人畜共患病PPT

这是一个关于人畜共患病PPT，主要是了解鼠疫的概念，鼠疫的三次大流行，鼠疫的传播途径与感染方式，诊断和治疗等内容。 鼠疫（Pestis）是由鼠疫杆菌引起的自然疫源性烈性传染病,也叫做黑死病。临床主要表现为高热、淋巴结肿痛、出血倾向、肺部特殊炎症等。本病远在2000年前即有记载。世界上曾发生三次大流行，第一次发生在公元6世纪，从地中海地区传入欧洲，死亡近1亿人；第二次发生在14世纪，波及欧、亚、非；第三次是18世纪，传播32个国家。14世纪大流行时波及我国。1793年云南师道南所著“《死鼠行》”中描述当时“东死鼠，西死鼠，人见死鼠如见虎。鼠死不几日，人死如圻堵”。充分说明那时在我国流行十分猖獗。

人畜共患病PPT是由红软PPT免费下载网推荐的一款疾病课件类型的PowerPoint.

鼠疫Plague, Black Death ,Bubonic plague
黑死病对于文明来说 是一剂几乎使人类灭绝的猛药。
由鼠疫耶尔森菌引起的，主要由媒介蚤类传播，在温血动物（啮齿类动物为主）间流行的自然疫源性疾病。
Plague is a zoonotic disease circulating mainly among small animals and their fleas.
The bacteria Yersinia pestis can also infect humans. It is transmitted between animals and humans by the bite of infected fleas, direct contact, inhalation and rarely, ingestion of infective materials.
Plague can be a very severe disease in people, with a case-fatality ratio of 30%-60% if left untreated.
烈性传染病也有历史，也是历史的一部分，但它的历史常常被历史学家忽略。
科学家们在寻找预防治疗方法,努力将其消灭的时候，也很少认真考虑其来龙去脉。
烈性传染病史的关键问题是，该病自古就存在，由于某种环境的改变而光顾人类社会？还是由于某种变异而出现新的品种 (Black Death、AIDS、SARS） ？
疾病对人类社会的影响有两种，一种是长期的病害折磨，人类渐渐麻木了，几十年下来，人们开始习惯和病魔共存，衍生出来的 是更多的迷信乃至邪教。而短期的病害则对人类社会造成强大的震动，尤其是精神上的。
鼠疫的三次大流行-世纪瘟疫
第一次大流行：查士丁尼鼠疫
541-542年的查士丁尼鼠疫是历史上第一次纪录的大流行。541年，鼠疫沿着埃及的培鲁沁(Pelusium)侵袭罗马帝国。鼠疫荼毒培鲁沁后，迅速蔓延至亚力山卓，再继续水陆贸易网扩散到首都君士坦丁堡与整个拜占庭帝国。此次流行导致帝国至少1/3人口死亡。严重影响该帝国经济税基与军制兵源，削弱了拜占庭帝国实力。
查士丁尼鼠疫爆发后，从541-717年，鼠疫沿着海陆贸易网扩散到西欧与不列颠。首先是法国，543年法国西南部亚耳爆发鼠疫病情，接着547年鼠疫传染至爱尔兰与不列颠西部，588-590年的一次鼠疫横扫马赛、亚威农(Avignon)，以及法国北部里昂地区的隆河流域(the Rhone Valley)，造成2500万人死亡，鼠疫不止波及英法等国，它使当时整个地中海贸易衰退。更造成许多昔日王国的势力因此消失，并改写整个欧洲的历史。
由于缺乏详细历史记录，时间及病因有一定的推测成分
第二次鼠疫大流行（黑死病）
14世纪30年代始于蒙古草原，先传入中国，据估计杀死30%的中国人口，然后经过蒙古商路传入欧洲和非洲。在欧洲被称为黑死病。三年间杀死欧洲30%到60%的人口。1400年全球人口有4.5亿下降到3.5亿。
这一轮鼠疫流行到1700年才结束，期间定期在欧洲流行，每次流行中死者以10万计。
第二次大流行：黑死病
在1346年到1350年大規模襲擊歐洲，导致欧洲人口急剧下降，死亡率高达30%。黑死病被認為是蒙古人帶來的。約1347年，往來克里米亞與墨西拿（西西里島）間的熱那亞貿易船隻帶來了被感染的黑鼠或跳蚤，不久便漫延到熱那亞與威尼斯，1348年疫情又傳到法國、西班牙和英國，1348—1350年再東傳至德國和斯堪的納維亞，最後在1351年傳到俄羅斯西北部。估計歐洲有約2500萬人死亡，而歐、亞、非洲則共約5,500萬—7,500萬人在這場疫病中死亡。當時無法找到治療藥物，只能使用隔離的方法阻止疫情漫延。此後在十五、十六世紀黑死病多次再次侵襲歐洲；但死亡率及嚴重程度逐漸下降。
有人認為，這場黑死病嚴重打擊了歐洲傳統的社會結構，削弱封建與教會勢力，間接促成了後來的文藝復興與宗教改革。
1352年，黑死病离开欧洲去了中东，其后150年里，每隔6-12年，某个地方就会流行一次。
1500年以后每15-20年出现一次。
1630-1631 威尼斯人口从142804降至98244
1651-1653 巴塞罗那杀死45%的居民
1665年伦敦 死亡55797人 占17%，一场大火结束欧洲的大流行。
1720年法国马赛最后一次鼠疫余波
鼠疫的离去，解除了欧洲文明的最后锁链。1760年开始的工业革命，70年间让欧洲跨入现代社会
1770莫斯科大鼠疫死亡超过10万
。
在中國，明代万历和崇祯二次的大疫相信是這次全球大流行的一部份。据估计，华北三省人口死亡总数至少达到了1000万人以上，崇祯“七年八年，兴县盗贼杀伤人民，岁馑日甚。天行瘟疫，朝发夕死。至一夜之内，百姓惊逃，城为之空”。“朝发夕死”、“一家尽死孑遗”。一些史學家相信，李自成入北京之前，明朝的京營兵士就正遭受鼠疫侵襲，谷應泰在《明史纪事本末》卷78中说“京师内外城堞凡十五万四千有奇，京营兵疫，其精锐又太监选去，登陴诀羸弱五六万人，内阉数千人，守陴不充”。“上天降灾，瘟疫流行，自八月至今（九月十五日），传染至盛。有一二日亡者，有朝染夕亡者，日每不下数百人，甚有全家全亡不留一人者，排门逐户，无一保全。……一人染疫，传及阖家，两月丧亡，至今转炽，城外遍地皆然，而城中尤甚，以致棺蒿充途，哀号满路。”
明朝（1368年1月23日－1644年4月25日[1]）是中国历史上最后一个由汉族建立并长期统治的君主制皇朝，历经十二世、十六位皇帝。明朝初期定都于应天府（今南京），号京师。永乐十九年（1421年），明成祖朱棣迁都至顺天府（今北京），而应天府改称为南京。
明朝建立始于1368年朱元璋推翻蒙古人建立的元朝，在南京建都称帝，国号大明[2]。因明朝的皇帝姓朱，故又称朱明。
明朝初年比较强盛，经过明太祖的洪武之治，精励图强并逐步恢复国力，到明成祖时期国力到达顶峰，是为永乐盛世。其后的明仁宗和明宣宗时期仍处于兴盛时期，史称仁宣之治。虽于明武宗、明世宗开始逐渐中衰，面临社会矛盾与外患，仍有隆庆新政与万历中兴中兴气象。但万历与崇祯年间连年灾荒与战事，各地爆发民变，至1644年明思宗遭受李自成的大顺军队攻占顺天府，明思宗自缢，随后清朝军队击败大顺军并入主中原，至此明朝享国祚276年。但后继南明与明郑政权仍延续了数十年，直到1683年清军占领台湾，明廷宗室才被清军完全灭绝。
