Genetic susceptibility to haemorrhagic fever with renal syndrome caused by Hantaan virus in Chinese Han population

We report a significantly higher occurrence of HLA‐DRB1*09 (51% vs. 23%, P = 0.002, OR = 3.57) and HLA‐B*46‐DRB1*09 (26% vs. 8%, P = 0.018, OR = 3.76) in patients with haemorrhagic fever with renal syndrome (HFRS) compared to the control group, suggesting Hantaan virus‐induced HFRS is associated with a genetic predisposition in the Chinese Han population.     

Seroepidemiology of haemorrhagic fever with renal syndrome in Bulgaria

During the period of 1954-1986, 399 cases of haemorrhagic fever with renal syndrome (HFRS) were registered in Bulgaria with 63 (15.7%) deaths. Three hundred serum samples from 214 patients who had contracted the disease from 1957 to 1986 were investigated by indirect fluorescent antibody test (IF-AT). As antigen Vero-E6 cells infected with the Asian Hantaan virus were used, as well as lung sections from bank voles (Clethrionomys glareolus) infected with strains Udmurt and Kazan 6-Cg from the European part of the U.S.S.R. Specific antibodies were detected in 194 sera, i.e. in 90.6% of persons investigated: in 131 single serum samples and in 63 paired sera. The results of the serological studies which covered 53.6% of all known local cases showed the territorial distribution of the natural foci in this country and the aetiologic relationship with the HFRS virus from the European part of the U.S.S.R.     

Outbreak of haemorrhagic fever with renal syndrome in Greece

An outbreak of eight cases of haemorrhagic fever with renal syndrome in North-West Greece is presented. The major clinical manifestation was fever and all patients subsequently developed decreased renal function and proteinuria. The disease was diagnosed by rising antibody titers to the Hantaan virus.     

Viral load and immune response dynamics in patients with haemorrhagic fever with renal syndrome

Haemorrhagic fever with renal syndrome (HFRS) in Slovenia can be caused by infection with either Dobrava (DOBV) or Puumala (PUUV) virus, but a clear difference in disease severity is observed. We hypothesized that the wide spectrum of disease observed among HFRS patients might be related to differing immune responses and viral load kinetics. To test this hypothesis we analysed sequential blood samples from 29 HFRS patients hospitalized in Slovenia. Measuring viral RNA in patient samples revealed that viraemia lasts for longer than previously believed, with DOBV or PUUV-infected patients having viraemias lasting on average 30 days or 16 days, respectively. DOBV-infected patients were found to have a higher viral load than the PUUV-infected patients (10⁷ vs. 10⁵ RNA copies/mL). Both DOBV and PUUV-infected patients had IgM at the time of hospital admission, but there was a difference in IgG antibody dynamics, with only a minority of DOBV-infected patients having IgG antibodies. In our study, elevated levels of IL-10, TNF-α and IFN-γ were detected in all of the samples regardless of the causative agent. In DOBV-infected patients the decrease in cytokine secretion level appeared around day 20 post-infection, while in PUUV-infected patients the change was earlier. In general, our findings point toward notable differences between PUUV and DOBV infections, in terms of viral load and antibody and cytokine response dynamics, all of which may be reflected in differing disease severities and clinical outcomes.     

Elevated sICAM-1 levels in patients with hemorrhagic fever with renal syndrome caused by Hantaan virus

Increased vascular permeability and vascular leakage are characteristic pathological changes in hemorrhagic fever with renal syndrome (HFRS). Vascular endothelial cells are the main targets of Hantaan virus, the etiological agent of the severe form of HFRS. Hantaan virus can induce extensive damage of small blood vessels and capillaries. In vitro infection of human umbilical vein endothelial cells by Hantaan virus can induce the expression of intercellular adhesion molecule-1 (ICAM-1). The involvement of this molecule is implied in human HFRS. In the present study, serum-soluble ICAM-1 (sICAM-1) levels were determined and their relationships with the clinical course and disease severity were investigated in 112 HFRS patients and 30 healthy controls. The results showed that the serum levels of sICAM-1 in HFRS patients at fever, hypotensive, oliguric, and polyuric phases were significantly higher than those in controls (p?<?0.001). However, no significant differences between the serum concentrations of sICAM-1 in the milder and more severe groups of patients were observed (p?>?0.05). It is suggested that sICAM-1 was involved in the progression of HFRS. Time-dependent determinations of sICAM-1 levels may be indicators for the progression of disease, and elevated levels of sICAM-1 were not suggested to be correlated to disease severity.     

Flow cytometric analysis of lymphocytic subsets in haemorrhagic fever with renal syndrome virus infection.

