Severity Biomarkers in Puumala Hantavirus Infection

Annually, over 10,000 cases of hemorrhagic fever with renal syndrome (HFRS) are diagnosed in Europe. Puumala hantavirus (PUUV) causes most of the European HFRS cases. PUUV causes usually a relatively mild disease, which is rarely fatal. However, the severity of the infection varies greatly, and factors affecting the severity are mostly unrevealed. Host genes are known to have an effect. The typical clinical features in PUUV infection include acute kidney injury, thrombocytopenia, and increased vascular permeability. The primary target of hantavirus is the endothelium of the vessels of different organs. Although PUUV does not cause direct cytopathology of the endothelial cells, remarkable changes in both the barrier function of the endothelium and the function of the infected endothelial cells occur. Host immune or inflammatory mechanisms are probably important in the development of the capillary leakage. Several immunoinflammatory biomarkers have been studied in the context of assessing the severity of HFRS caused by PUUV. Most of them are not used in clinical practice, but the increasing knowledge about the biomarkers has elucidated the pathogenesis of PUUV infection.     

Long-Term Consequences of Puumala Hantavirus Infection

Several viral infections are associated with acute and long-term complications. During the past two years, there have been many reports on post-infectious symptoms of the patients suffering from COVID-19 disease. Serious complications occasionally occur during the acute phase of Puumala orthohantavirus caused nephropathia epidemica. Severe long-term consequences are rare. Fatigue for several weeks is quite common. Hormonal insufficiencies should be excluded if the patient does not recover normally.     

汉坦病毒感染致血小板减少的机制

汉坦病毒主要感染血管内皮细胞,引起两种人类疾病,即肾综合征出血热和汉坦病毒心肺综合征,它们的共同特点是毛细血管广泛损伤,通透性升高.汉坦病毒感染者血小板数量严重减少,不仅与"外周破坏增加"有关,而且还可能与"血小板生成和功能障碍"有关.尽管汉坦病毒感染引起血小板减少的机制尚不完全明确,但近年也取得了一些重要进展.本文主...     

Alcohol Consumption and Its Influence on the Clinical Picture of Puumala Hantavirus Infection

Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome. Characteristic clinical findings include acute kidney injury (AKI), thrombocytopenia, and capillary leakage. Smoking increases the risk of severe AKI, but it is not known whether alcohol consumption predisposes patients to a more severe infection. Liver and pancreatic enzymes, as well as biomarkers of alcohol consumption (gamma-glutamyl transferase, GGT; carbohydrate-deficient transferrin, CDT; GGT-CDT combination; and ethyl glucuronide, EtG), were measured from 66 patients with acute PUUV infection during hospitalization and at the convalescence phase. Alcohol consumption was present in 41% of the study population, 15% showing signs of heavy drinking. Alcohol use did not affect the severity of PUUV induced AKI nor the overall clinical picture of the infection. Liver enzyme levels (GGT or alanine aminotransferase, ALT) were elevated in 64% of the patients, but the levels did not associate with the markers reflecting the severity of the disease. Serum amylase activities at the convalescent stage were higher than those at the acute phase (p < 0.001). No cases with acute pancreatitis were found. In conclusion, our findings indicate that alcohol consumption does not seem to affect the clinical course of an acute PUUV infection.     

2007年浙江丽水地区汉坦病毒的分离与型别鉴定

目的对2007年从浙江省丽水地区肾综合征出血热(hemorrhagic fever with renal syndrome,HFRS)疫区鼠肺分离的汉坦病毒进行型别鉴定和分子生物学特性研究。方法将汉坦病毒抗原阳性的鼠肺标本接种Vero-E6细胞,分离汉坦病毒。提取病毒总RNA,应用逆转录聚合酶链反应(RT-PCR)扩增病毒S基因全片段,克隆入质粒载体,进行核苷酸序列测定及分析,应用DNA STAR软件分析比较,确定病毒型别。结果从疫区7份阳性鼠肺中分离到2株汉坦病毒,经汉坦病毒单克隆直接荧光血清检查和基因序列测定,结果为汉滩型(HTN)病毒,2株病毒与国际标准株76-118(HTN型)和80-39(SEO型)S片段核苷酸的同源性分别为84.7%、84.6%和64.2%、64.0%。结论浙江省丽水地区可能存在以HTN型病毒为主的肾综合征出血热自然疫源地。     

