Clinical characteristics of patients with hemorrhagic fever with renal syndrome during pregnancy: a multicenter clinical study / 中华传染病杂志

Objective:To analyze the clinical characteristics and prognosis of pregnant women with hemorrhagic fever with renal syndrome (HFRS).Methods:A total of 11 pregnant women with HFRS admitted to The Second Affiliated Hospital of Xi′an Jiaotong University (four cases), The Second Affiliated Hospital of Air Force Medical University (four cases), The First Affiliated Hospital of Xi′an Jiaotong University (one case) and Central Hospital of Xianyang City (two cases) between November 2009 and February 2019 were included as the study group, and 24 age-matched non-pregnant women with HFRS were selected as the control group. The age, complications, clinical classification and laboratory indexes of the two groups were analyzed retrospectively, and the clinical outcomes of pregnant women and their fetuses in the study group were followed up. The data between two groups were compared using Mann-Whitney U test or chi-square test. Results:Patients in the study and control groups were 29 (22, 33) and 32 (24, 37) years old, respectively. Seven of 11 patients in study group were severe and critical cases, which was significantly higher than that in the control group (16.7%(4/24), χ2=7.722, P=0.015). In the study group, 10 patients had hypervolemic syndrome, 10 patients had pulmonary edema and six patients had overlapping hypotension shock phase and oliguria phase, which were all higher than those in the control group ((2/24, 8.3%), (2/24, 8.3%) and (2/24, 8.3%), respectively; χ2=22.828, 22.828 and 9.135, respectively, all P<0.01). Compared with the control group, the pregnant patients in study group had a higher urea nitrogen maximum and serum creatinine maximum, and the differences were both statistically significant ( Z=-2.453 and -2.336, respectively, both P<0.05), while they had a lower serum albumin minimum, hemoglobin maximum and hemoglobin minimum, and the differences were all statistically significant ( Z=-3.742, -3.350 and -4.034, respectively, all P<0.01). All pregnant women with HFRS recovered. Nine pregnant women gave birth to nine healthy infants. All of them received breastfeeding and the feeding duration were more than six months. No abnormal growth and development were found during an average follow-up of three years. Conclusions:Pregnancy can aggravate the severity of HFRS, and pregnant women have higher risk of the multiple stages overlap and the complications such as hypervolemic syndrome and acute pulmonary edema. After recovery from HFRS, mother may carry to full-term pregnancy.

Introduction of Vaccinomics to Develop Personalized Vaccines in Light of Changes in the Usage of Hantaan Virus Vaccine (Hantavax®) in Korea / 예방의학회지

The Ministry of Food and Drug Safety of Korea made an official announcement in March 2018 that the total number of inoculations of Hantaan virus vaccine (Hantavax®) would change from 3 to 4. Some aspects of this decision remain controversial. Based on the characteristics of Hantaan virus (HTNV) and its role in the pathogenesis of hemorrhagic fever with renal syndrome, it might be difficult to develop an effective and safe HTNV vaccine through the isolate-inactivate-inject paradigm. With the development of high-throughput ‘omics’ technologies in the 21st century, vaccinomics has been introduced. While the goal of vaccinomics is to develop equations to describe and predict the immune response, it could also serve as a tool for developing new vaccine candidates and individualized approaches to vaccinology. Thus, the possibility of applying the innovative field of vaccinomics to develop a more effective and safer HTNV vaccine should be considered.

Complete genome sequence analysis of Hantaan virus strain AYW89-15 isolated in Jiangxi, China / 中国人兽共患病学报

We investigated the complete genome characteristic of the Hantaan virus strain AYW89-15 isolated in Jiangxi Province,China.Primers were designed and were used to amplify the complete S,M and L segments by RT-PCR.The PCR product were then cloned and sequenced,the gene sequences were analyzed with DNAStar and MEGA6.0 software.Result showed that the complete gene sequence was 11 848 nucleotides in length,the S,M and L segments were 1 699 nt,3 616 nt and 6 533 nt respectively,encoding 429,1 133 and 2 151 amino acids respectively.The sequence identities between stain AYW89-15 and other Hantaan virus were 79.7％-87.3％ at the nucleotide level and 92.3％-98.4％ at the amino acid level.Phylogenetic analysis of HV showed AYW89-15 belonged to a new HTNV lineage.AYW89-15 was a new subtype of HTNV that exists in Jiangxi Province.