明朝的领土曾囊括今日内地十八省之范围。东北初年抵日本海、鄂霍次克海、乌地河流域，后改为辽河流域；初年北达 西喇木伦河一带，后改为今长城；西北至新疆哈密，后改为嘉峪关；并曾在今东北地区、新疆东部、西藏等地设有羁縻机构。明成祖时期甚至短暂征服并统治安南（今越南北部）。
中国的1644年，北京“城头变幻大王旗”
王朝：大明、大顺、大清
人物：朱由检 (崇祯）
                     职业：皇帝                    
           李自成（闯王）
                     职业：造反                  
           吴三桂 （明朝将军）
                      职业：军人
           多尔衮 (清朝实际领导人）
                       职业：造反
  明朝后期大疫病在北方多次流行，山西、河间府、通州、昌平、保定等。
       原因：土地兼并严重，老百姓丢掉土地: 成为流寇或经山西去草原垦荒与草原鼠争夺地盘。
  明朝亡于民不聊生、李闯亡于鼠疫，天下归清也要归功于耗子和它们身上的 小小细菌
1944年郭沫若《甲申三百年祭》
第三次大流行
1855年中國雲南首先發生了大型鼠疫，1894年在廣東爆發，並傳至香港，經過航海交通，最終散佈到所有有人居住的大陸，估計在中國和印度便導致約1200萬人死亡。此次全球大流行一直維持至1959年，全球死亡人數少於250人方才正式結束。
第三次鼠疫大流行
1855年始于中国，1955年结束。首波流行于中国和印度 ，死亡1200万人。
1894年印度大鼠疫，1910-1911年中国东北大鼠疫。
1860年前后战乱中的中国，瘟疫已遍地流行，除霍乱外，安徽等地发生鼠疫，远离战乱的云南也爆发鼠疫，死亡200多万。
    关内民众东北大迁移。
科学家发现鼠疫细菌的竞赛
Louis Pasteur
Born December 27, 1822)Dole, Jura, Franche-Comté, France
Died  Sept. 28, 1895 (aged 72)Marnes-la-Coquette, Hauts-de-Seine, FranceNationality French
Fields ChemistryMicrobiology
InstitutionsUniversity of StrasbourgUniversité Lille Nord de FranceÉcole Normale Supérieure
Alma materÉcole Normale Supérieure
Notable students Charles Friedel
Heinrich Herman Robert Koch
Born      11 December 1843)         Clausthal, Kingdom of Hanover
Died      27 May 1910 (aged 66)          Baden-Baden, Grand Duchy of Baden
Fields     Microbiology
Institutions   Imperial Health Office, Berlin,                        University of Berlin
Alma mater   University of Göttingen
Doctoral advisor  Friedrich Gustav Jakob Henle
Known for       Discovery bacteriology                   Koch's postulates of germ theory
 He became famous for isolating Bacillus anthracis (1877), the Tuberculosis bacillus (1882) and the Vibrio cholera (1883) and for his development of Koch's postulates.
 He was awarded the Nobel Prize in Physiology or Medicine for his tuberculosis findings in 1905. He is considered one of the founders of  microbiology—he inspired such major figures as Paul Ehrlich and Gerhard Domagk.
1894年5月8日香港公立医院代理主管-詹姆斯.劳森确定香港出现鼠疫病例。向欧洲求援
6月31日Alexandre Yersin从河内来到香港
Alexandre Emile Jean Yersin (September 22, 1863–March 1, 1943) was a Swiss physician and bacteriologist. Along with Shibasaburo Kitasato he is remembered as the co-discoverer of the bacillus responsible for the bubonic plague or pest, which was later re-named in his honour (Yersinia pestis).
Yersin was born in 1863 in  Switzerland, to a family originally from France. From 1883 to 1884, Yersin studied medicine at Lausanne, Switzerland; and then at Marburg, Germany and Paris (1884-1886). In 1886, he entered Louis Pasteur's research laboratory at the École Normale Supérieure, by invitation of Emile Roux, and participated in the development of the anti-rabies serum. In 1888 he received his doctorate with a dissertation entitled Étude sur le Développement du Tubercule Expérimental and spent two months with Robert Koch in Germany. He joined the recently-created Pasteur Institute in 1889 as Roux's collaborator, and discovered with him the diphtheric toxin (produced by the Corynebacterium diphtheriae bacillus).
