancy. Virol Sin 2021;36(3):345–353. doi:10.1007/s12250-020-00300-8.
41. Thrombosis and Haemostasis Group of the Hematology Branch of the Chinese Medical Association. Chinese expert consensus on the diagnosis of disseminated intravascular coagulation (2017 version). Chin J Hematol 2017;38(5):361–363. doi:10.3760/cma.j.issn.0253-2727.2017.05.001.
42. Jiang H, Wang LM, Du H, et al. Clinical significance of serum viral RNA in hantavirus-infected patients. J Virol 2020;36(2):322–327. doi:10.13242/j.cnki.bingduxuebao.003628.
43. Qiu J, Dong ZP, Hang CS, et al. Application of reverse transcription-set PCR to detect serum hantavirus-specific RNA in the patients with hemorrhagic fever with renal syndrome. J Virol 1997;13(2):119–125.
44. PangZ LA, Li J, et al. Comprehensive multiplex one-step real-time TaqMan qRT-PCR assays for detection and quantification of hemorrhagic fever viruses. PLoS One 2014;9(4):e95635. doi:10.1371/journal.pone.0095635.
45. Jiang W, Yu HT, Zhao K, et al. Quantification of Hantaan virus with a SYBR green I-based one-step qRT-PCR assay. PLoS One 2013;8(11):e81525. doi:10.1371/journal.pone.0081525.
46. Wei YL, Wang QJ, Li AL, et al. Diagnostic value of CT in patients with hemorrhagic fever with renal syndrome complicated by pulmonary edema. E-J Transl Med 2016;3(2):21–22.
47. Liu ZF, Bai X, He WG, et al. 2263 cases of hemorrhagic fever with renal syndrome. Chin J Infect Dis 2003;21(5):365–368. doi:10.3760/j.issn:1000-6680.2003.05.024.
48. Wang M, Wang J, Wang T, et al. Thrombocytopenia as a predictor of severe acute kidney injury in patients with Hantaan virus infections. PLoS One 2013;8(1):e53236. doi:10.1371/journal.pone.0053236.
49. Kim YO, Yoon SA, Ku YM, et al. Serum albumin level correlates with disease severity in patients with hemorrhagic fever with renal syndrome. J Korean Med Sci 2003;18(5):696–700. doi:10.3346/jkms.2003.18.5.696.
50. Du H, Li J, Jiang W, et al. Clinical study of critical patients with hemorrhagic fever with renal syndrome complicated by acute respiratory distress syndrome. PLoS One 2014;9(2):e89740. doi:10.1371/journal.pone.0089740.
51. Du H, Wang PZ, Li J, et al. Clinical characteristics and outcomes in critical patients with hemorrhagic fever with renal syndrome. BMC Infect Dis 2014;14:191. doi:10.1186/1471-2334-14-191.
52. Du H, Li J, Yu HT, et al. Early indicators of severity and construction of a risk model for prognosis based upon laboratory parameters in patients with hemorrhagic fever with renal syndrome. Clin Chem Lab Med 2014;52(11):1667–1675. doi:10.1515/cclm-2014-0016.
53. El-Mashad AE, El-Mahdy H, El Amrousy D, et al. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. Eur J Pediatr 2017;176(2):233–240. doi:10.1007/s00431-016-2830-7.
54. Driver B, Marks DC, van der Wal DE. Not all (N)SAID and done: effects of nonsteroidal anti-inflammatory drugs and paracetamol intake on platelets. Res Pract Thromb Haemost 2019;4(1):36–45. doi:10.1002/rth2.12283.
55. Prowle JR, Kirwan CJ, Bellomo R. Fluid management for the prevention and attenuation of acute kidney injury. Nat Rev Nephrol 2014;10(1):37–47. doi:10.1038/nrneph.2013.232.
56. Prowle JR, Echeverri JE, Ligabo EV, et al. Fluid balance and acute kidney injury. Nat Rev Nephrol 2010;6(2):107–115. doi:10.1038/nrneph.2009.213.
57. Chinese Medical Association, Critical Care Medicine Branch. Chinese guidelines for the treatment of severe sepsis/septic shock. Chin Crit Care Med 2015;27(6):401–426. doi:10.3760/cma.j.issn.0578-1426.2015.06.021.
58. Bansal M, Farrugia A, Balboni S, et al. Relative survival benefit and morbidity with fluids in severe sepsis: a network meta-analysis of alternative therapies. Curr Drug Saf 2013;8(4):236–245. doi:10.2174/15748863113089990046.