Percentage counts of T-lymphocytes (helper and suppressor subpopulation) and B-lymphocytes were performed in the peripheral blood of two confirmed cases of HFRS infection using Coulter Clone monoclonal antibodies and Becton Dickinson flow cytometry. The individual values were compared with those from healthy subjects. HFRS patients had lower total T-cell (CD2) and T-helper (CD4 subset) counts. This seems linked with the role of the CD4 determinant as viral receptor. The measuring of specific lymphocyte helper and suppressor subpopulations might be useful in predicting the course of the disease and in following the effects of therapy.     

Serological survey with the antigen of haemorrhagic fever virus with renal syndrome in small rodents in Slovakia

Results of serological survey in small rodents with the antigen of haemorrhagic fever with renal syndrome (HFRS) virus indicate the existence of a natural focus of this virus in Slovakia. Antibodies were found in the following free-living rodent species: Clethrionomys glareolus, Apodemus agrarius, Apodemus sylvaticus, Pitymys subterraneus, Microtus arvalis and Microtus economus. A total 10 out of 120 (8.2%) small rodents trapped in investigated localities of Western and Eastern Slovakia had antibodies to the HFRS virus antigen as detected by complement fixation (CF) and/or immunofluorescence (IF) tests.     

HFRS患者汉滩病毒核蛋白特异性T细胞克隆及其靶细胞的建立

目的　建立肾综合征出血热 (HFRS)患者汉滩病毒 (HTNV)核衣壳蛋白 (NP)特异性CTL克隆 ,为HTNVNPT细胞表位鉴定及HFRS患者T细胞免疫功能研究奠定基础。方法　采用Fi coll密度梯度离心法分离HFRS患者外周血单个核细胞 (PBMC) ,用灭活HTNV和IL 2体外刺激 ,有限稀释法建立T细胞克隆 ,流式细胞术鉴定克隆表型。并用EB病毒 (EBV)转化B淋巴细胞 ,建立B淋巴母细胞样细胞系 (B LCL) ,以含HTNVS基因的重组痘苗病毒感染B LCL作靶细胞 ,以CTL克隆作效应细胞进行细胞毒杀伤试验 ,测定T细胞克隆的抗原特异性。结果　T细胞克隆能特异性识别表达NP的B LCL。在 5名患者中 ,3名有较高的杀伤率 ,并自 2名患者建立了 5株HTNV特异性CTL克隆 ,其表型为CD8 均大于 6 0 %。结论　成功建立了HFRS患者HTNVNP特异性CTL克隆及其靶细胞。NP是HFRS患者HTNV特异性CTL应答的主要靶抗原之一。     

肾综合征出血热病毒50kD结构蛋白的抗原位点分析

采用23株抗HFRS病毒McAb,以放射免疫沉淀及ELISA等试验,证实HFRS病毒的50kD蛋白为该病毒的核蛋白(NP)。用抗NP的McAb对经亲和层析纯化的NP以ELISA阻断试验进行抗原位点分析,结果表明该蛋白与一般有囊膜病毒的NP相比,有两点明显的不同。一是HFRS病毒的NP上不仅有组特异性抗原位点,而且有型特异性抗原位点,两者都至少分布在2个区域,这些抗原位点及其分布区域之间有部分重叠或比较靠近。二是HFRS病毒的NP上可能存在中和抗原及血凝抗原位点。     

Increased plasma levels of soluble CD23 in haemorrhagic fever with renal syndrome; relation to virus-specific IgE

In 15 consecutive patients hospitalized with nephropathia epidemica, a European form of haemorrhagic fever with renal syndrome (HFRS) caused by Puumala virus, plasma concentrations of soluble CD23 (sCD23) and Puumala virus-specific IgE were determined. In the acute phase of illness, 11/15 patients had increased sCD23 levels (> 91 U/ml), whereas in convalescence, values of 8/10 patients were normalized. Maximal sCD23 values were correlated to maximal concentrations of Puumala virus-specific serum IgE (r= 0.597; P= 0.025). The results are compatible with a known ability of sCD23 to augment IgE production.     

Dynamic changes of apoptosis-inducing ligands and Th1/Th2 like subpopulations in Hantaan virus-induced hemorrhagic fever with renal syndrome

