Sanford H. Feldman, David N. Easton, in 2006
Hemorrhagic fever with renal syndrome (HFRS) caused by members of the Bunyaviridae family of RNA viruses in the genus Hantavirus. These viruses include viruses Seoul, Korea Dengue and Hantaan virus (LeDuc, 1989). In 1985, 126 human cases of laboratory HFRS were reported in Japan (Kawamata et al., 1987). Laboratory research staff more often than caregivers of infected animals, and the animal caretaker died of the disease. Inhalation of aerosol virus and wound infection is the primary modality of transmission of laboratory mice to humans. Ornithonyssus bacoti tropical rat mite may act as vectors for Hantaan and Seoul virus transmission between mice and from mice to humans (Zhuge et al., 1998). Symptoms of hemorrhagic fever with renal syndrome in humans manifest initially fever, bradycardia, and conjunctival congestion. The disease progresses with the development of abdominal pain, vomiting, bleeding, and nephropathy. Symptoms of renal involvement is hematuria, oliguria, proteinuria, and, then, excessive urine production isosthenuric. Fatality may occur during the oliguric phase.
Omar Lupi, … Laila Klotz, in 2017
The symptoms of hemorrhagic fever with renal syndrome (HFRS) associated with hantaviruses from Old world usually occurs about 5-6 weeks after exposure to the virus , early onset characterized by non-specific flu-like symptoms: fever, myalgia, headache, abdominal pain, nausea, and vomiting.41,43 There reddish facial characteristics, and usually petechial rash (usually limited to the axilla, or armpit) 0.41 abrupt and extreme albuminuria occurred on day 4; This is characteristic of severe HFRS.43 The bleeding manifestations also include bleeding skin with petechiae, purpura, ecchymosis, gingival and nasal bleeding, and hematuria. Gastrointestinal bleeding is very common, with hematemesis and melena, and increased menstrual flow.41,43 Additional symptoms may include hypotension, respiratory distress and / or failure, and renal impairment and / or failure.43
Phillip R. Pittman, Stanley A. Plotkin, in 2018
Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) has been, and continues to be, a significant endemic disease threats to US military forces in the Korean peninsula and throughout Europe.105 at least 14 different strains of virus that cause HFRS virus is distributed worldwide.106 three viral proteins are able to induce protection: two surface glycoproteins, G1 and G2 (also called Gn and Gc), and the nucleocapsid protein N. protective antibodies, although the T-cell response may also useful.107 addition to HFRS, hantaviruses responsible for hantavirus pulmonary syndrome syndrome.106,108 The hantavirus causes this in the southwestern United States called Sin Nombre virus (SNV). Humans infected with hantaviruses through rodent inhalation aerosol excreta.109 prototype hantavirus, Hantaan, first isolated in Korea, and also the first vaccine developed there to protect against this HFRS.108,110,111 inactive vaccine, which ROK84 / 105 strain, harvested from breastfeeding rat brain, concentrated by protamine sulfate precipitation and centrifugation. concentrate is then exposed to formalin inactivated and purified by ultrafiltration and sucrose gradient ultracentrifugation. Aluminum hydroxide as adjuvant added to the vaccine, thimerosal as a preservative, and gelatin as stabilizers. The end product, which is produced by Rhein Biotech, reported having less than 0.01 ng / mL of myelin basic protein. Recommended regimens for these products, Hantavax, is two doses of 5120 ELISA units (0.5 mL) was given 1 month apart route subcutaneously or intramuscularly.