Becoming an International Scientist in South Korea: Ho Wang Lee's Research Activity about Epidemic Hemorrhagic Fever / 의사학

In the 1960-70s, South Korea was still in the position of a science latecomer. Although the scientific research environment in South Korea at that time was insufficient, there was a scientist who achieved outcomes that could be recognized internationally while acting in South Korea. He was Ho Wang Lee(1928~ ) who found Hantann Virus that causes epidemic hemorrhagic fever for the first time in the world. It became a clue to identify causative viruses of hemorrhagic diseases that were scattered here and there throughout the world. In addition, these outcomes put Ho Wang Lee on the global center of research into epidemic hemorrhagic fever. This paper examines how a Korean scientist who was in the periphery of virology could go into the central area of virology. Also this article shows the process through which the virus found by Ho Wang Lee was registered with the international academia and he proceeded with follow-up research based on this progress to reach the level at which he generalized epidemic hemorrhagic fever related studies throughout the world. While he was conducting the studies, experimental methods that he had never experienced encountered him as new difficulties. He tried to solve the new difficulties faced in his changed status through devices of cooperation and connection. Ho Wang Lee's growth as a researcher can be seen as well as a view of a researcher that grew from a regional level to an international level and could advance from the area of non-mainstream into the mainstream. This analytic tool is meaningful in that it can be another method of examining the growth process of scientists in South Korea or developing countries.

Analysis of hantaviruses origin and molecular evolution in China / 第二军医大学学报

Objective: To investigate the first appearance and geographic distribution of hantaviruses in China. Methods: Some sequences of M segment of hantaviruses isolated in China were retrieved from GenBank. Some recently sequenced viruses which have not been registered in GenBank were obtained from authors who reported them. Program MEGA 3.1 was employed for the phylogenetic analysis of the above virus sequences. Nucleotide divergence rates were estimated by comparing the closely related sister sequences isolated in the same geographical region at no less than a 5-year interval. Based on these calculated divergence rates, together with their isolating time and region, we explored the first appearance and geographic distribution of hantaviruses in China. Results and conclusion: The distribution of hantaviruses was in cluster, with Guizhou Province having the most subgenotypes, which supports the previous hypothesis that hantaviruses first appeared in Guizhou Province of China. A novel subgenotype virus was found in Anhui Province, indicating that it might be easier for the virus to have mutation in Anhui Province. We also found that Gou3 strain might be the earliest one to separate from a common ancestral strain; it is speculated that hantaviruses migrated in China about 315 years ago.

TLR4 mediated the nuclear translocation of transcription factor NF-κB and IRF-3 in HTNV infected vascular endothelial cells / 中华微生物学和免疫学杂志

Objective To observe the nuclear translocation of transcription factor NF-κB and IRF-3 in TLR4 silenced EVC304 cells infected by HTNV and to provide new information for anti-HTNV innate immunity and its signal transduction. Methods TLR4~- cells and TLR4~+ cells were infected by HTNV 76-118, respectively. The cells stimulated by LPS were selected as positive control groups, and the cells without stimulation were selected as negative control groups. After 6 hours, indirect immunofluorescence assay(IFA) was used to detect the nuclear translocation of NF-κB and IRF-3. Results The transcription factor NF-κB and IRF-3 transfered into nuclear 6 hours after stimulated by HTNV 76-118. Conclusion TLR4 may mediate the nuclear translocation of transcription factor NF-κB and IRF-3 in HTNV infected human umbilical vein endothelial cells.

Reversible Splenium Lesion of the Corpus Callosum in Hemorrhagic Fever with Renal Failure Syndrome

This is the first case of virus-associated encephalitis/encephalopathy in which the pathogen was Hantaan virus. A 53-yr-old man presented fever, renal failure and a hemorrhagic tendency and he was diagnosed with hemorrhagic fever with renal failure syndrome (HFRS). In the course of his illness, mild neurologic symptoms such as dizziness and confusion developed and magnetic resonance images revealed a reversible lesion in the splenium of the corpus callosum. This case suggests that HFRS patients with neurologic symptoms like dizziness and mental slowing should be considered to have structural brain lesions and to require brain imaging studies.

