【作者】 杨占清；

【导师】 俞守义；

【作者基本信息】 第一军医大学 ， 流行病学与卫生统计学， 2005， 博士

【摘要】 近20年来肾综合征出血热流行病学和病原学研究有了飞跃的发展。肾综合征出血热(Hemorrhagic fever with renal Syndrome, HFRS),又名流行性出血热(Epidemic hemorrhagic fever EHF),是由汉坦病毒(Hantavirus, HV)引起、以鼠类为主要传染源,可通过多种途径传播的一种自然疫源性疾病。临床上以发热、低血压、出血、少尿及多尿等肾功损伤为特征,是十余种病毒性出血热(Viral hemorrhagic fever, VHF)中在世界上分布较广,发病数较多,危害性较大的一种。本病于1931～1932年在黑龙江沿岸的中苏交界地区被发现。1935年起驻扎在我国东北北部的侵华曰军中发生暴发流行,病死率高达30%,曾按发病地区相继称为“二道岗热”、“孙吴热”、“黑河热”和“虎林热”等,1942年确定为一种独立的疾病,20世纪40年代后,在北欧斯堪的纳维亚半岛、朝鲜半岛、巴尔干半岛相继发生此病。我国建国初期病例很少,直到1955年内蒙古大兴安岭地区的图里河和陕西宝鸡秦岭北坡修筑宝成铁路的工人中暴发流行后,才开始认识到它的危害,相继在东北、华中、华东、华南和西北广大农村陆续证实有此病流行,以黑线姬鼠(Apodemus agrarius)为主要传染源。并于1956年将此病定为报告疾病。目前,世界上四大洲(亚洲、欧洲、非洲和美洲)32个国家有疫情报告,病例主要分布在亚洲,占92.68%。在我国汉坦型(HTN)和汉城型(SEO)HFRS每年流行,除青海、新疆未发现病例外,其余各省(区、市)均曾有过HFRS病例报告,病例占世界病例数的90%以上。是仅次更多还原