The expression of the apoptosis-inducing ligands, TNF-alpha, FasL and TRAIL on peripheral blood mononuclear cells (PBMC) and the levels of their soluble form (TNF-alpha, sFasL and sTRAIL) in plasma from 40 hemorrhagic fever with renal syndrome (HFRS) patients as well as 26 healthy blood donors were determined by flow cytometry (FCM) analysis and sandwich ELISA, respectively. The status of Th1, Th2, Tc1 and Tc2 subsets in PBMC was evaluated by intracellular cytokine staining and FCM. Compared to controls, the expression of membrane bound FasL and TRAIL was up-regulated on surface of PBMC isolated from the HFRS patients, particularly on CD8+ T lymphocytes. The levels of TNF-alpha, sFasL and sTRAIL in plasma from the HFRS patients in the acute phase increase 4.7-fold, 6.0-fold and 1.8-fold, respectively, over those from the healthy donors. The percentage of Th1, Tc1 and Tc2 subsets in PBMC from the patients also increased significantly compared with those from healthy donors. These results indicate that dynamic changes occurred in both the membrane bound and soluble forms of apoptosis-inducing ligands (FasL, TRAIL and TNF-alpha) and proportions of Th1 and CTL in HFRS patients increased. Both factors may play an important role in the etiology of Hantaan virus infection in humans.     

Distribution of hantavirus serotypes Hantaan and Seoul causing hemorrhagic fever with renal syndrome and identification by hemagglutination inhibition assay.

An epidemiologic evaluation of patients with hemorrhagic fever with renal syndrome from different locations in the People's Republic of China was conducted to define the prevalence of two Hantavirus serotypes, Seoul (SEO) and Hantaan (HTN). Serum specimens were collected between 5 and 14 days after the onset of illness and were tested for antibodies by both hemagglutination inhibition (HI) and plaque reduction neutralization (PRN). By the HI test, the geometric mean titer (GMT) of antibodies to SEO in the sera from individuals from Kaifeng City of Henan Province was five times higher than that to HTN. In contrast, by the HI test, the sera from individuals from Jiande County of Zhejiang Province had a GMT of antibodies to HTN that was seven times higher than that to SEO. In the sera from individuals from Shanghai, only a twofold difference was observed in HI antibody titers to the two hemagglutinins by the HI test, with that to HTN being higher than that to SEO. By the PRN test, the GMT ratios of antibody between HTN and SEO strains from individuals in Kaifeng, Jiande, and Shanghai were found to be 1:13, 14:1, and 2:1 respectively. A close correlation (r = 0.8219) and concordance rate (78.3%) were observed between the PRN and HI tests for the identification of the serotypes of individual cases of hemorrhagic fever with renal syndrome. The hantavirus serotypes from individuals in Kaifeng and Jiande were identified as predominantly SEO and HTN, respectively, and those from individuals in Shanghai had an indeterminant serotype defined by these two techniques. The HI test appears to be a simple and reliable way of determining the predominant hantavirus that causes HFRS in a given geographic area.     

The role of Hantaan virus serotypes in the etiology of hemorrhagic fever with renal syndrome in the Far East of the USSR

The employment of two serological tests (indirect fluorescence antibody technique and neutralization test) demonstrated the leading role of Hantaan virus serotype 1 strains isolated from field mice in the pattern of the incidence of hemorrhagic fever with renal syndrome (HFRS). Proofs of the etiological importance of strains of serotypes 3 and 5 occurring in brown rats and Cl. rufocanus were obtained. No data on any association of human HFRS cases with strains of serotype 4 isolated from reed voles could be demonstrated.     

Clinical and laboratory features and factors predicting disease severity in pediatric patients with hemorrhagic fever with renal syndrome caused by Hantaan virus

The clinical features and factors associated with disease severity in children with hemorrhagic fever with renal syndrome (HFRS) have not been well characterized. This study analyzed the clinical and laboratory factors associated with disease severity in children with HFRS caused by Hantaan virus. Data in pediatric patients with HFRS were retrospectively collected from Xi'an Children's Hospital over a 9-year period. Independent factors associated with disease severity were identified. Nomogram predicting disease severity was constructed based on variables filtered by feature selection. In total, 206 children with HFRS were studied. Fever, digestive tract symptoms, headache, backache, bleeding, and renal injury signs were the common symptoms. Elevated white blood cell, reduced platelet, hematuria, proteinuria, coagulation abnormalities, increased blood urea nitrogen (BUN) and procalcitonin (PCT), decreased estimated glomerular filtration rate and low serum Na⁺, Cl⁻, and Ca²⁺ were the common laboratory findings. In the 206 patients, 21 patients had critical type disease and 4 patients (1.9%) died. Hydrothorax, hypotension and cerebral edema/cerebral herniation at hospital admission were independent clinical characteristics, and neutrophil %, prothrombin activity, PCT, BUN, and Ca²⁺ at hospital admission were independent laboratory factors associated with critical disease. Feature selection identified BUN, PCT and prothrombin time as independent factors related to critical disease. A nomogram integrating BUN and PCT at admission was constructed and calibration showed high accuracy for the probability prediction of critical disease. In conclusion, this study characterized the clinical and laboratory features and constructed a nomogram predicting disease severity in pediatric HFRS, providing references for disease severity evaluation in managing children HFRS.