Hemorrhagic Fever with Renal Syndrome

Hemorrhagic fever with renal syndrome (HFRS) is an acute febrile illness caused by Eurasian hantaviruses and characterized by renal insufficiency, hemorrhage, thrombocytopenia, and shock. Each hantavirus is primarily associated with a single rodent host species or genus, and is transmitted to human via aerosols of rodent excreta. During the last decades, clinical features of HFRS in Korea have changed with mild degree of hypotension and very low prevalence of oliguria. Treatment of HFRS is mainly supportive. Recently, however, treatment of HFRS patients with ribavirin in China and Korea, within 7 days after the onset of fever, resulted in a reduced mortality as well as shortened course of illness. Although a commercial inactivated Hantaan virus vaccine has been on the market in Korea for more than 15 years, the effect of vaccination is not clear. Further efforts are necessary to develop safer and more effective hantavirus vaccines.

Hemorrhagic Fever with Renal Syndrome

Hemorrhagic fever with renal syndrome (HFRS) is an acute febrile illness caused by Eurasian hantaviruses and characterized by renal insufficiency, hemorrhage, thrombocytopenia, and shock. Each hantavirus is primarily associated with a single rodent host species or genus, and is transmitted to human via aerosols of rodent excreta. During the last decades, clinical features of HFRS in Korea have changed with mild degree of hypotension and very low prevalence of oliguria. Treatment of HFRS is mainly supportive. Recently, however, treatment of HFRS patients with ribavirin in China and Korea, within 7 days after the onset of fever, resulted in a reduced mortality as well as shortened course of illness. Although a commercial inactivated Hantaan virus vaccine has been on the market in Korea for more than 15 years, the effect of vaccination is not clear. Further efforts are necessary to develop safer and more effective hantavirus vaccines.

Retrospective analysis of epidemiological and clinical features of patients with hemorrhagic fever renal syndrome over past 10 years in Harbin region / 中华传染病杂志

Objective To investigate the changes of epidemiological and clinical features of patients with hemmorrhagic fever renal syndrome (HFRS) over past 10 years in Harbin region. Methods The epidemiological, clinical and laboratory data of patients with HFRS in 1995 and 2005 in The Second Affiliated Hospital of Harbin Medical University were retrospectively analyzed. The genotypes of Hantaan virus of patients in 2005 having an onset within 5 days were examined by reverse transcriptase polymerase chain reaction (RT-PCR). Positive rates in different groups were compared using chi square test. Results One hundred and sixty-five cases were collected, including 78 in 1995 and 87 in 2005. There were significant differences in epidemiological area (X2=10. 483, P<0.05), clinical classification (X2=7. 907, P<0.05), clinical stage (X2=10.500, P<0.05), the variance of total white blood cells (X2=20. 315, P<0.01) and blood sugar changes (X2=9.958, P<0.01) between two groups of patients. Bases on clinical manifestations, there were significant differences in two groups (1995 and 2005): headache, 70.5% and 50.6% (X2=6.812, P<0.01); lumbago, 60.3% and 40.2% (X2=6.598, P<0.05); fossaorbitalis pain, 50.0% and 19.5% (X2=17.019, P<0.01); melena, 60.3% and 40.2% (X2=6.598, P<0.05); bleeding point and eeehymosis, 50.0% and 33.3% (X2=4.715, P<0.05) ; flush of faee, neck and upper chest, 59.0% and 40.2% (X2=5.782, P<0.05); membrane-like object in urine, 44.9 % and 29.9% (X2=3.964, P<0.05) rates of thrombocytopenia, 79.5% and 64.4% (X2=4.615, P<0.05) ; rates of liver dysfunction, 50.0% and 80.5% (X2=17.019, P<0.01); rates of cardiac muscle enzymoiogy dysfunction, 50.0% and 92.0% (X2=36.003, P<0.01). The genotypes of patients in 2005 were Hantaan virus (34.8%) and Seroul virus (65.2%). Conclusion The differences in epidemiological and clinical feature of patients with HFRS over past 10 years may be related with the change of virus genotypes, and further study should be done.

