人感染新斑点热群立克次体的发现及自然疫源地调查研究
发布时间：2018-09-09 19:11
【摘要】：一、研究背景蜱传斑点热群立克次体病是一类人兽共患的自然疫源性疾病。世界各地广泛存在着这类疾病,在历史上是人类发病和死亡的重要原因之一,当今仍严重威胁着人类的健康。同时该类疾病也是生化武器的重要来源之一,国际反恐已将落基山斑点热列入生物战剂目录中。蜱是该群立克次体的保菌宿主,可经卵垂直传递和经期水平传播立克次体,保持立克次体种群的延续性。斑点热群立克次体在自然界中的感染循环是在蜱及哺乳动物如野生啮齿动物间维持的。人类因偶然接触到感染蜱,被其叮咬从而发生感染。人被感染蜱叮咬或被其粪便污染皮肤伤口、粘膜后,立克次体侵入机体进入淋巴系统和血液系统,在血管内皮细胞开始生长繁殖,通过血流播散到全身组织和器官,引起一系列功能变化。不同基因型的斑点热群立克次体临床症状有所不同,但也有相似之处。患者一般被蜱叮咬2-14天后发病,出现发热、头痛、乏力、皮疹、焦痂、局部淋巴结肿大等症状和体征,发病初期类似病毒性感染,常被误诊、漏诊。因此,虽然斑点热群立克次体遍布世界各地,但经实验室确诊的蜱传斑点热群立克次体病例报道多来自于欧美等发达国家和地区。本研究之前,在我国大陆共发现了9种斑点热群立克次体基因型:Rickettsia sibirica和Rickettsia heilongjiangensis在我国已有实验室确诊病例报道,然而仅有27例斑点热散发病例报道,其中8例为Rickettsia sibirica,19例为Rickettsia heilongjiangensis;Ricekettsia mongolotimona虽在我国内蒙古亚东璃眼蜱中成功分离,并在法国马赛证实了对人类致病,但在我国尚无确诊病例报道;Rickettsia hulinii和Rickettsia sibirica subspecies sibirica BJ-90分别在嗜群血蜱和中华革蜱中发现,R.slovaca和R.raoultii在我国新疆森林革蜱中发现,Candidatus Rickettsia hebeiii在我国河北的草原革蜱和长角血蜱中发现,Rickettsia monacensis在我国的安徽、河南和湖北的全沟硬蜱中发现,除了Rickettsia raoultii、R.slovaca和Rickettsia monacensis被证实对人类有致病性外,其他均在世界上尚无对人类致病的证据报道。近十几年来,根据蜱和宿主动物的调查发现了多种新发立克次体,然而这些立克次体对人是否致病;如果致病,有何临床表现;如何治疗等一系列问题一直缺乏系统的研究,因此亟需针对蜱接触高危人群开展立克次体病监测工作。东北地区森林覆盖率高,蜱种和宿主动物种类丰富,是我国重要蜱媒传染病的自然疫源地,我们以往的调查发现媒介蜱和宿主动物携带多种蜱媒病原体,包括嗜吞噬细胞无形体、斑点热群立克次体、伯氏疏螺旋体、查菲埃立克体、巴贝西虫、森林脑炎病毒等,并且此前在东北地区均报道过人感染Rickettsia sibirica和Rickettsia heilongjiangensis,因此是监测斑点热的重要地域。二、研究目的本研究于2012-2013年在哨点医院---黑龙江牡丹江林业中心医院开展了斑点热群立克次体病的监测,旨在发现蜱传立克次体病确诊病例,了解其病原学特征,临床致病特点与治疗方案。发现病例后,开展斑点热群立克次体自然疫源地调查,以摸清我国东北地区斑点热群立克次体的流行病学特征。三、研究方法以蜱叮咬史或斑点热样症状作为病例入选标准。采集纳入病例的流行病学信息和临床病历信息。采用聚合酶链式反应(PCR)扩增病例全血、皮肤焦痂以及病例体表叮咬蜱中的斑点热群立克次体特异的基因片段并进行序列系统进化发育分析;采用间接免疫荧光(IFA)方法检测病例急性期和/或恢复期血清的斑点热群立克次体的Ig G和Ig M抗体水平;分析确诊病例的临床表现特征和治疗方法的合理性;在斑点热病例居住地采集游离蜱和野生啮齿动物,采用PCR扩增斑点热群立克次体特异的基因片段并进行序列系统进化发育分析。四、研究结果在1801例斑点热疑似病人中,11例患者的全血或皮肤焦痂斑点热群立克次体核酸检测阳性。经序列进化分析确定5例为新塔拉塞维奇立克次体(Candidatus Rickettsia tarasevichiae),2例为拉欧蒂立克次体(Rickettsia raoultii),1例为西伯利亚立克次体BJ-90亚种(Rickettsia sibirica subspecies sibirica BJ-90),3例为黑龙江立克次体(Rickettsia heilongjiangensis),其中6例病例急性期和恢复期双份血清抗体发生阳转或抗体滴度呈四倍升高;5例病例急性期血清Ig G和Ig M抗体阳性,血清学证据进一步支持近期感染了斑点热群立克次体。该11名患者均有近期蜱咬史。5例感染Candidatus Rickettsia.tarasevichiae临床症状和实验室检查出现发热(2/5),皮肤焦痂(3/5),淋巴结炎(2/5),白细胞计数升高(3/5),无皮疹。其余6例患者均出现了皮疹。1例感染Rickettsia sibirica subspecies sibiricaBJ-90的患者和2例Candidatus Rickettsia tarasevichiae患者临床表现危重,肝脏转氨酶水平升高,肾功能衰竭,其中1例Candidatus Rickettsia tarasevichiae患者因呼吸衰竭死亡。同时在1例感染Rickettsia raoultii的患者体表取下的饱血森林革蜱经PCR扩增显示携带有Rickettsia raoultii。在确诊病例居住地附近开展的斑点热立克次体自然疫源地调查发现,游离蜱中Candidatus Rickettsia tarasevichiae感染率为8.7%(46/528),Rickettsia raoultii感染率为0.6%(3/528),Rickettsia heilongjiangensis感染率为1.3%(7/528),其中46只(46/453)全沟硬蜱携带Candidatus Rickettsia tarasevichiae,3只森林革蜱(3/75)携带Rickettsia raoultii,1只全沟硬蜱(1/453)和6只森林革蜱(6/75)携带Rickettsia heilongjiangensis;啮齿动物中Candidatus Rickettsia tarasevichiae感染率为0.9%(5/531),Rickettsia heilongjiangensis感染率为0.2%(1/531),其中3只黑线姬鼠(3/236)、1只仓鼠(1/20)、1只褐家鼠(1/58)感染Candidatus Rickettsia tarasevichiae,1只红背鼠平(1/16)感染Rickettsia heilongjiangensis。五、研究结论本研究发现我国东北地区存在4种斑点热群立克次体同时流行。世界首次报道了人感染Candidatus Rickettsia tarasevichiae和Rickettsia sibirica subspecies sibirica BJ-90立克次体病,欧洲以外地区首次报道了人感染Rickettsia raoultii立克次体病。这四种斑点热临床表现不同,轻则出现流感样症状,重则发生多器官功能障碍,甚至死亡。多西环素治疗有效,但常因出现非典型斑点热症状而发生误诊、漏诊或迟诊。同时病例居住地蜱和啮齿动物的调查证实了东北地区是上述病原体的自然疫源地。六、意义与创新性由于经常性的误诊忽视了斑点热群立克次体病,我们的研究进一步证实斑点热群立克次体病远比我们想象的要普遍存在,需要引起临床医生及公共卫生工作人员的高度重视。我们在世界或欧洲以外地区首次报道的3种新发立克次体病,丰富了人们对立克次体病的认识,为进一步研究致病性立克次体提供了重要依据。