基于空间信息技术的北京市肾综合征出血热宿主动物感染与环境因素关系研究

目的 探讨北京市肾综合征出血热（HFRS）宿主动物的感染情况与环境因素之间的关系。方法 选择北京市9个区（县）作为研究试验区，设立14个调查点，对HFRS动物宿主感染情况进行调查，应用全球定位系统对调查点进行定位，在ArcGIS软件支持下，建立调查点矢量图层，并与北京市1：100000地形图、北京市Landsat-7 TM卫星遥感影像图及北京市高程图进行叠加，分别提取调查点周围2km缓冲区内的平均海拔，校正植被指数及土地利用信息，导出后在SPSS13．0中分析宿主感染情况与环境因素的联系。结果 不同地区间HFRS动物宿主密度和带毒率的差异具有统计学意义；宿主带毒率和带毒指数与园地、水浇地面积成正相关关系；宿主带毒情况和校正植被指数之间无相关性；褐家鼠带毒率与海拔、水浇地面积之间呈正相关荚系。结论 北京地区肾综合征出血热动物感染情况与土地利用等地理环境因素有关，提示应根据不同地理环境特点采取有针对性的防控措施。     

Hantavirus Research in Finland: Highlights and Perspectives

Finland has the highest incidence of hantavirus infections globally, with a significant impact on public health. The large coverage of boreal forests and the cyclic dynamics of the dominant forest rodent species, the bank vole Myodes glareolus, explain most of this. We review the relationships between Puumala hantavirus (PUUV), its host rodent, and the hantavirus disease, nephropathia epidemica (NE), in Finland. We describe the history of NE and its diagnostic research in Finland, the seasonal and multiannual cyclic dynamics of PUUV in bank voles impacting human epidemiology, and we compare our northern epidemiological patterns with those in temperate Europe. The long survival of PUUV outside the host and the life-long shedding of PUUV by the bank voles are highlighted. In humans, the infection has unique features in pathobiology but rarely long-term consequences. NE is affected by specific host genetics and risk behavior (smoking), and certain biomarkers can predict the outcome. Unlike many other hantaviruses, PUUV causes a relatively mild disease and is rarely fatal. Reinfections do not exist. Antiviral therapy is complicated by the fact that when symptoms appear, the patient already has a generalized infection. Blocking vascular leakage measures counteracting pathobiology, offer a real therapeutic approach.     

福建省鼠间肾综合征出血热流行病学调查

目的掌握福建省鼠间肾综合征出血热(HFRS)流行情况和疫源地分布,为控制HFRS的流行提供参考。方法根据福建省啮齿动物地理区划以及肾综合征出血热病例分布状况,选择18个县、市作为调查地区,用笼夜法捕鼠采集血清标本,用双抗原夹心ELISA法检测血清中抗汉坦病毒(Hantan virus,HV)抗体,分析鼠间HFRS流行情况。结果各个地区HV宿主动物种类分布不均衡,但以褐家鼠为主要宿主动物,其次为黄胸鼠,野外鼠密度较低。褐家鼠抗体阳性率最高,达到9.89%。各个地理区划中II区即闽东山地抗体阳性率最高,为9.32%,而III区即闽中、闽西南山地抗体阳性率最低,为2.74%。调查点中泰宁、周宁、福鼎、厦门、福清、莆田、平潭等地鼠血清HV抗体阳性率均超过10%。而上杭、漳平、漳浦、安溪等地鼠血清均未检出HV抗体。结论福建省HFRS的疫源地以家鼠型疫区为主,降低家鼠尤其是褐家鼠密度,可控制本病在福建的扩大流行。     