100 years ago, in 1894, Alexandre Yersin discovered the causative agent of plaque in Hong Kong.
Only a few people know that the native Swiss and student of Pasteur and Roux spent nearly 50 years of his life in Vietnam, where he became director of the Pasteur institutes and earned merits by his engagement for the control of communicable diseases in humans and animals.
 He, furthermore, successfully introduced tropical plants such as rubber, cacao, coffee and quinquina tree. In 1943, at the age of 80, Yersin died as a personality venerated by all classes of the vietnamese population.
He studied under Dr. Robert Koch in University of Berlin from 1885 to 1891. In 1889, he was the first person to grow the tetanus bacillus in pure culture, and in 1890 cooperated with Emil von Behring in developing a serum therapy for tetanus using this pure culture. He also worked on antitoxins for diphtheria and anthrax. Kitasato and Behring demonstrated the value of antitoxin in preventing disease by producing a passive immunity to tetanus in an animal that received graded injections of blood serum from another animal infected with the disease.
After returning to Japan in 1891 he founded the Institute for Study of Infectious Diseases with the assistance of Fukuzawa Yukichi. One of his early assistants was August von Wassermann. Kitasato demonstrated how dead cultures can be used in vaccination. He also studied the mode of infection in tuberculosis.
He traveled to Hong Kong in 1894 at the request of the Japanese government during an outbreak of the bubonic plague, and unsuccessfully identified the bacterium causing the disease; his results were not as widely disseminated as Yersin's, however, Yersin was for many years given primary credit for the discovery, and the bacterium was named after him. Four years later, Kitasato and his student Kiyoshi Shiga were able to isolate and describe the organism that caused dysentery.
字联星，祖籍广东新宁县(今台山)，1879年３月10日出生于马来亚槟榔屿（今马来西亚的槟城州
1896—1899年留学英国剑桥大学意曼纽学院。
1899—1902年考入圣玛丽医院实习。
1902—1903年在英国利物浦热带病学院、德国哈勒大学卫生学院及法国巴斯德研究所实习、研究。
1903年，获英国剑桥医学博士学位。后返回原马来亚，在吉隆坡医学研究院从事热带病研究。1904年在马来亚槟榔屿开设私人诊所。1907年应邀赴英国伦敦参加由神学博士文英兰主持的禁鸦片烟会议。
1908年，受清政府邀聘回国任教，担任天津陆军军医学堂副监督（副校长职）。
1910年12月东北发生鼠疫大流行，清政府任命伍连德为东三省防鼠疫全权总医官，到哈尔滨进行调查、防治。
1911年４月出席在奉天（今沈阳）召开的万国鼠疫研究会议，任会议主席。1912年在哈尔滨筹建东三省防疫事务总管理处及附属医院。
1915年建立中华医学会，任书记并兼任《中华医学杂志》总编辑。
1916年任黎元洪总统特医及京汉、京张、京奉、津浦四条铁路总医官。当选为中华医学会会长，并兼任公共卫生部委员。
1918年任北洋政府中央防疫处处长、北京中央医院（今位于白塔寺的北京医科大学人民医院分院）院长。
1919年１月代表外交部到上海监督焚烧鸦片。哈尔滨流行霍乱，伍连德利用防疫医院收治2000余名病人。
1920年去美国约翰·霍普金斯大学进修学校卫生和公共卫生。
1922年受奉天督军张作霖委托，在沈阳创建东北陆军医院。
1923-1924年获美国约翰·霍普金斯大学公共卫生硕士学位、上海圣约翰大学名誉科学博士学位、日本东京帝国大学名誉医学博士学位、苏联科学院名誉院士及苏联微生物学会外国会员。
1926年创办哈尔滨医学专门学校（哈尔滨医科大学前身），任第一任校长。
1927年国际联盟卫生处聘伍连德为该处中国委员，并授予鼠疫专家称号。出席国际联盟在印度召开的第七次远东热带病学会，被选为副主席。
1930年任上海全国海港检疫管理处处长、技监，兼任上海海港检疫所所长。1931年代表南京国民政府卫生署刘瑞恒署长出席国际联盟卫生会议。在上海主持召开第一届检疫学术研究会。1937年４月任中华医学会公共卫生学会会长。
八一三事变，举家重返马来亚，定居怡保市，开设私人诊所。1960年１月21日病逝于马来亚槟榔屿，享年82岁。
东北大鼠疫是人类对旱獭死死相逼的结果。
人类活动无限制的扩张、贪婪地索求引发某些共患病的蔓延和扩散、酿成系列的人间悲剧！
Geographic Distribution: Natural foci of infection persist on nearly all continents. They do not exist in Australia, New Zealand, or New Guinea
China seals off town amid plague outbreak updated 9:42 p.m. ET Aug. 3, 2009 Associated Press
BEIJING - An outbreak of pneumonic plague in a remote farming town in northwestern China has killed a third person, the official Xinhua News Agency said Tuesday, as authorities locked down the town and moved to disinfect the region.
Police set up checkpoints around Ziketan in Qinghai province after the outbreak was first detected last Thursday. The lung infection can kill a human in 24 hours if left untreated. Townspeople reached by The Associated Press by phone said the streets were largely deserted and most shops shut.
The latest victim was a 64-year-old man named Danzhi, Xinhua said. He was a neighbor of a 32-year-old herdsman in Ziketan and a 37-year-old man who died earlier. A further nine people — mainly relatives of the herdsman — are infected and in a hospital, according to the local health bureau.
Of those, one is in a serious condition and one other has developed symptoms of coughing and chest pain, but there have been no reports of new infections, Xinhua said.
The local government has sealed off the town, and medical staff are disinfecting the region and tracking down those who have been in close contact with those affected, it said.
Authorities urged anyone who had visited the town of 10,000 people since mid-July and has developed a cough or fever to seek hospital treatment..