[Abstract]:1. Background Tick-borne spotted fever group rickettsiasis is a natural zoonotic disease. It is widespread in the world. It is one of the most important causes of human disease and death in history. It is still a serious threat to human health. Rocky Mountain spotted fever has been listed as a biological warfare agent in the anti-terrorism list. Ticks are the preservative hosts of this group of rickettsia, which can be transmitted vertically and horizontally through eggs to maintain the continuity of the Rickettsia population. The infection cycle of spotted fever group rickettsia in nature is maintained between ticks and mammals such as wild rodents. After being bitten by an infected tick or contaminated by its feces, Rickettsia invades the body's lymphatic and blood systems, and begins to grow and reproduce in vascular endothelial cells, which spread through the bloodstream to tissues and organs throughout the body, causing a series of functional changes. The clinical symptoms of different genotypes of spotted fever group Rickettsia are different, but there are similarities. Patients usually develop fever, headache, fatigue, rash, eschar, local lymph node enlargement and other symptoms and signs 2-14 days after being bitten by ticks. Early onset of the disease is similar to viral infection, often misdiagnosed, missed diagnosis. Rickettsia sibirica and Rickettsia heilongjiangensis have been found in the mainland of China before this study. However, only 27 sporadic cases of spotted fever have been reported, including 8 cases of Rickettsia sibirica, 19 cases of Rickettsia heilongjiangensis, Ricekettsia mongolotimona, which has been successfully isolated from Euphorbia asiatica in Inner Mongolia and confirmed to be pathogenic to humans in Marseilles, France. Ini and Rickettsia sibirica subspecies sibirica BJ-90 were found in Haemaphysalis multilocularis and Dermatophyta sinensis, respectively. R. slovaca and R. raoultii were found in forest ticks in Xinjiang, China. Candidatus Rickettsia hebeiii was found in grassland leathers and Haemaphysalis longicornis in Hebei, China. Rickettsia monacensis was found in Anhui, Henan and Hubei provinces. There is no evidence of human pathogenicity in Ixodes persulcatus except that Rickettsia raoultii, R. slovaca and Rickettsia monacensis have been confirmed to be pathogenic to humans. There is a lack of systematic study on the pathogenesis, clinical manifestations, and treatment of tick-borne infections. Therefore, it is urgent to carry out surveillance of Rickettsia disease in high-risk populations. Vector ticks and host animals were found to carry a variety of tick-borne pathogens, including phagocytosis, spotted fever group rickettsia, Borrelia burgdorferi, chaffei-erik, babesia, and forest encephalitis virus. Human infections with Rickettsia sibirica and Rickettsia heilongjiangensis were previously reported in Northeast China, and were therefore supervised. Objective To investigate the etiology, clinical characteristics and treatment of tick-borne rickettsiasis. The surveillance of spotted fever group rickettsiasis was carried out in the Mudanjiang Forestry Center Hospital of Heilongjiang Province from 2012 to 2013. The epidemiological characteristics of spotted fever group rickettsia in Northeast China were investigated. 