59. Finfer S, Bellomo R, et al. SAFE Study Investigators. Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study. BMJ 2006;333(7577):1044. doi:10.1136/bmj.38985.398704.7C.
60. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358(2):125–139. doi:10.1056/NEJMoa070716.
61. Guidet B, Martinet O, Boulain T, et al. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: the CRYSTMAS study. Crit Care 2012;16(3):R94. doi:10.1186/cc11358.
62. McIntyre LA, Fergusson D, Cook DJ, et al. Fluid resuscitation in the management of early septic shock (FINES): a randomized controlled feasibility trial. Can J Anaesth 2008;55(12):819–826. doi:10.1007/BF03034053.
63. Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl JMed 2012;367(2):124–134. doi:10.1056/NEJMoa1204242.
64. Malbrain MLNG, Langer T, Annane D, et al. Intravenous fluid therapy in the perioperative and critical care setting: executive summary of the International Fluid Academy (IFA). Ann Intensive Care 2020;10(1):64. doi:10.1186/s13613-020-00679-3.
65. Agrawal A, Gupta A, Consul S, et al. Comparative study of dopamine and norepinephrine in the management of septic shock. Saudi J Anaesth 2011;5(2):162–166. doi:10.4103/1658-354X.82784.
66. Chinese Physicians Association, Emergency Physicians Branch, Chinese Society of Research Hospitals, Shock and Sepsis Specialty Committee. Guidelines for the emergency treatment of sepsis/septic shock in China. J Clin Emerg Med 2018;19(9):567–588. doi:CNKI:SUN:ZZLC.0.2018-09-001.
67. Sayer WJ, Entwhisle G, Uyeno B, et al. Cortisone therapy of early epidemic hemorrhagic fever: a preliminary report. Ann Intern Med 1955;42(4):839–851. doi:10.7326/0003-4819-42-4-839.
68. Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998;26(4):645–650. doi:10.1097/00003246-199804000-00010.
69. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized double-blind, single-center study. Crit Care Med 1999;27(4):723–732. doi:10.1097/00003246-199904000-00025.
70. Huggins JW, Hsiang CM, Cosgriff TM, et al. Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. J Infect Dis 1991;164(6):1119–1127. doi:10.1093/infdis/164.6.1119.
71. Rusnak JM, Byrne WR, Chung KN, et al. Experience with intravenous ribavirin in the treatment of hemorrhagic fever with renal syndrome in Korea. Antiviral Res 2009;81(1):68–76. doi:10.1016/j.antiviral.2008.09.007.
72. Moreli ML, Marques-Silva AC, Pimentel VA, et al. Effectiveness of the ribavirin in treatment of hantavirus infections in the Americas and Eurasia: a meta-analysis. Virus Dis 2014;25(3):385–389. doi:10.1007/s13337-014-0219-7.
73. Uchino S, Doig GS, Bellomo R, et al. Diuretics and mortality in acute renal failure. Crit Care Med 2004;32(8):1669–1677. doi:10.1097/01.ccm.0000132892.51063.2f.
74. Cerda J, Sheinfeld G, Ronco C. Fluid overload in critically ill patients with acute kidney injury. Blood Purif 2010;29(4):331–338. doi:10.1159/000287776.
75. Chertow GM, Burdick E, Honour M, et al. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16(11):3365–3370. doi:10.1681/ASN.2004090740.
76. Du H, Li J, Zheng R, et al. Study on the application of continuous renal replacement therapy and heparin anticoagulation in hemorrhagic fever with renal syndrome. Med J Chin PLA 2014;26(4):46–49. doi:10.3969/j.issn.2095-140X.2014.04.014.
77. , et alEditorial board of the Chinese Journal of Internal Medicine, Editorial board of the Chinese Journal of Medicine, Editorial board of the Chinese Journal of Gastroenterology. Guidelines for the diagnosis and treatment of acute non-variceal upper gastrointestinal bleeding (Hangzhou, 2018). Chin Intern Med 2019;58(3):173–180. doi:10.3760/cma.j.issn.0254-1432.2019.02.002.
78. Kaufman RM, Djulbegovic B, Gernsheimer T, et al. Platelet transfusion: a clinical practice guideline from the AABB. Ann Intern Med 2015;162(3):205–213. doi:10.7326/M14-1589.
Keywords:

Hemorrhagic fever with renal syndrome; Expert consensus; Prevention; Treatment

Copyright © 2022 The Chinese Medical Association, published by Wolters Kluwer Health, Inc.