Recent Evidence of Hantavirus Circulation in the American Tropic

Hantaan virus was discovered in Korea during the 1970s while other similar viruses were later reported in Asia and Europe. There was no information about hantavirus human infection in the Americas until 1993 when an outbreak was described in the United States. This event promoted new studies to find hantaviruses in the Americas. At first, many studies were conducted in Brazil, Argentina, Chile, Uruguay and Paraguay, while other Latin American countries began to report the presence of these agents towards the end of the 20th century. More than 30 hantaviruses have been reported in the Western Hemisphere with more frequent cases registered in the southern cone (Argentina, Chile, Uruguay, Paraguay, Bolivia and Brazil). However there was an important outbreak in 2000 in Panama and some rare events have been described in Peru, Venezuela and French Guiana. Since hantaviruses have only recently emerged as a potential threat in the tropical zones of the Americas, this review compiles recent hantavirus reports in Central America, the Caribbean islands and the northern region of South America. These studies have generated the discovery of new hantaviruses and could help to anticipate the presentation of possible future outbreaks in the region.     

肾综合征出血热抗病毒治疗及疫苗研发进展

肾综合征出血热(hemorrhagic fever with renal syndrome, HFRS)是由汉坦病毒感染引起的一种自然疫源性疾病,在世界范围内广泛流行,我国一直是流行高发区,患者占所有HFRS患者一半以上,其主要临床特征为发热、出血、低血压休克和肾脏损害,严重危害人类健康。尽管抗病毒治疗和疫苗免疫接种可以防治汉坦病毒感染,但目前尚无特效抗病毒药物。近年来,随着医学科技进步,汉坦病毒的抗病毒治疗和疫苗研发有了新的进展。本文基于近年体内外研究及临床试验结果,对HFRS抗病毒治疗和疫苗研发进展作一综述。     

肾综合征出血热发病机制的研究进展

肾综合征出血热(hemorrhagic fever with renal syndrome, HFRS)是由汉坦病毒感染引起的以发热、休克、出血和肾脏损害为主要特征的急性自然疫源性疾病。汉坦病毒主要感染人血管内皮细胞,引起小血管和毛细血管广泛损伤。血管通透性增加是HFRS临床表现的病理基础。国内外学者尽管在汉坦病毒致病机制方面开展了诸多研究,如病毒诱导的免疫病理反应、宿主遗传与细胞凋亡、血小板减少与功能障碍、血管内皮损伤等,但HFRS发病机制仍未完全阐明,也无特效治疗药物,深入探讨汉坦病毒致病的分子机制,寻找有效治疗药物仍是汉坦病毒/HFRS领域的研究热点。本文结合近年来国内外相关研究,阐述HFRS发病机制的研究进展。     

肾综合征出血热患者血浆MCP-1水平及其临床意义

目的　分析肾综合征出血热（hemorrhagic fever with renal syndrome, HFRS）患者不同病期及不同临床型血浆单核细胞趋化蛋白-1（monocyte chemotactic protein-1, MCP-1）浓度变化与疾病相关性,为HFRS临床诊治提供参考依据。方法　以2012年10月—2014年1月期间在空军军医大学唐都医院住院就诊的81例HFRS患者及15例健康志愿者（正常对照组）作为研究对象,用酶联免疫吸附法分别检测其血浆中MCP-1水平,同步检测血常规、肾功能等指标,并分析MCP-1与临床常规检测指标的相关性。结果　在急性期,所有患者血浆MCP-1水平均明显升高,其中重型/危重型患者血浆MCP-1水平升高比轻型/中型更为显著;中型、重型、危重型患者血浆MCP-1水平急性期均高于恢复期及正常对照组（P均＜0.05）,恢复期与正常对照组比较差异无统计学意义（P＞0.05）。Spearman相关分析显示血浆MCP-1水平与白细胞、尿素氮、肌酐水平呈正相关,与血小板水平呈负相关。结论　HFRS患者血浆MCP-1水平与疾病严重程度及疾病进程密切相关。     