Comparison on the difference of virulence between Hantaan virus and Seoul virus isolated both from Rattus norvegicus / 中华流行病学杂志

Objective Comparing the difference of virulence between the strain CGRn5310 (HTNV) and the strain HR54 (SEOV) isolated both from Rnttus norvegicus. Methods Suckling mice were used to compare the difference of virulence between the two strains. Hantavirus antigens were detected in brain and lung tissues collected from the infected mice. Results Compared with the control group, all infected mice grew slowly. Furthermore, the mice inoculated intracerebrally with either CGRn5310 or HR45 appeared ruffled fur, and reduced activity, followed by neurological symptoms, such as paralyses and convulsions. The half lethal dose (LD_(50)) of CGRn5310 strain was 10~-6.42, whereas the LD_(50) of HR54 strain was 10~-4.51. Hantavirus antigens were identified in brain and lung tissues from the mice infected with the strain CGRn5310 and the strain HR54. Conclusion LD_(50) of the strain CGRn5310 was significantly higher than that of the strain HR54. Our results suggested that the virulence of the spillover hantavirus might only slightly be influenced by the non-reservoir rodents.

Rescue of Hantaan virus 84FLi strain minigenomes by RNA polymerase Ⅰ-driven system / 中华传染病杂志

Objective To develop a reverse genetics system for Hantaan virus (HTNV) 84FLi strain by using RNA polymerase [ (pol Ⅰ)-mediated transcription. Methods Complementary DNA (cDNA) containing the coding sequence for chloramphenicol acetyhransferase (CAT) was inserted into the 5'-and 3'-terminal untranslated regions of HTNV 84FLi L segment. These chimeric cDNAs (pol Ⅰ expression cassette) were cloned into plasmids and between the human pol Ⅰ promoter and terminator to generate sense and anti-sense RNA pol Ⅰ transcription reporter plasmids. The reporter plasmids were transfeeted into 293T cells or the 1:1 combination of 293T and HTNV infected Vero cells. These cells were cotransfected with expression plasmids encoding Ⅰ. (RNA dependent RNA polymerase) and N (nucleoprotein) viral proteins, Cells were harvested 48 h post-transfection and the CAT activity was detected. The 293T cells were infected with the supernatant to explore the passage ability of CAT activity. ResultsThe reporter plasmids pLvRNA-CAT and pLcRNA-CAT were constructed successfully. CAT activity was detected in transfected cells and could also be serially passaged in the rescued virus minigenomes. Conclusion The RNA polymerase ]-driven reverse genetics system successfully rescues HTNV 84FLi minigenomes.

A Case of Graves' Disease Combined with Hantaan Virus Infection

Graves' disease (GD) is generally presented by thyrotoxicosis with hyperthyroidism, and it is an organ-specific autoimmune disease induced by thyroid-stimulating hormone receptor autoantibodies. However, among diverse etiologies, viral infections have been suggested to trigger or to be involved in the pathogenesis of GD. Hantaan virus infection causing hemorrhagic fever with renal syndrome (HFRS) is common in South Korea and its pathogenesis is suggested to be an immunologic mechanism. We have experienced a patient who was diagnosed as HFRS with thyrotoxicosis. So we herein report the case as GD combined with the hantaan virus infection.

The influence of vaccination on the clinical features of hemorrhagic fever with renal syndrome in the last 5 years / 대한내과학회지