3. The history of tick bites or spotted fever-like symptoms were used as the criteria for case selection. Epidemiological and clinical information of the cases were collected and amplified by polymerase chain reaction (PCR). Specific gene fragments of spotted fever group rickettsia in whole blood, skin eschar and tick bites were sequenced and phylogenetic analysis was carried out; serum Ig G and Ig M antibodies against spotted fever group rickettsia in acute and/or convalescent stages were detected by indirect immunofluorescence assay (IFA); and clinical manifestations of confirmed cases were analyzed. Characteristics and rationality of treatment methods; free ticks and wild rodents were collected from the habitats of spotted fever cases, and Rickettsia-specific gene fragments of spotted fever group were amplified by PCR and sequenced for phylogenetic analysis. The nucleic acid test of Rickettsia was positive. Sequence evolution analysis showed that 5 cases were neo-Talasevichiae (Candidatus Rickettsia tarasevichiae), 2 cases were Rickettsia raoultii, 1 case was Rickettsia subspecies sibirica BJ-90, and 3 cases were Rickettsia Heilongjiang Rickettsia BJ-90. Six of the 11 patients had a recent history of tick bites and 5 had a recent history of Ca infection. Ndidatus Rickettsia. tarasevichiae had fever (2/5), skin char (3/5), lymphadenitis (2/5), elevated white blood cell count (3/5) and no rash. The other six patients had rash. One patient was infected with Rickettsia sibirica subspecies sibirica BJ-90 and two patients with Candidatus Rickettsia tarasevichiae. One of the patients died of respiratory failure. Meanwhile, one patient infected with Rickettsia raoultii was found to be carrying Rickettsia raoultii. PCR amplification showed that Rickettsia raoultii was present on the surface of a patient infected with Rickettsia raoultii. Candidatus Rickettsia tarasevichiae infection rate was 8.7% (46/528), Rickettsia raoultii infection rate was 0.6% (3/528) and Rickettsia heilongjiangensis infection rate was 1.3% (7/528) among the free ticks, 46 (46/453) Ixodes carrying Candidatus Rickettsia tarasevichiae, 3 ticks carrying all ditches. Rickettsia raoultii was carried by 3/75 ticks, 1 Ixodes persulcatus (1/453) and 6 ticks (6/75) carried Rickettsia heilongjiangensis, Candidatus Rickettsia tarasevichiae infection rate was 0.9% (5/531) and Rickettsia heilongjiangensis infection rate was 0.2% (1/531) in rodents, including 3 Apodemus AGUS agrarius (3/236) and 1 hamster (1/20). A brown house mouse (1/58) was infected with Candidatus Rickettsia tarasevichiae and a red-backed mouse (1/16) with Rickettsia heilongjiangensis. 5. The study concluded that four species of spotted fever group Rickettsia were prevalent simultaneously in Northeast China. Human infection with Candidatus Rickettsia tarasevichiae and Rickettsia sibirsi was first reported in the world. Rickettsia raoultii Rickettsia is reported for the first time outside Europe. The four types of spotted fever have different clinical manifestations, including flu-like symptoms, multiple organ dysfunction and even death. Doxycycline therapy is effective, but often due to atypical spotted fever symptoms. At the same time, the investigation of ticks and rodents in the habitat confirms that the northeast is the natural focus of the above pathogens. 6. Significance and innovativeness due to frequent misdiagnoses that overlook spotted fever group rickettsiasis, our study further confirms that spotted fever group rickettsiasis is far more common than we thought The three new rickettsiasis reported for the first time in the world or outside Europe have enriched people's understanding of rickettsiasis and provided an important basis for further research on pathogenic rickettsiasis.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R513