病原 Causative agent
日本学者Kitassato和法国学者Alexandre J. Yersin于1894年在香港分离到病原
分类归属
    肠杆菌科、耶尔森菌属、鼠疫耶尔森菌种
     两个亚种：Yersinia pseudotuberculosis pestis
                       Y. pseudotuberculosis pseudotuberculosis
 形态： 卵圆形短杆菌 1-2 um x 0.5-0.7 um,
              有荚膜， G-
鼠疫菌的抗原与毒力因子
封套抗原（ F1, Fraction 1) 位于菌体周围的多糖蛋白复合物。
   温度（37C）、CO2、甘氨酸、人血液促进其产生、毒力强产量高。
V和W 抗原  毒力抗原的一种
菌体抗原  非特异性性抗原
鼠疫菌毒力决定因子：
    F+/F-
   VW+/VW-
    依赖钙离子或嘌呤化合物作营养源
    产色素能力
    产鼠疫毒素能力
鼠疫菌毒素：
   鼠毒素(murine toxin)   一种可熔性毒蛋白（外毒素）
   作用于血管及淋巴管内皮细胞引起炎症、坏死、出血、致死性休克、毒血症而导致器官衰绝。对鼠心肌线粒体有选择性毒性作用。
  内毒素
流行病学
流行病学
动物鼠疫流行病学
   自然疫源地判定标准：
   1）具有适宜于各类鼠疫疫源地存在的相应景观；
   2）在该景观内有连续成片分布的主要动物宿主，其种群覆盖度通常占该景观20%以上，其密度高且稳定；
  3）主要宿主的主要媒介，蚤指数应≥1；
  4）在该景观内的主要宿主或其主要体外寄生虫体内检出鼠疫菌。
鼠疫自然疫源地世界分布
   我国鼠疫自然疫源地的分布特点：
    鼠疫自然疫源地分布在19 个省区273 个县(旗),各疫源地疫情发生发展差异不一。
1、疫情稳定性疫源地:
    呼伦贝尔高原蒙古旱獭疫源地：1910-1921年间东北两次鼠疫大流行时被波及。建国后至今，在疫源地进行细菌学检验旱獭11550 余只，均为阴性，未发生人、动物鼠疫，疫源地疫情处于静息状态。但这块疫源地的俄罗斯和蒙古的部分地区，仍有动物鼠疫发生流行，为此，今后要加强监测，密切注视疫情，防止疫源传入，防患于未然。
2 、疫情活跃性疫情地
1） 青藏高原喜马拉雅旱獭疫源地
1966 年西藏在日喀则地区仲巴县首次确诊人间鼠疫后到2000 年共发生#18 起人间鼠疫，腺鼠疫，传播途径为食肉和剥皮。新的疫源县不断出现，疫源地面积也在扩大增加。
2）内蒙古高原长爪沙鼠疫源地
内蒙古杭锦后旗、陕西定边、宁夏灵武
3）锡林郭勒高原布氏田鼠疫源地
4）滇西居民区黄胸鼠疫源地
5）天山山地灰旱獭、长尾黄鼠疫源地
6）松辽平原达乌尔黄鼠疫源地
7）青藏高原青海田鼠疫源地
3、疫情偶发性疫源地
阿拉善黄鼠、长尾旱獭和大绒鼠、齐氏姬鼠疫源地，疫情波动不稳，处于疫情稳定的上峰期和疫情活跃的下峰期
青藏高原和天山山地的鼠疫疫源地相对比较活跃，鼠疫动物病每年都有流行。
滇、黔、桂黄胸鼠鼠疫发病有上升趋势。
宿主
主要宿主  在长期保存鼠疫菌中起决定性作用的宿主。优势种、密度高、数量大、分布广、易感。
     达乌尔黄鼠、阿拉善黄鼠、长尾黄鼠、蒙古旱獭、灰旱獭、红旱獭、喜马拉雅旱獭、黄胸鼠、长沙沙鼠、大绒鼠、齐氏姬鼠、布氏田鼠和青海田鼠。
次要宿主  在疫源地中经常参加鼠疫动物病的流行，但对保持鼠疫疫源地中的长期存在不起主要作用的温血动物。家栖或半家栖鼠类：褐家鼠、小家鼠、黑家鼠等
偶然宿主 疫源地中有些数量比较少的啮齿类和食肉动物。跳鼠、野兔、狐、鼬、貂、猫等偶尔可感染鼠疫
223种啮齿类动物
媒介
在鼠疫疫源地，鼠疫菌主要通过蚤类在宿主动物间传播。
我国已发现59种节肢动物可以自然感染鼠疫菌
51种蚤类、4种蜱类、2种螨类、2种虱类
动物鼠疫流行病学特点及影响因素
长时间的间断性以及经过一段时间的间歇期后再次爆发流行的突然性。
影响因素包括：
        宿主和媒介（数量）
        病原体（自然弱毒的出现）
        自然和人为因素
        非生物因素地理因素，如水文、地质、气象和太阳黑子活动等
人类鼠疫流行病学
传染源
    1、野生动物作为传染源 （10-100万CFU/ml血液）
    ★寄生蚤在吸血后，鼠疫菌在蚤的前胃中繁殖形成菌栓，逐渐堵塞消化道而使蚤处于饥饿状态，从而更加频繁吸血，冲刷菌栓，因不能进入后面的消化道而只能反吐回去。栓塞蚤每次反吐可吐出2.5-10万个鼠疫菌。
    ★捕杀旱獭等
  2、家畜作为传染源  藏系绵羊、藏黄羊、山羊、骆驼、家兔、猫和犬。
   3、人作为传染源--鼠疫肺炎咳嗽
流行特征
   ★地域性
   ★季节性及与职业关系
预防、监测与控制
预防
    原则：针对传染病流行的三环节
    灭鼠灭蚤
    卫生检疫
鼠疫的监测
监测类型及标准
动物鼠疫监测在世界上大致分为2 类:
  ★以中国和俄罗斯为代表的主动监测;
 ★以美国为代表的被动监测 ,只有在高危险区啮齿类动物发生变化、出现人间病例或在食肉动物中检出抗体阳性血清时才进行主动监测。
中国制定了《中国动物鼠疫监测标准》[ GB 1688221997 ] ,作 为各类鼠疫疫源地进行动物鼠疫监测依据,规范监测工作。
监测方式
根据全国鼠疫监测工作方案,鼠疫疫源地的动物鼠疫监测以固定监测点和流动监测点相结合的方式进行。在那些地广人稀、但鼠疫又活跃的地区,需要重点加强流动监测,并为这种类型的监测工作设计合理的巡回路线,以扩大监测覆盖面。
监测内容
　宿主动物监测　主要监测啮齿类宿主动物的异常情况、种群结构、密度、季节变动等方面的内容。宿主动物的异常,主要由专业人员和群众目测观察获得。我国的“疫情三报”(包括在监测期间发现自毙鼠及其他自毙动物,疑似鼠疫病例,不明原因的高热急死病例) ,是一项控制人间鼠疫发生及早期发现疫情的有效措施
     媒介监测　动物鼠疫的主要传播媒介为蚤类,蚤类的种群数量、生态习性、季节消长直接关系到动物鼠疫发生、流行的时间和强度。
病原学和血清学监测　是鼠疫监测的重要部分,可为确定或追溯鼠疫发生,探索鼠疫自然疫源地鼠疫菌保存机制和预测预报等服务。
     主要在宿主、媒介、疑似病例、指示动物中进行,将捕获宿主的血清学和病原学及其寄生蚤病原学监测作为重点。国内研究认为鼠疫细菌学监测应以自毙鼠为主。指示动物在我国主要是犬、猫、猪等。
其他监测　鼠疫流行是病原体、宿主、媒介、人文环境和地理环境相互作用的结果,同时生态系的改变直接影响动物鼠疫流行的变化
临床表现
潜伏期1-6天， 多为2-3天
严重的全身中毒症状，发病急剧、恶寒颤栗、高烧39-40C（呈稽留热），头剧疼并可能出现中枢性呕吐、头晕和呼吸急迫很快进入极度虚弱状态。
临床表现型：
     腺鼠疫
     肺鼠疫
     鼠疫败血症
     皮肤鼠疫
     脑膜炎型鼠疫
     眼鼠疫
     肠鼠疫
     扁桃体型鼠疫
诊断
临床诊断
 原则：
  患者有流行病学线索并具有鼠疫临床症状；
  鼠疫细菌学诊断阳性或被动血凝试验（PHA）血清F1抗体诊断阳性。
诊断标准
   发病前10天有与病原接触史；
   突然发病并表现相关症状；
   患者穿刺液或分泌液分离到鼠疫菌；
  患者2次采血清（间隔10天）PHA检测F1抗体呈4倍增长。