BACKGROUND/AIMS: Hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus is an endemic febrile disease in Korea. Although inactivated Hantaan virus vaccine has been introduced, the effect of vaccination is not clear. We evaluated the effect of vaccination on the incidence rate and clinical features of HFRS based on our clinical experience. METHODS: Group I consisted of the patients with confirmed HFRS from a total of 131 patients who were seropositive for Hantaan virus at one tertiary teaching hospital from January 2002 to December 2006. Group II contained 100 patients treated as HFRS at the same hospital from January 1986 to December 1990, before the introduction of the vaccine. Then, we compared the clinical features of the two groups. We confirmed whether the patients had been vaccinated by reviewing their medical records and from telephone interviews. RESULTS: Only 16 (12.2%) of the 131 patients who were seropositive for Hantaan virus were confirmed to have overt HFRS during the most recent 5 years. The incidence of overt HFRS was significantly lower in vaccinees (5%, 3 of 56) than in non-vaccinees (20%, 10 of 50) (p=0.025). The prevalence of renal failure (62.5 vs. 95%, p<0.001) and oliguria (6.25 vs. 46%, p=0.002) was significantly lower in group I than in group II. Three patients were treated with dialysis and none died in group I, versus 17 and 8, respectively, in group II. CONCLUSIONS: It appears that Hantaan virus vaccine has helped to reduce the amount of serious illness and the occurrence of HFRS.

Analysis on Hantaan virus in hemorrhagic fever patients with renal syndrome in Heilongjiang / 中国地方病学杂志

Objective To separate and amplify Hantaan virus(HV)in serum of hemorrhagic fever patients with renal syndrome(HFRS)in Heilongjiang,and look for its difference from intemational standard type strain(76-118strains).Methods HVs of different phase in the 8erum of 50 HFRS patients were separated and amplified by RTnested-PCR,its products were analyzed the amplified by sequencing.Results Detectable rate of HV in the patients serum was 36.36%(8/22)in 7 days after onset,it Was 13.04%(3/23)in patients having an onset 8 days to 14 days earlier,5 cases were not detectable 15 days after onset.Comparing the sequence of HV S gene fragment,sample 1,9,18,31,37,38,44 strain had a homology of 90.24%,86.72%,89.97%,89.16%,86.45%,87.26%and 89.43%to 76-118 strains,respectively.Conclusions The positive rate is the highset in 7 days after onset.Nucleotide sequence difference exists between pathogenic strain of Heilongjiang's HV and international standard strain,indicating that not only hosts but also locations can affect HV.

Cultured cortical astrocytes of newborn rat can be infected by Hantaviruses / 中华传染病杂志

Objective To confirm that astrocytes from cerebral cortex of newborn rat can be the target cells of Hantaan virus (HTNV)and Seoul virus (SEOV)infection and to observe changes of astrocytes after different infection time. Methods Astrocytes were prepared from cerebral cortex of newborn rat, and then infected with HTNV and SEOV. The established virus infections were confirmed by detection of virus nucleocapsid protein (NP) and S segment RNA in astrocytes using double-label immunofluoreseence, Western-blot and reverse transcriptase-polymerase chain reaction (RT-PCR). Results The astrocytes from cerebral cortex of newborn rat were cultured successfully in vitro, which could be infected by HTNV and SEOV. The number of infected astrocytes and the virus titer in the infected astrocytes kept on increasing along with the extended infection duration. Conclusions Astrocytes from cerebral cortex of newborn rat are the target cells for HTNV and SEOV infection. Then establishment of in vitro cultured astrocytes model for Hantaviruses infection will be helpful for the study on the pathogenesis of hemorrhagic fever with renal syndrome.

Hantaan Virus Reduces the von Willebrand Factor in Human Umbilical Vein Endothelial Cells

To understand the molecular mechanism of hemorrhagic tendency represented in hemorrhagic fever with renal syndrome (HFRS), the effect of Hantaan virus (HTNV) on the von Willebrand factor (vWF) was observed in human umbilical vein endothelial cells (HuVECs). An immunofluorescence assay (IFA) showed a significant reduction of the vWF in the cytoplasm of HTNV-infected HuVECs. The amount of vWF protein in HTNV-infected HuVECs was reduced to 86, 49, 67, and 42% of those in control HuVECs at 1(st), 3(rd), 5(th), and 7(th) days of post infection (d.p.i.), respectively. However, there were no significant differences in the vWF mRNA expression in both groups at all time courses by reverse transcriptase polymerase chain reaction (RT-PCR). The amounts of secreted vWF in the culture supernatants of the HTNV-infected HuVECs were 79, 87, 83, and 82% of those in control HuVECs at 1(st), 3(rd), 5(th), and 7(th) d.p.i., respectively. These results indicated that the reduction of vWF by HTNV was regulated at post-transcriptional level and this might delay the coagulation process on the site of HTNV infection, thus leading to hemorrhage in HFRS.