[Abstract]:1. Background Tick-borne spotted fever group rickettsiasis is a natural zoonotic disease. It is widespread in the world. It is one of the most important causes of human disease and death in history. It is still a serious threat to human health. Rocky Mountain spotted fever has been listed as a biological warfare agent in the anti-terrorism list. Ticks are the preservative hosts of this group of rickettsia, which can be transmitted vertically and horizontally through eggs to maintain the continuity of the Rickettsia population. The infection cycle of spotted fever group rickettsia in nature is maintained between ticks and mammals such as wild rodents. After being bitten by an infected tick or contaminated by its feces, Rickettsia invades the body's lymphatic and blood systems, and begins to grow and reproduce in vascular endothelial cells, which spread through the bloodstream to tissues and organs throughout the body, causing a series of functional changes. The clinical symptoms of different genotypes of spotted fever group Rickettsia are different, but there are similarities. Patients usually develop fever, headache, fatigue, rash, eschar, local lymph node enlargement and other symptoms and signs 2-14 days after being bitten by ticks. Early onset of the disease is similar to viral infection, often misdiagnosed, missed diagnosis. Rickettsia sibirica and Rickettsia heilongjiangensis have been found in the mainland of China before this study. However, only 27 sporadic cases of spotted fever have been reported, including 8 cases of Rickettsia sibirica, 19 cases of Rickettsia heilongjiangensis, Ricekettsia mongolotimona, which has been successfully isolated from Euphorbia asiatica in Inner Mongolia and confirmed to be pathogenic to humans in Marseilles, France. Ini and Rickettsia sibirica subspecies sibirica BJ-90 were found in Haemaphysalis multilocularis and Dermatophyta sinensis, respectively. R. slovaca and R. raoultii were found in forest ticks in Xinjiang, China. Candidatus Rickettsia hebeiii was found in grassland leathers and Haemaphysalis longicornis in Hebei, China. Rickettsia monacensis was found in Anhui, Henan and Hubei provinces. There is no evidence of human pathogenicity in Ixodes persulcatus except that Rickettsia raoultii, R. slovaca and Rickettsia monacensis have been confirmed to be pathogenic to humans. There is a lack of systematic study on the pathogenesis, clinical manifestations, and treatment of tick-borne infections. Therefore, it is urgent to carry out surveillance of Rickettsia disease in high-risk populations. Vector ticks and host animals were found to carry a variety of tick-borne pathogens, including phagocytosis, spotted fever group rickettsia, Borrelia burgdorferi, chaffei-erik, babesia, and forest encephalitis virus. Human infections with Rickettsia sibirica and Rickettsia heilongjiangensis were previously reported in Northeast China, and were therefore supervised. Objective To investigate the etiology, clinical characteristics and treatment of tick-borne rickettsiasis. The surveillance of spotted fever group rickettsiasis was carried out in the Mudanjiang Forestry Center Hospital of Heilongjiang Province from 2012 to 2013. The epidemiological characteristics of spotted fever group rickettsia in Northeast China were investigated. 