CDC Diagnosis:
The typical sign of the most common form of human plague is a swollen and very tender lymph gland, accompanied by pain. The swollen gland is called a "bubo." Bubonic plague should be suspected when a person develops a swollen gland, fever, chills, headache, and extreme exhaustion, and has a history of possible exposure to infected rodents, rabbits, or fleas. A person usually becomes ill with bubonic plague 2 to 6 days after being infected.
When bubonic plague is left untreated, plague bacteria invade the bloodstream. As the plague bacteria multiply in the bloodstream, they spread rapidly throughout the body and cause a severe and often fatal condition. Infection of the lungs with the plague bacterium causes the pneumonic form of plague, a severe respiratory illness. The infected person may experience high fever, chills, cough, and breathing difficulty and may expel bloody sputum. If plague patients are not given specific antibiotic therapy, the disease can progress rapidly to death. About 14% (1 in 7) of all plague cases in the United States are fatal.
Laboratory Test Criteria for Diagnosis of Plague
SUSPECTED PLAGUE SHOULD BE CONSIDERED IF THE FOLLOWING CONDITIONS ARE MET:
1. Clinical symptoms that are compatible with plague, i. e., fever and lymphadenopathy in a person who resides in or recently traveled to a plague-endemic area.
2. If small gram-negative and/or bipolar-staining coccobacilli are seen on a smear taken from affected tissues, e.g.:
Bubo (bubonic plague)
Blood (septicemic plague)
Tracheal/lung aspirate (pneumonic plague)
PRESUMPTIVE PLAGUE SHOULD BE CONSIDERED WHEN ONE OR BOTH OF THE FOLLOWING CONDITIONS ARE MET:
If immunofluorescence stain of smear or material is positive for the presence of Yersinia pestis F1 antigen.
If only a single serum specimen is tested and the anti-F1 antigen titer by agglutination is >1:10.*
CONFIRMED PLAGUE IS DIAGNOSED IF ONE OF THE FOLLOWING CONDITIONS IS MET:
1.If a culture isolated is lysed by specific bacteriophage.
2.If two serum specimens demonstrate a four fold anti-F1 antigen titer difference by agglutination testing.*
3.If a single serum specimen tested by agglutination has a titer of >1:128 and the patient has no known previous plague exposure or vaccination history.*
*Agglutination testing must be shown to be specific to Y. pestis F1 antigen by hemagglutination inhibition.
实验室诊断
细菌学诊断
    取材-  患者的渗出液、血液、脑脊髓液等
               鼠的脾脏、肝脏和血液等
               昆虫
    分离培养
血清学诊断
   间接血凝试验
   细菌凝集反应
   免疫荧光
    ELISA
分子生物学诊断
Human specimens:
Specimens should be obtained from appropriate sites for isolating the bacteria.
The preferred specimen for microscopic examination and isolation from a bubonic case is material from the affected bubo, which should contain numerous organisms.
Blood cultures should be taken whenever possible.
 In cases where live organisms are unculturable, e.g., in specimens taken postmortem, lymphoid tissues, lung and bone marrow samples may yield evidence of plague infection by FA test or by detection of Y. pestis DNA.
Specimens intended for culture should be taken before initiation of antibiotic treatment.