2004——2017年全国肾综合征出血热变化趋势分析

目的 分析近年来全国HFRS疫情特征,总结变化趋势。方法 收集2004——2017年全国HFRS资料。采用描述性流行病学方法描述全国疫情概况、病例年龄组构成比、病例年龄组发病率,分省份比较HFRS季节性、长期趋势;采用分段线性回归分析2004——2017年全国及各省(市、自治区)HFRS趋势变化;采用季节分解法计算序列季节项。结果 全国累计报告HFRS 178 237例,死亡1 753例,年均发病率0.95/10万,死亡率0.009/10万,病死率0.98%。全国出血热疫情整体呈下降趋势(AAPC=-8.56%,95%CI: -10.26%~-6.86%)。广东省、海南省、福建省和湖北省等呈上升趋势(AAPC>0)。发病率、死亡率前5位的地区依次为黑龙江省(5.80/10万,0.059/10万)、陕西省(4.48/10万, 0.035/10万)、吉林省(3.79/10万, 0.030/10万)、辽宁省(3.71/10万, 0.027/10万)、山东省(1.57/10万, 0.018/10万)。HFRS发病呈双峰,最高峰出现在10月-次年1月,报告病例数占总病例数的46.76%;次高峰出现在4-7月,报告病例数占总病例数的32.17%。≥60岁年龄组发病率随年份波动不大,15~59岁年龄组发病率随年份整体呈下降趋势。2004年-2017年,HFRS病例中60岁及以上年龄组占比由9.75%上升至24.48%。结论 2004——2017年全国HFRS疫情整体呈下降趋势。华中、华南地区是今后HFRS疫情防控的重点地区。HFRS高发年龄组有向60岁及以上转移趋势,今后应加强该人群疫苗接种工作以保证HFRS疫情逐步下降。     

皖南地区HLA-Brs34933313基因多态性与肾综合征出血热的相关性分析

目的 探讨皖南地区汉族人群HLA-B基因单核苷酸多态性(Single Nucleotide Polymorphisms,SNP)rs34933313与肾综合征出血热(Hemorrhagic fever with renal syndrome,HFRS)的相关性。方法 采集HFRS患者14例(病例组)和健康组50例(对照组)新鲜血样,提取基因组DNA,通过等位基因特异引物-聚合酶链反应(ASP-PCR)对HLA-B基因位点分型,应用SPSS22.0统计分析其等位基因及基因型两组间的差异。结果 HLA-B基因rs34933313位点受试人群分布符合哈迪-温伯格(Hardy-Weinberg,H-W)遗传平衡,两组等位基因G、C(χ²=4.38,OR=2.45,P=0.04)和基因型GG、GC、CC(χ²=6.47,P=0.04)频率分布差异均有统计学意义;病例组中C等位基因的分布频率高于G等位基因,且携带C等位基因罹患HFRS的概率是G等位基因的2.45倍;亚组分析发现 HLA-B基因rs34933313位点在显性遗传模型下(χ²=6.45,P=0.01,OR=10.21,95%CI=1.24~84.18)与HFRS发病风险具有相关。结论 皖南地区汉族人群HLA-B基因rs34933313位点与HFRS发病风险存在相关性,且携带C等位基因者会提高HFRS的发生风险。     