3. The history of tick bites or spotted fever-like symptoms were used as the criteria for case selection. Epidemiological and clinical information of the cases were collected and amplified by polymerase chain reaction (PCR). Specific gene fragments of spotted fever group rickettsia in whole blood, skin eschar and tick bites were sequenced and phylogenetic analysis was carried out; serum Ig G and Ig M antibodies against spotted fever group rickettsia in acute and/or convalescent stages were detected by indirect immunofluorescence assay (IFA); and clinical manifestations of confirmed cases were analyzed. Characteristics and rationality of treatment methods; free ticks and wild rodents were collected from the habitats of spotted fever cases, and Rickettsia-specific gene fragments of spotted fever group were amplified by PCR and sequenced for phylogenetic analysis. The nucleic acid test of Rickettsia was positive. Sequence evolution analysis showed that 5 cases were neo-Talasevichiae (Candidatus Rickettsia tarasevichiae), 2 cases were Rickettsia raoultii, 1 case was Rickettsia subspecies sibirica BJ-90, and 3 cases were Rickettsia Heilongjiang Rickettsia BJ-90. Six of the 11 patients had a recent history of tick bites and 5 had a recent history of Ca infection. Ndidatus Rickettsia. tarasevichiae had fever (2/5), skin char (3/5), lymphadenitis (2/5), elevated white blood cell count (3/5) and no rash. The other six patients had rash. One patient was infected with Rickettsia sibirica subspecies sibirica BJ-90 and two patients with Candidatus Rickettsia tarasevichiae. One of the patients died of respiratory failure. Meanwhile, one patient infected with Rickettsia raoultii was found to be carrying Rickettsia raoultii. PCR amplification showed that Rickettsia raoultii was present on the surface of a patient infected with Rickettsia raoultii. Candidatus Rickettsia tarasevichiae infection rate was 8.7% (46/528), Rickettsia raoultii infection rate was 0.6% (3/528) and Rickettsia heilongjiangensis infection rate was 1.3% (7/528) among the free ticks, 46 (46/453) Ixodes carrying Candidatus Rickettsia tarasevichiae, 3 ticks carrying all ditches. Rickettsia raoultii was carried by 3/75 ticks, 1 Ixodes persulcatus (1/453) and 6 ticks (6/75) carried Rickettsia heilongjiangensis, Candidatus Rickettsia tarasevichiae infection rate was 0.9% (5/531) and Rickettsia heilongjiangensis infection rate was 0.2% (1/531) in rodents, including 3 Apodemus AGUS agrarius (3/236) and 1 hamster (1/20). A brown house mouse (1/58) was infected with Candidatus Rickettsia tarasevichiae and a red-backed mouse (1/16) with Rickettsia heilongjiangensis. 5. The study concluded that four species of spotted fever group Rickettsia were prevalent simultaneously in Northeast China. Human infection with Candidatus Rickettsia tarasevichiae and Rickettsia sibirsi was first reported in the world. Rickettsia raoultii Rickettsia is reported for the first time outside Europe. The four types of spotted fever have different clinical manifestations, including flu-like symptoms, multiple organ dysfunction and even death. Doxycycline therapy is effective, but often due to atypical spotted fever symptoms. At the same time, the investigation of ticks and rodents in the habitat confirms that the northeast is the natural focus of the above pathogens. 6. Significance and innovativeness due to frequent misdiagnoses that overlook spotted fever group rickettsiasis, our study further confirms that spotted fever group rickettsiasis is far more common than we thought The three new rickettsiasis reported for the first time in the world or outside Europe have enriched people's understanding of rickettsiasis and provided an important basis for further research on pathogenic rickettsiasis.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R513
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