Specimens are inoculated on general laboratory media and into laboratory mice for isolation; a thin smear is made from the remaining materials for examination by fluorescent microscopy. If a specimen is suspected to contain mixed flora, passage of the material through laboratory mice will increase the likelihood of recovery of a pure Y. pestis culture.
Plague bacilli express a unique diagnostic envelope glycoprotein called the Fraction 1 (F1) antigen or capsular antigen at >33°C; this unique envelope antigen is the primary target antigen used for plague diagnostic FA and antibody tests.
Plague bacilli are susceptible to lysis by a specific bacteriophage at both 25°C and 37°C.
 If a patient has been treated with a static antibiotic (e.g., tetracycline) for more than 4 days, bacterial cultures should be incubated for more than 5 days to give organisms a chance to recover.
 In case cultures yield negative results, serologic testing is advised. One serum specimen should be taken as early in the illness as possible to be followed by a second sample 1-4 months after antibiotic therapy has ceased.
Animal/flea specimens:
 Lymphoid tissues should be removed for testing of the presence of F1 antigen by FA and by culture.
Bone marrow from dessicated animal carcasses may yield positive results when other tissues are not available.
 In addition, serum and blood specimens may be taken for detection of antibody by agglutination.
Fleas should be identified and may be placed in pools for tituration and examination. Titurated flea materials may be inoculated into laboratory mice for isolation of plague bacteria and for examination of mouse tissues by FA for expression of F1.
Fleas or flea pool material may be directly examined by FA if the samples are pre-incubated at 37°C for 24 hours to encourage F1 antigen expression.
The serum from inoculated laboratory mice may be examined for presence of antibody to F1.
For serosurveillance of plague in animal populations, blood may be soaked and dried onto filter paper strips and sent to the laboratory for the detection of F1 antibody.
In cases where no cultures or serum specimens are available for testing, both animal and flea material may be tested by polymerase chain reaction (PCR) to determine if plague DNA is present in the specimens.
Vaccines
Current
The existing Killed whole cell vaccines (KWCV)  for plague comprises heat-killed bacteria,in aqueous medium incorporating a preservative such as phenol.
It requires multiple immunising doses and is reactogenic. The primary immunisation schedule comprises an initial sub-cutaneous 0.5 ml dose, followed by a 0.5 ml booster dose at 1–4 weeks and every 6 months thereafter.
Additionally, production of the vaccine involves microbial culture within containment which is costly, hazardous and restricts manufacturing location. These factors have led to research into an improved vaccine.
Recombinant vaccine candidates
the Fraction 1 (F1) and V (virulence) proteins which as virulence factors are pivotal in preventing phagocytosis of, and inregulating type three secretion (TTS) by the bacteria, respectively.
土拉杆菌病 tularemia
一、病名定义与历史概述
      土拉杆菌病是由土拉杆菌引起的一种高度传染性的自然疫源性疾病，曾称为“野兔热”。
Synonyms: Francis disease, deer-fly fever, rabbit fever, Ohara’s disease, hare fever
      该病最早由McCoy于1911年正式报道。1914年在美国Ohio确定了首例人感染，到1919年美国科学家Edward  Francis从California的Tulare地区啮齿动物流行爆发中分离到该菌。
      为纪念Edward  Francis在该病研究所作出的先驱性工作以及突出的贡献，后人将该细菌命名为Francisella tularensis。
该病在北美、欧洲和亚洲均有报道，1960年以前一直呈较高的流行态势。
近年来，在欧美各国的发病数呈明显的下降趋势，美国有2000年前的每年感染病例约200-500个下降到目前每年约50个感染病例。
我国于1957年首次在内蒙古通辽地区黄鼠分离到细菌。
1959年首次在黑龙江省哈拉海屯14人因直接和间接接触野兔和鼠而爆发土拉杆菌病。