Little has been published in the vaccine, but reported a good tolerance producers, although an allergic reaction occurs, probably as a result of the rat brain antigen. A serological response measured by fluorescence is not directly visible in most vaccines. antibodies are usually no after one dose, but measured in approximately 75% of the subjects after the second dose.112 They fell to 16% at 12 months, when the booster is recommended. Although placebo controlled data on the efficacy of the vaccine is not available, a similar vaccine made in North Korea reportedly showed 88% to 100% efficacy, and Hantavax own haHave been effective in not controlled epidemiological studies conducted in South Korea and Yugoslavia.113,114 Although neutralizing antibody response is not persistent and not stimulated by booster dose, 107 115 case-control study conducted in the Republic of Korea is estimated efficacy of 46% for two doses and 75% for three doses, but with wide confidence limits.116
The vaccine is made in cell culture against viral strain Seoul hantavirus and licensed in China. Renal cell culture substrates of gold or Mongolian gerbil hamster kidney. The efficacy of the bivalent vaccine is reported to be better than 90%, with fewer reactions than after the use of the mouse brain-derived vaccine.113,114
Another Korean company has developed a hantavirus vaccine prepared in Vero cells protected the animals challenged by generating a strong response to the G1, G2, and N protein of virus.117
at USAMRIID, technological advances driven artificial hantavirus vaccine development. Two experimental approaches including recombinant vaccinia vectors carrying Hantaan virus vaccine genes118,119 envelope and nucleocapsid and the same gene inserted into the bacterial plasmid DNA vaccine. Hantaan virus vaccine is efficacious recombinant vaccinia vectors in a hamster model of infectivity; even if the preexisting immunity to vaccinia virus is present, it can be treated with intramuscular injection of two vaccines candidate.118 A double-blind, placebo-controlled clinical trial involving 142 volunteers used two subcutaneous injections four weeks apart showed that, for vaccinia volunteers -naïve , antibodies against Hantaan virus or vaccinia virus was detected in 72% or 98%, respectively, whereas antibodies against Hantaan virus detected only 26% of the vaccinia-immune volunteers, showing the effect of vector-directed immunity before 0.119 this vaccine has been abandoned.
plasmid DNA coding for the G1 and G2 proteins protected monkeys against challenge with South America and causing hantavirus antibodies provided passive protection in monkeys Increase hamsters.120 1 to 2 years later showed that the Immunological memory has induced.121 alphavirus replicons, baculovirus-produced proteins, and chimeric VLP hepatitis B are all under stu dy as additional hantavirus vaccine candidates.113,122,123
Boudreau and colleagues124 report on Phase I clinical trials that evaluated the virus Hantaan and Puumala virus DNA vaccine M -segmen to prevent HFRS. Each volunteer received both Hantaan DNA vaccine (n = 9), Puumala DNA vaccine (n = 9), or both the vaccine (n = 9). Three doses (containing 8 mg of DNA / 4 mg gold per dose), given 4 weeks, given to volunteers with particle-mediated epidermal delivery. Single vaccines induce antibodies to the virus Hantaan or Puumala virus, respectively, 30% and 44% of the vaccine. Neutralizing antibodies to one or both viruses were detected in 56% of volunteers who received the combined vaccine. In an effort to increase seroconversion, Hooper and colleagues125 conduct a Phase I clinical trial of two DNA vaccine was delivered by intramuscular electroporation, similar to studies Boudreau. Volunteers (three groups of nine each) received three doses, 28 days apart, both DNA vaccines Hantaan, Puumala DNA vaccine, or a mixture of both vaccines. Each dose of vaccine contains 2 mg of DNA in a total volume of 1 mL of saline; The combined vaccine contained 1 mg of DNA vaccines. antibodies are found in 56% and 78% of volunteers who received the vaccine Hantaan or Puumala DNA, respectively. The results of the combined vaccine showed that 78% of the vaccine developed antibodies against Puumala virus. Three volunteers with the highest antibody levels against Puumala also develop antibodies against Hantaan. No serious side effects resulting from the vaccine were noted in either study.
Hooper and colleagues126,127 also found that a DNA vaccine that encodes the viral envelope glycoprotein of SNV or Andes virus (both of which cause hantavirus pulmonary syndrome) Potential high titer neutralizing antibodies in animal models. Hamsters vaccinated with three doses of DNA vaccine SNV fully protected from lethal challenge with SNV. Furthermore, pan-hantavirus vaccine using virus Andes, SNV, Hantaan virus, Puumala virus and plasmid induce antibodies againstThe fourth viruses.126
Richard Heller, Loree C. Heller, 2015
Hantavirus infection causes hemorrhagic fever with renal syndrome is endemic in Europe and Asia. A Phase I clinical trial in 31 healthy adult volunteers (NCT02116205) is focused on vaccine encoding the envelope glycoproteins Gn and Gc genes from two hantaviruses, virus Hantaan and Puumala virus (Hooper et al., 2014). After each of the three intramuscular injections of as much as 2 mg DNA vaccine Hantaan virus, Puumala virus vaccine, or a combination, an electric pulse is applied (TDS-IM device, pus Medical Systems, San Diego, CA, USA). Both electrodes and a pulse protocol employed otherwise. No serious adverse events related to study. Only two subjects reported muscle contractions with pulse applications. Twenty-eight subjects reported local pain at the injection site; seven patients also develop a bruise. Five of nine and seven of nine individuals developed antibodies when virus Hantaan and Puumala virus plasmid is delivered as a single vaccine. When the combination is tested, seven of the nine developed neutralizing antibodies to Puumala virus, while the number was reduced (three of nine) develop antibodies against Hantaan virus.