Interferon-Stimulated Genes Response in Endothelial Cells Following Hantaan Virus Infection

The regulation mechanism of interferon (IFN) and IFN-stimulated genes is a very complex procedure and is dependent on cell types and virus species. We observed molecular changes related to anti-viral responses in endothelial cells during Hantaan virus (HTNV) infection. We found that there are two patterns of gene expression, the first pattern of gene expression being characterized by early induction and short action, as in that of type I IFNs,' and the other being characterized by delayed induction and long duration, as those of IRF-7, MxA, and TAP-1/2. Even though there are significant differences in their induction folds, we found that all of IFN-alpha/beta , IRF- 3/7, MxA, and TAP-1/2 mRNA expressions reached the peak when the viral replication was most active, which took place 3 days of post infection (d.p.i.). In addition, an interesting phenomenon was observed; only one gene was highly expressed in paired genes such as IFN-alpha/beta??(3/277-folds), IRF-3/7 (2.2/29.4-folds), and TAP- 1/2 (26.2/6.1-folds). Therefore, IFN-beta, IRF-7, and TAP-1 seem to be more important for the anti-viral response in HTNV infection. MxA was increased to 296-folds at 3 d.p.i. and kept continuing 207-folds until 7 d.p.i.. The above results indicate that IFN-beta works for an early anti-viral response, while IRF7, MxA, and TAP-1 work for prolonged anti-viral response in HTNV infection.

Epidemiological Survey of Hantaan Virus Infection of Wild Rodents Trapped in Jeollanam-do, 2003~2004

Hantaan virus (HTNV) is widely distributed in Korea and has been known to cause haemorrhagic fever with renal syndrome (HFRS). Hantaviruses are carried by numerous rodent species throughout the world. Especially, the stripedfield mice, Apodemus agrarius, is the natural host for Hantaan virus in Korea, In this study, a total 117 wild rodents of 2 species (A. agrarius, Crocidura laciura) were trapped from six county (Damyang- gun, Hwasun-gun, Gokseong-gun, Jangheung-gun, Hampyeong-gun and Boseong-gun) in Jeonnam province from Sep. 2003 to Nov. 2004 for epidemiological survey. As determined by the indirect immunofluorescent antibody (IFA) test, IgG antibodies against HTNV were detected in 13.4% (14/103) of A. agrarius captured on above the areas. Serologic evidence for HTNV infection was not found in 14 C. laciura. 5 of A. agrarius were positive of hantaan viral RNA amplication from lung tissue of 14 seropositive A. agrarius by RT-PCR. For isolation of the hantaan virus, the lung tissue homogenate of 14 seropositive A. agrarius inoculated Vero E6 cells, but virus was not isolated.

Clinical characteristics and predictors of acute oliguric renal failure in hemorrhagic fever with renal syndrome / 대한내과학회지

BACKGROUND: Hemorrhagic fever with renal syndrom (HFRS), caused by hantaviruses infection, develops acute renal failure (ARF) of variable severity. Because oliguric ARF is severe form, associated with more complications and hemodialysis requirement, we investigated the characteristics and predictors of oliguric ARF in HFRS patients. METHODS: From Oct. 2000 to Dec. 2004, Sixty one patients, admitted at Armed Forces Capital Hospital, with typical clinical feature of HFRS and serologically confirmed hantaan virus infection were studied. The medical records were reviewed retrospectively and patients were categorized into oliguric and nonoliguric ARF group according to urine output (or=15x10(9)/L (RR 2.36 [95% CI 1.19-4.67]), platelet countor=110IU/L (RR 3.10 [95% CI 1.43-6.73]) and microscopic hematuria>or=5/HPF (RR 3.68 [95% CI 1.24-10.91]). CONCLUSIONS: HFRS patients with oliguric ARF showed more elevation of serum creatinine and more requirement of hemodialysis than HFRS patients with non-oliguric ARF and leukocyte count, platelet count, AST and microscopic hematuria on admission were helpful to predict the development of oliguric ARF in HFRS patients.