2008-2012年河北省肾综合征出血热监测及流行特征研究

目的 通过分析2008 2012年的监测资料,描述河北省肾综合征出血热（HFRS）流行特征和变化趋势,为疾病的防控提供依据.方法 对河北省2008 2012年HFRS病例资料及宿主动物监测资料,采用描述性流行病学方法进行统计分析.结果2008 2012年,河北省共报告HFRS病例1 853例,死亡6例,平均发病率为0.524 2/10万,病死率0.32％;2008 2010年发病维持在低发态势,2011年以后发病逐渐上升,但病死率较低.发病主要集中在东北部的秦皇岛市、唐山市和中部的石家庄市,三市占总报告病例数的77.60％;全年各月均有病例报告,但呈现出“双峰型”分布,3～6月为全年发病最高峰;男女性别比为2.60∶1,发病以青壮年为主,其中40～50岁年龄组病例最多.≥60岁的病例上升明显,大年龄组发病有增加的趋势;职业分布以农民居多;鼠密度变化趋势不明显,波动不大;2008 2010年鼠带毒率呈逐年下降趋势,2011年和2012年鼠带毒率较前3年明显升高;PCR分型结果均为汉城型（Ⅱ型）,序列同以往的测序株比较,同源性较高;鼠带病毒指数与人群发病率呈正相关（r＝0.969,P＝0.006）.结论 河北省HFRS疫情呈上升趋势,尤其对于高发地区需加强监测,并强化疫苗接种意识和落实防鼠灭鼠工作;≥60岁的病例上升明显,应及时关注大年龄组人群.     

肾综合征出血热10种细胞因子的动态变化及作用机制

目的了解10种细胞因子在肾综合征出血热中的动态变化及作用机制。方法前瞻性选取肾综合征出血热病例53例,轻型9例,中型16例,重型15例,危重型13例。按病期采集血清标本,血透治疗时透析前后采集,20例正常人血清作对照;ELISA法检测上述标本中的细胞因子(IL-1β、IL-2、IL-4、IL-6、IL-8、IL-10、IL-12、IL-15、IFN-α和TNF-α);按病期、病型和血透干预3个层次进行分析。结果TNF-α、IL-1β、IL-2、IL-4、IL-6、IL-8、IL-10、IL-12、IL-15在发热期即明显高于对照组,在低血压少尿期达高峰(P<0.01),IFN-α水平在各期均低于对照组(P<0.01);多数细胞因子在重症组高于轻症组(P<0.01);血透后大部分细胞因子有明显下降(P<0.01)。结论10种细胞因子均参与肾综合征出血热发病的炎症过程;促炎与抗炎介质分泌失衡,TNF-α、IL-1β、IL-2、IL-4、IL-6、IL-8、IL-10、IL-12和IL-15分泌过量、导致明显的全身炎症反应,分泌量与炎症损害呈正相关;IFN-α分泌不足,可能导致细胞免疫功能受限,不利于炎症的控制;血透能显著减少患者血清中的细胞因子、减轻炎症损害。     

2006-2015年福建省漳州市肾综合征出血热流行病学分析

目的 分析福建省漳州市肾综合征出血热(HFRS)流行特征和发病风险,为疾病防控提供科学依据.方法 整理和分析2006-2015年漳州市HFRS病例个案资料及宿主动物监测资料.结果 10年间,漳州市共报告HFRS 171例,死亡1例.年均发病率为0.352/10万,疫情呈上升趋势(x…d 2=58.60,P＜0.01).累计波及全市11县区70乡镇(56.00％),高发乡镇为华安县仙都镇、华丰镇,南靖县靖城镇,诏安县深桥镇、南诏镇.农村地区报告142例,职业以农民为主(79.58％),其中生猪养殖人员占该职业病例23.01％.病例报告单位集中在市级医院(86.55％),常见临床表现为发热、恶心、呕吐、腰疼、头疼、全身痛、少尿或无尿、眼睑浮肿等,血小板减少占72.67％,蛋白尿阳性83.09％.对比前后5年,病家屋内有鼠比例(80.49％,45.83％)明显下降,工作场所有鼠或鼠排泄物比例(60.98％,73.33％)-直较高.家栖鼠平均鼠密度为6.40％,鼠总带毒率7.42％,主要带病毒鼠种为褐家鼠,携带Ⅱ型汉城病毒.结论 漳州市是HFRS家鼠型疫源地,近年整体上处于高度散发,部分县区呈现逐年上升的趋势,建议加大高发地区监测和防治力度,开展全市基层医疗机构HFRS诊疗培训.     