Another trial may take place but not yet published or stored in this Clinical Trials Registry. In some experiments, electrodes and electroporation parameters used for shipping are not detailed. Changing the pulse parameters (pulse number, intensity, length, and frequency) cause variations in the level and duration of expression of the transgene. Pulse parameters is an important part of the delivery criteria and must be clearly delineated when results from each trial were published.
In each trial, patients complain universal local, temporary pain for pulse applications. However, in general, well tolerated pulses.
This study surveyed patients after complete treatment regimen by intramuscular electrotransfer using different pulse protocols. Different protocols may explain the varied patient responses from patients.
Christopher J. Burrell, … Frederick A. Murphy, in 2017
clinically severe hemorrhagic fever with renal syndrome (HFRS) in humans involves five overlapping but distinct stages: fever, hypotension, oliguria, diuretic, and the stage of recovery, not all are visible in each case. The emergence of this disease abruptly with intense headache, back pain, fever, and chills. Bleeding, if it occurs, manifested during febrile phase, with conjunctival injection and mucous membranes. Petechial rash may also appear. Sudden and extreme hypotension, albuminuria, nausea, and vomiting around the fourth day, is a feature of severe disease. One third of the deaths occurred during this stage due to the leakage of blood vessels and acute shock, while up to 50% of deaths occur during (oliguria) the later stages of kidney failure. Patients who survive and advance to the event diuretics increase renal function but can still die from shock or pulmonary complications. Phase recovery can last weeks to months before the recovery is complete. The disease is believed to be mediated immunopathologically, because antibodies are present usually from the first day the patient for medical care. supportive therapy, with certain constraints in the use of fluids and in some cases the use of hemodialysis, has resulted in a decrease in the mortality rate from 15% to 5% or less. The drug ribavirin demonstrated antiviral activity against hantaviruses in cell culture, and has been used in clinical trials HFRS with reduced mortality report.
Charles F. Fulhorst, … CJ Peters, in 2011
HFRS has been known by many names, including hemorrhagic disease nephrosonephritis and Churilov in the Russian Far East, the Korean peninsula dengue fever Korea, dengue epidemics in China, and nephropathia epidemica in Europe. The name “hemorrhagic fever with renal syndrome” recommended in 1983 to consolidate these and other febrile illnesses caused by hantaviruses and marked with hemostatic and renal disturbances.93
The incubation period of HFRS usually 2- 4 weeks but have ranged from 1 to 8 weeks.94-96 severe HFRS clinical course can be divided into five phases: prodrome, hypotension (shock), oliguric, diuretic, and cured (Figure 71.4.). Death, when it occurs, usuallyly is due to kidney failure in oliguric phase in hypotension or shock, oliguria, or diuretic phase.
Figure 71.4. , Schemes clinical course of severe hemorrhagic fever with renal syndrome (HFRS)
Description of the five phases in severe disease caused by Hantaan virus provides a framework for understanding the pathogenesis of HFRS caused by other hantaviruses; However, the spectrum of disease caused by Hantaan virus including a very mild disease that is not easily identifiable as HFRS, disease “jumping” one or more phases, and fulminant disease with early death.97
prodrome in severe HFRS usually lasts 3-7 days, beginning with the abrupt onset of high fever and chills, and then include headache, blurred vision, myalgia, and thirst. Anorexia, abdominal pain, nausea, vomiting, mild cough, hiccup, and dizziness often. capillary dilation is evidenced by rinsing the face and neck, and conjunctival injection and pharynx. Increased capillary permeability common and usually results in retroperitoneal edema accompanied with severe back pain. Low grade disseminated intravascular coagulation (DIC), thrombocytopenia and bleeding (eg, petechiae and epistaxis) may occur at the end prodrome.98 sudden onset of albuminuria extreme end of the prodrome are usually the first sign of kidney involvement.