【Abstract】 Hemorrhagic fever with renal syndrome (HFRS, also epidemic hemorrhagic fever: EHF), which is caused by a rodent borne pathogen—Hantavirus (HV), is one of the most widespread and damaging diseases with highest morbidity. It is clinically characterized by fever, hypotension, bleeding and acute renal failure.In 1931-1932, HFRS was first recognized in the Eurasian landmass and adjoining areas and then gained a lot of attention in 1935 when it outbroke with a lethality of more than 30% in Japanese military invading in northeastern China. In China, HFRS was first reported as an emerging infectious disease in 1955 and was found in 28 provinces out of 31 till now. The first clue to the natural reservoir of hantaviruses was claimed to be Apodemus mice by a Japanese who made persons fall in sick by injecting bacteria-free filtrates of tissues from Apodemus agrarius or mites that fed on the Apodemus mice. It was not until 1978 that a rodent reservoir for HFRS was confirmed by a Korean investigator who demonstrated that sera of the patients reacted with antigen of lung tissue of wild Apodemus agrarius (Lee H et al, 1978). Systematical research of HV pathogen began in 1981 when HV could be cultivated in cell successfully. Currently at least 20 serotypes and genotypes of the Hantavirus genus (family: Bunyaviridae) have been identified worldwide. Athough some viruses could be isolated from some other animals and insects, rodents are the natural reservoir for the hantaviruses. In China, It is mainly Hantanvirus (HTNV), Seoul virus (SEOV), which are carried by the striped field mouse (Ap. agrarius) and black rat (R. Rattus) respectively that cause HFRS among all thehantaviruses. Approximately 150,000 to 200,000 cases of HFRS involving hospitalization are reported each year throughout the world, with more than 90% in China. The total number cases is 1256,431 from 1950 to 1997, with 44,304 death (3.53%). 50,000-100,000 cases could be registered annually since 1981 when the presence of the Rattus-type HFRS was first identified serologically in China, with the highest peak in 1986 (115,985 cases). Three types of endemicity have been differentiated: the Apodemus-type, the rattus-type and the mixed type of the two, by their peculiar seasonal distributions of cases and by methods of serotyping (HI, MAbs serotyping kits). Now there are three kinds of inactivated vaccines used to prevent from HFRS in China. Although great progress has been made in the knowledge of epidemiology, epizootiology and molecular biology of hantavirus infection, some still-unidentified factors influence the status of a pathogen to remain unnoticed or evolves into a worldwide threat: ?the typing of the natural epidemic areas of HFRS. As different kinds of natural areas of HFRS have their different epidemic characters, different kinds of host animals, clinical signs, mortalities and morbidities, to determine the type of epidemic focus is very important; ?Identifying of the new serological types; ?The relationships between host animals and infectious resources; (Dtransmitting ways; ?Establishments of a simple, quick, sensible, and specific diagnosis techniques for early diagnosis and surveillance of HFRS: such as dot-ELISA, HI, RPHI and RT-PCR, etc. In brief, HFRS has multiple serotypes and genotypes, different transmission ways in clinical demonstration, four host animal classes including mammalia, Aves, Reptilia and Amphibia, therefore HFRS is difficult to prevent and control. In order to determine the natural epidemic areas and epidemic characteristics of HFRS in Shandong, and to analyze the serotypes/genotypes of the viruses isolated from these areas, the epidemic situation in the populations, and wild and domestic animals in the areas prevalent for HFRS were studied. The results are reported bellow.1. Epidemical investigation of HFRS among the wild host animals of HFRS in Shandong.1.1 It was found that HFRS was multi-hosts, which reached to 12 kinds. Rattus norregicus and Apodemus agrarius were dominant in the wild rats, and the formes made greater roles than the latter.Cricetulus triton could play very important roles in the dry and hilly areas.1.2Yellow weasel, rabbit and pigs were first found to infected HFRS, andsheep could infect HFRSV, which suggested that the host animals ofHFRS could have tendency to be extended.1.3 Under the natural condition, rat infection of HFRS had clusterphenomena by litter and their infection rates increased according to theincrease of litter. The positive rate of viral antigen from the adult rats(15.54%) was more than that of the young rats.1.4It was first demonstrated that Cricetulus triton could be verticallyinfected.1.5HFRSV and Rickettsia trutsugamushi of L. scutellare weresimultaneously isolated from Chigger mites, and HFRSV and R.trutsugamushis appeared during September to December with high peak inNovember, it was also the dominant species on the rodential bodies duringOctober to November. This suggested that L. scutellare had naturalinfection of HFRSV and R. trutsugamushi had the prerequisite for actingas the transmitting vector of HFRS and scrub typhus..2. Epidemical investigation of HFRS among the domestic host animals.2.1 The antigens of HFRS were detected and the viruses of HFRS were isolated from the tissues of heart, liver, spleen and kidney of the domestic pigs, so the pigs could excrete the viruses by many ways and could contaminated the surrounding environment. It was concluded that the domestic pigs should be managed and inspected to prevent and control HFRS.2.2 In nature foci infection, HFRSV antigens were detected in serum, urine, feces and saliva samples from a pregnant sow and its suckling pigs, which showed that HFRSV could be vertically infected in pigs.2.3 HFRSV antigens were detected in spleen, lung, kidney and brain tissues from suckling pigs. Especially, HFRSV antigens were detected from the brain tissues, which could be explained that at the early stage of HFRSV infection, the patients showed some nerve system symptoms.3. Serological epidemic studies on HFRS patients.3.1 Serotype of HFRSV could be divided into three: SEO HTN and un-identified. Among them SEO was over 90%, and sometimes some new serotypes could be found in these places.3.2 The antigen and serum types were in accordance with the types of host animals. That meant SEO was dominant in domestic rats and HTN was dominant in wild rats, which was accordance with the serotypes of the patient in Shandong.3.3 The patients could be found all the year round. Type SEO’s peak was between March and June, and type HTN’s peak was from November to February.3.4 There were some differences between antigen and virulence in HFRSV isolates. SEO isolates, which contained positive HTN antigens, were more virulent.4. Genotyping of HFRSV isolates from the patients serum by RT-Nested PCR together with RFLP and SSCP.4.1 RT-Nested PCR could be used to detect HFRSV from the patients within one week after infection, which was more sensitive, specific, rapid and accurate than ELISA.4.2 RT-Nested PCR together with RFLP and SSCP could be used to differentiate isolates of this virus.4.3 In Shandong province there were two genotypes of HFRSV: SEO and HTN. SEO was dominant.S.Further research:5.1 Whether blending, overlapping and contradiction effects between HFRS and chigger disease in chiggers are existed or not is still unkown, and whether the HFRS’transmission will be weakened or not in chigger disease prevalent areas needs our progressive research.5.2 We will do our research on geographic information system of HFR in ShanDong province by using star tele-sensing technic, therefore providing a scientific method for the forecast and warning for this disease.更多还原