Serological Evidence of Hantavirus Infection in Apparently Healthy People from Rural and Slum Communities in Southern Chile

Hantavirus disease in America has been recognizable because of its rapid progression in clinical cases, occurrence in previously healthy young adults, and high case fatality rate. Hantavirus disease has been proposed now to define the diversity of clinical manifestations. Since 1995, a total of 902 cases of hantavirus pulmonary syndrome have been reported in Chile, caused by Andes virus (ANDV), with overall fatality of 32%. This report describes the sero-epidemiology of hantavirus in apparently healthy people in rural and urban slum communities from southern Chile. Ten of 934 samples yielded a positive result resulting in a seroprevalence of 1.07% (95% confidence intervals: 0.05%–2.0%). A higher proportion of positive samples was found among individuals from rural villages (1.3%) and slums (1.5%) compared with farms (0.5%). Seropositivity was associated with age (p = 0.011), low education level (p = 0.006) and occupations linked to the household (homemaker, retired, or student) (p = 0.016). No evidence of infection was found in 38 sigmodontinae rodents trapped in the peri-domestic environment. Our findings highlight that exposure risk was associated with less documented risk factors, such as women in slum and rural villages, and the occurrence of infection that may have presented as flu-like illness that did not require medical attention or was misdiagnosed.     

云南省恙虫病与肾综合征出血热混合感染的诊断及分析

目的 调查云南省不明原因发热患者中是否存在恙虫病与肾综合征出血热混合感染病例.方法 采用间接免疫荧光法和胶体金法检测不明原因发热患者血清中的恙虫病东方体(OT)抗体及肾综合征出血热(HFRS)病毒抗体,用巢式PCR扩增患者血液中的OT 基因sta56片断与汉坦病毒(HV)基因L片断.结果 79例患者中,实验室确诊HFRS 5例,恙虫病3例,HFRS与恙虫病混合感染4例;巢式PCR检测到HV L片断核酸2例(DLR2和DLR6), 序列分析两者间的同源性100%,DLR2与老挝汉城病毒L0199株核苷酸序列同源性最高为94.6%, 与中国汉城病毒L99株的同源性80.5%, 与云南汉坦病毒YN06-256的同源性69.8%.结论 首次证实云南省存在恙虫病与肾综合征出血热混合感染病例,其HFRS病原体遗传进化关系与老挝汉城病毒L0199株密切相关.     

连续性肾脏替代治疗与间断性血液透析在重症肾综合征出血热治疗中的应用

目的回顾性观察连续性肾脏替代治疗(continuous renal replacement therapy,CRRT)与间断性血液透析(intermittent hemodialysis,IHD)在重症肾综合征出血热(hemorrhagic fever with renal syndrome,HFRS)患者中的应用。方法依据临床分型标准,将2008年1月—2012年8月在我中心行血液净化治疗的147例重症HFRS患者分为重型组和危重型组;参照中华医学会ICU血液净化指南,对纳入患者行CRRT或IHD治疗,比较2组行CRRT或IHD治疗的病死率、并发症发生率和急性期的实验室指标。结果重型组患者均存活;危重型组患者行CRRT与IHD后的病死率比较差异无统计学意义(P=0.124);危重型组行CRRT的比例明显高于重型组(P0.001)。病程中存在重叠期的重症患者,行CRRT初始治疗的例数明显多于行IHD的例数,但其生存率比较差异无统计学意义(P=1.000)。CRRT组患者病情较IHD组重,其疾病本身的肾外并发症也较IHD组常见。结论 CRRT可广泛应用于危重型HFRS患者的救治。CRRT可有效减轻水负荷,稳定机体的血流动力学状态,将有助于使危重患者平稳地渡过急性期。