在青海、西藏和新疆发现多个自然疫点和感染病例，特别是西藏波密县易贡地区居民变态反应阳性率为8.43%，牛血清凝集反应阳性率高达80.9% (72/89) 。
值得注意的是在内陆地区的山东胶南某食品加工厂1986年1月发生一起典型的人间土拉弗氏菌病爆发流行，在短短10天内兔肉加工车间86％（31/36）的操作工人显性感染发病，表现为突然发病和持续高热，平均病程为11天。
由于该菌具有高度的传染性，对人具有很强的致病力，经呼吸道感染10个细菌即可引起发病和死亡，因此一直被用作潜在的生物武器。
1940至1960年代美国和前苏联一直将其作为生物武器储备。第二次世界大战期间，臭名昭著的日本731部队曾在中国对中国公民开展人体试验。
世界卫生组织（WHO）美国疾病控制中心（CDC）曾预测，如果用50公斤土拉杆菌作为生物武器对一个有500万人口的城市发动袭击可造成25万人感染，约19000人死亡。每10万感染者造成的经济损失为54亿美元，其危害可能高于其他生物武器。
美国CDC将其列为A类生物武器病原。
二、病原学
土拉杆菌为革兰氏阴性球杆菌，为严格的细胞内寄生。
属弗朗西丝菌科（Francisellaceae）弗朗西丝菌属。
    目前在该属包括2个种：
        土拉弗朗西丝菌（ Francisella tularensis）
        菲洛米拉弗朗西丝菌(F. philomiragia)。
土拉弗朗西丝菌包括4个亚种：
1）土拉弗朗西丝菌土拉亚种（ F.  tularensis subsp. tularensis）     主要分布于北美、北欧、墨西哥，为毒力最强的亚种。人经呼吸道感染10个细菌即可引起发病，致死率高于30%；少于5个细菌可以100%致死小白鼠，属严格的生物安全3级病原微生物。
      该亚种又进一步分为A1和A2两个亚群。在美国A1亚群菌株主要分布于东部地区，而A2亚群则主要分布于西部。
2）土拉弗朗西丝菌全北区亚种（ F.  tularensis subsp. holarctica）, 主要分布于北美、欧洲、亚洲。对人具有较强的致病性，但比A型菌株毒力低。
3）土拉弗朗西丝菌中亚亚种（ F.  tularensis subsp. mediasatica）。该菌目前仅报道于前苏联的中亚加盟共和国，分自于野兔、沙鼠和蜱，对该菌目前缺乏详细的鉴定资料，但其致病性似乎明显比A型弱。
4）土拉弗朗西丝菌novicida亚种（ F.  tularensis subsp. novicida）。对小鼠具有强的致病力，但对人无致病性。
菲洛洛米拉弗朗西丝菌(F. philomiragia)，或意译为爱蜃景弗朗西丝菌
    主要分自于水、麝鼠和人。鱼类也有感染类似菌的报道
培养特性
土拉弗朗西丝菌为专性需氧菌，最适生长温度为35-37C，5%CO2环境有助于细菌生长。
     该对营养要求相对较高，生长速度缓慢。在普通琼脂培养基上不易生长，采用Mueller-Hinton培养基、胰酶大豆琼脂（TSA）、胱氨酸心琼脂、GC琼脂II做基础培养基，添加1%牛血红蛋白、1% 葡萄糖和0.1%L-半胱氨酸及1% IsoVitalex后生长良好。
     液体培养可采用添加1% 葡萄糖和0.1%L-半胱氨酸及1% IsoVitalex 的MH肉汤或Chamberlain氏培养基。
土拉弗朗西丝菌novicida亚种和菲洛米拉弗朗西丝菌对培养基的营养要求相对较低，易于分离培养。
流行特点 Epidemiology
土拉杆菌的传播模式
流行特点
自然条件下，土拉弗朗西丝菌的宿主范围非常广泛，可感染至少100多种哺乳动物和20多种鸟类。啮齿类和兔形目动物可能是主要的储存宿主和传染来源，包括野兔、田鼠、麝鼠，其中A型多见于兔形目动物，B型多见于啮齿类。
野兔和麝鼠对土拉弗朗西丝菌非常敏感，感染后大部分死亡，因此能否长久带菌仍不能完全确定。
      欧洲一些地区观察发现，野兔流行本病期间，同一地区先有田鼠流行，因此推测多数地区的感染人的主要传染源虽然是野兔，但保菌宿主更可能是鼠类。体表寄生虫在动物之间不断传播细菌对于细菌能在宿主动物群内长时间存在起着很重要的作用，而蜱类很可能是病原体能够在疫源地长期存在的保菌宿主。
在欧洲，多起感染的爆发都与水源污染有关，并且从水和淤泥中检测到土拉弗朗西丝菌
节肢动物，包括虻、跳蚤、虱子、蜱、蚊子和蝇均可传播本病。鼠间和野兔间的流行主要通过这些吸血节肢动物传播，尤其是蜱。疫源地的家畜和家禽也可能被感染。
我国曹务春等对采用PCR技术我国吉林、新疆、黑龙江内蒙古和浙江等地14种啮齿动物样品进行检测发现总体感染率为4.76%，除浙江的样品全部阴性外，阳性率分别为11.65%、10%、 6.54%和1.76%。
吉林省成年革蜱的阳性率为3.67%、黑龙江和内蒙古硬蜱的阳性率分别为2.25%和3.0%。
对20个阳性样品的PCR产物进行序列分析证明，感染的菌株为土拉弗朗西丝菌全北区亚种。
本病可通过多种途径传播给人包括：
1）直接接触感染动物的尸体、排泄物或污染的水体。我国报道的的人间感染病例很多与狩猎和加工野兔有关。
2）经呼吸道和眼结膜感染带有细菌的气溶胶和粉尘。如堆积或加工被污染的干草等可发生呼吸道吸入感染。
3）经吸血昆虫叮咬感染。目前尚未发现有人与人之间直接感染传播的报道。
临床症状
人感染发病的潜伏期为1-15天不等，平均为3-5天。表现为突然发病，体温迅速升高，同时怕冷，全身疼痛和头疼。根据感染途径的不同土拉杆菌病可分为：
腺型和腺溃疡型土拉杆菌病：主要通过吸血昆虫叮咬、直接接触感染动物或通过接触被动物污染的用具或垫料而间接感染。病变主要见于接触细菌的部位，首先形成丘疹，周边有明显的炎性反应带，随后形成脓肿。感染后的几天内，体温升高、局部淋巴结肿大，变硬，表面皮肤发红和水肿。
眼腺型土拉杆菌病：比较少见，主要细菌通过结膜感染引起。除了发热和全身症状外，可见单侧结膜、眼睑红肿，流泪和畏光等。
咽喉型土拉杆菌病：主要通过口腔摄入被污染的饮水和食物感染。主要表现为口炎和咽喉炎，也可能伴有扁桃体炎。有时可见口腔和咽喉黏膜化脓性病变和一侧性淋巴腺炎。
呼吸型土拉杆菌病：为最严重和致命性感染，主要是吸入含有细菌的气溶胶感染。有典型的肺炎症状，如咳嗽、胸痛、呼吸频率增加，也可能仅表现高热和全身性症状，如恶心和呕吐。A型强度感染表现为突然发病、怕冷、高热、呼吸困难、咳嗽、胸部疼痛、头疼、出汗和身体虚弱，表现某些伤寒热的特征，出现神志紊乱。相比较而言，B型呼吸道感染的肺炎症状相对较轻，但X光检查可见肺脏病变。
Human infection
--Ulceroglandular tularemia— infection through the skin or mucous membranes
--Ocularglandular tularemia—direct contamination of eye with the bacterium
--Oropharyngeal tularemia—ingestion of   contaminated water or food
--Typhoidal tularemia—severe systemic infection
--Respiratory tularemia —infection by inhalation
动物感染
诊断
    局部皮肤出现红肿、溃疡、单侧淋巴结重大，结合流行病学资料和职业特点。
    特别是有与野兔或野鼠接触史，或者被吸血昆虫，尤其是蜱叮咬过等对诊断具有重要的参考价值。对可疑病例可采用下面的方法进行确诊。
细菌分离培养  
  1）由于土拉弗朗西丝菌营养要求比较高，生长缓慢，在临床诊断中很少进行细菌分离培养。
  2）在进行实验诊断时应采取严格的实验室生物安全措施。
  3）样品的运送和保存是细菌分离成功与否的关键。
     对新鲜的淋巴结和组织可冻存于-80C，或用改良的Thayer-Martin培养基运送到相关实验室。也可就地将养品，以脾脏和肝脏组织为佳，划线接种到添加了9%巧克力化绵羊血的胱氨酸心琼脂上，密封后在常温下2-3天运送到实验室进行培养。为了减少污染，提高分离率，可以在培养基中添加多黏菌素、林可霉素和两性霉素等抑制杂菌生。
4）对生长的菌落可采用玻片凝集或免疫荧光染色进行鉴定，也可采用PCR技术检测fopA或tul4基因。
血清学诊断 
  ★试管凝集或微量凝集试验具有很高的敏感性和特异性。人在发病后2周抗体效价可达到320-1280。临床康复后血清抗体下降很慢，20年后还能检测到抗体。
  ★作为诊断，应采取双份血清进行检测，一份为发病急性期血清，另一份为3周后血清，如果抗体效价增加4倍即可确诊。