hypotension stage begins with defervescence or a mild fever to normal body temperature, lasting hours to several days, and is characterized by thrombocytopenia, nausea, and vomiting. Proteinuria and increased back pain, urine (which contains cells, red blood cells, white blood cells, and casts) decrease in volume, specific gravity moves urine to 1,010, hemokonsentrasi can result in hematocrit of 55% or higher, and platelets may fall below 70 000 / uL. white blood cells in peripheral blood increased, often above 30 000 / uL, and sometimes reached the level leukemoid. shock occurs in about 15% of patients.98 Careful management with Trendelenburg position, pressors, and inotropic agents usually results in survival; but some of the patients died of shock during this phase. Administration of large amounts of fluid in hypotension phase can be dangerous due to hyperpermeability of the microvasculature, particularly in the lungs. cardiovascular measurements in cases of HFRS in Korea showed that the patients had low cardiac output and high peripheral light shock resistance.99 Patients with peripheral vasoconstriction is often given 1-2 units of albumin with an apparent increase.
In the oliguric phase, heavy bleeding (hemoptysis, gastrointestinal bleeding, and hematuria) can be troublesome, urine output fell dramatically, the concentration of serum creatinine and blood urea nitrogen increased, and the fluid is reabsorbed. circulation can be overexpanded, that lead to high-output state, hypertension, and pulmonary edema sometimes fatal. Dialysis for treatment of overhydration may be very necessary because the risk of intracranial hemorrhage and pulmonary edema. Approximately half of the deaths in HFRS occurred during the oliguric phase, with deaths mainly due to kidney failure.
spontaneous diuresis, with polyuria larger than 3 liters per day, heralds the onset of a recovery. Dehydration and electrolyte imbalance can threaten patient welfare during this phase. Urine specific gravity remained at about 1,010 from 3 weeks to 3 months. A recovery phase can last weeks to months. Recovery is usually complete, but the rest of the inability to concentrate urine has been documented in a minority of patients.
The results of other clinical laboratory tests may be informative. Aspartate transaminase (AST) levels are usually elevated. Often abnormal electrocardiograms with sinus bradycardia, low voltage, or nonspecific ST-T wave findings.100,101 Atrial arrhythmias are not uncommon; However, there is usually no specific changes in the electrocardiogram regardless of hemorrhagic lesions typically seen in the liver at autopsy. The kidneys are usually not seen in the survey radiography for retroperitoneal edema. renogram often show a consistent pattern with damage.100 tubular obstruction or magnetic resonance imaging may suggest kidney bleeding for T2-weighted signal intensity along the lower outer medulla.102 pulmonary infiltrates are not common except in the face of overhydration; However, pulmonary edema and pleural effusion may be present even in the early disease.100
Some complications of HFRS has been observed. kidney rupture can occur in oliguric or diuretics phase.103 Transient intrapituitary hypopituitarism and frank bleeding has been associated with pituitary apoplexy, abnormal hormonal response of the anterior pituitary, delayed diuresis, and the final appearance of Sheehan syndrome.104
death overall in HFRS caused by Seoul virus obtained from wild-type mice (R. norvegicus) in Asia is about 1% .105,106 macroscopic hemorrhagic manifestations are rare. Liver involvement in HFRS caused by Seoul virus is more prevalent than in HFRS caused by Hantaan virus.29,53 Recovery is usually complete; However, a minority of patients may not regain their ability to concentrate urine. Also, an extensive study conducted in the United States associated with chronic renal failure hypertension in the presence of IgG antibodies to Seoul virus.107
The disease is usually mild, usually begins with a sudden onset of fever, chills, myalgia, and headache, often followed by gastrointestinal symptoms, abdominal pain, and back pain.62,108 Myopia, blurred vision, and even glaucoma has been reported in a significant proportion of patients and is highly suggestive of thrombocytopenia diagnosis.109-111 often develops at the end prodrome.62 slight mucosal bleeding gastroscopically in the gastrointestinal tract can be detected in almost all cases, but petechiae and other manifestations of bleeding (eg, visible hematuria and melena) were observed in less than one third of the end of the prodrome patients.108 Urinalysis revealed proteinuria and hematuria in almost 100% of cases. Hypotension was reported in up to 40% of patients but is generally mild.62 Increased abdominal pain, may be associated with nausea and vomiting, can lead to suspicion of emergency surgery, but the incidence of oliguria, increased concentrations of serum creatinine and blood urea nitrogen, and proteinuria and hematuria are usually ignorant intervention.62,63,108 operation Less than half of patients become oliguri, and severe hypertension, excessive blood volume, or life-threatening electrolyte imbalance occurs only a minority of patients. fatal cases have been associated with marked leukocytosis and shock.112,113 diuresis and may hyposthenuria famous and enduring the recovery period. Sequelae are rare and include hypertension convalescence.114,115
Some people infected with Puumala virus has a well-known disease without apparent kidney involvement.63,108,116 Sometimes, patients have shown an image suggestive dominant neurological encephalitis virus or other neurological disorders , including Guillain-Barré syndrome.109 ratio of clinical to subclinical (mild or atypical or undiagnosed) Puumala virus infection ranges from 1: 5 to 1: 10117.118
The case-fatality rates in HFRS is caused by a virus Dobrava have ranged from 7% to 12% .119,120 clinical course of disease caused by a virus Dobrava may include severe thrombocytopenia, DIC, bleeding manifestations, oliguric renal failure requiring dialysis, pleural effusion or stomach, and electrocardiographic abnormalities. Hypopituitarism may be a complication of viral Saaremaa infection.121,122 Dobrava virus is the cause of a mild form of HFRS in northern Europe.
Timothy P. Endy, … Stuart T. Nichol, 2020
hantavirus cardiopulmonary syndrome (HCP) occurs across America, and dengue fever with renal syndrome (HFRS) occurs throughout Asia and Europe. Most infections are a direct result, airborne transmission of rodent droppings, but transmission from person-to-person from the Andes virus (ANDV) occurred in Argentina and Chile. The average incubation period of three weeks and range from 1 to 8 weeks. HFRS Incidence is higher in Asia than in Europe and truer than HCP; HCP higher incident in South compared to North America. HCP case fatality rate, 35% for Sin Nombre virus (SNV) and ANDV, higher than that of HFRS. Quickly, a presumptive diagnosis of HCP in cardiopulmonary phase can be done with a complete blood count and smear evaluation. Wherever feasible, patients with a presumptive diagnosis of HCP in or out of the area where the SNV infection, ANDV, or other highly pathogenic hantaviruses are found should be immediately referred to the center of the artificial lung.
hantavirus cardiopulmonary syndrome
hemorrhagic fever with renal syndrome
virus Sin Nombre
extracorporeal membrane oxygenation (ECMO)
ADT Barrett, SC Weaver, in 2012.
this virus causes either (1) a severe illness, called hemorrhagic fever with renal syndrome, because the virus Hantaan in Japan, Korea, China and Siberia and viruses Puumala in Scandinavia, or (2) a mild disease, called nephropathia epidemica, because the virus Puumala in Scotland, France, Belgium and Germany, the Balkans and Greece. Hantaan virus was first identified in soldiers who served in Korea in 1951 and named after the area where it was detected. major vertebrate reservoirs consist agrarius Apodemus rodents in Asia and Clethrionomys glareolus (bank rat) in Europe.
Steven J. Chadban, Robert C. Atkins, in 2008
Hantaan and related viruses induce disease known as nephropathia epidemica or dengue fever with renal syndrome, which is endemic in Asia southeast and southern Europe and appeared in worldwide.37 epidemic spread of the virus by inhaling aerosol containing particles formed from the feces of infected mice, the virus causes a spectrum of illnesses ranging from mild febrile illness to life-threatening disorders. Severe disease is characterized by several stages. Originally a high fever and myalgia dominate, while the facial flushing and truncal and petechiae develop in association with thrombocytopenia. Sudden fever subsides after a few days, but a profound hypotension develops, associated with acute oliguric renal failure. Systemic hypotension, derangements intrarenal vasomotor tone, coagulation, and related interstitial nephritis cause kidney injury. membranoproliferative glomerulonephritis have been reported; However, the generally mild glomerular involvement.
The diagnosis is confirmed by an increase in specific antibody titers for Hantaan virus in serum samples taken 1 week apart. Leptospirosis and scrub typhus should be issued, also on the basis of serology, since these agents can produce a similar illness but agreed to treatment with tetracycline. Treatment of hemorrhagic fever with renal syndrome support only.37 particular vaccine is currently being tested in Korea.
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