 ★当出现土拉杆菌病的临床症状，而且血清效价高于160，也可以确诊。
 ★血清效价较低时，可能为非特异性的交叉反应，应注意排除布氏杆菌病和耶尔森菌病。此外，还可采用ELISA检测抗体。
直接免疫学方法检测抗原 
   可以采用免疫荧光抗体染色方法检测尸体或剖检样品中的细菌抗原，但该方法不太适合人土拉杆菌病的诊断。但ELISA方法可以用于组织、分泌物和环境（如水和淤泥）中抗原的检测。
分子生物学检测 
    PCR技术目前已广泛用于土拉杆菌病诊断和鉴定，具有很高的敏感性和特异性，可用于多种样品的检测。目标基因有fopA、tul4和16S rRNA基因等。荧光实时PCR还可用于不同亚种的检测。
鹦鹉热 Psittacosis
History
In 1879, psittacosis or parrot fever was documented for the first time when Ritter (1880) described an epidemic of unusual pneumonia associated with exposure to tropical pet birds in seven individuals in Switzerland.
In 1907, Halberstaedter and von Prowazek were the first to make drawings of chlamydia-infected conjunctival cells of trachoma (Chlamydia trachomatis) patients.
In the following years, similar infective agents causing inclusion conjunctivitis of the newborn or infection of the adult genital tract were described. The inability to grow these germs, in fact C. trachomatis organisms, on artificial media made scientists assume that they were viruses.
During the winter of 1929–1930, a pandemic of human psittacosis (occurred in the United States and Europe.
The disease was attributed to the importation of Green Amazon parrots from Argentina. Shortly afterwards, 174 cases of human psittacosis were reported from the Faroe Islands in the period from 1930 to 1938. The human death rate was 20% and was especially high (80%) in pregnant women. Humans contracted the infection while capturing juvenile fulmars (Fulmarus glacialis) and preparing them for cooking.
病原学 etiology
分类 classification
衣原体科(Chlamydiaceae)
    衣原体属(Chlamydia)
         沙眼衣原体(C. trachomatis)
         猪衣原体( C.suis)
         鼠衣原体( C. muridarum)
    嗜性衣原体属(Chlamydophila)
         鹦鹉热嗜性衣原体(C. psittaci)
         肺炎嗜性衣原体( C. pneumoniae)
         反刍动物嗜性衣原体( C. pecorum)
         流产嗜性衣原体( C. abortus)
         猫嗜性衣原体( C. felis)
         豚鼠嗜性衣原体( C. caviae)
Morphology
   Morphologically distinct forms of  Chlamydophila are termed elementary body (EB,始体), The EB is a small, electron-dense, spherical body, of about 0.2–0.3 mm in diameter
The reticulate body (RB 网状体is larger, measuring approximately 0.5–2.0 mm in diameter.
   During this maturation, morphologically intermediate body (IB，中间体measuring about 0.3–1.0 mm in diameter can be observed inside the host cell.
Model of chlamydial cell wall or envelope
衣原体(Chlamydiae) 广泛分布于世界各地,引起动物和 人的多种疾病,特别是鹦鹉热嗜性衣原体( Chlamydophila psittaci , C. p) 和流产嗜性衣原体( C. abortus) ,可由动物传染 给人,导致严重的人兽共患病(zoonotic infections) 。
衣原体 是专性细胞内寄生菌,具有独特的两阶段生活方式,即细胞 外感染期和细胞内寄生期,致使由其所引发的各种病症很难 控制。
感染人的最重要的动 物衣原体病是鹦鹉热(psittacosis) ,该病是鹦鹉鸟类的一种 全身性疾病,可表现为急性、亚急性、慢性或亚临床性。
Infection biology
C. psittaci is an obligate intracellular bacterium（专性细胞内寄生） replicating within a non-acidified vacuole, termed an inclusion（包涵体）.
Within the inclusion, C. psittaci undergoes a unique biphasic developmental cycle alternating between the EB, which guarantees extracellular survival and infection of host cells and RB, which is responsible for intracellular replication and generation of infectious progenitor bacteria.
EBs
Attachment (黏附）
Endocytosis（内吞）
Aggregate at Golgi region
(Microtubule Organizing Center)
Differentiate into RBs（分化）
Replicate by binary fission（二分裂繁殖）
RBs detach from inclusion membrane
     (IBs + RBs)
first few hours: EBs differentiating ( losss infectivity)
20 h PI : active replicating (1:1000)
50 h PI: inclusion lysing
Persistence infection（持续感染）
Persistent chlamydiae fail to complete their development from RBs into infectious EBs, but retain metabolic activity.
Persistent RBs appear morphologically aberrant from oval shaped to strongly enlarged and form small inclusions. While they accumulate chromosomes because of continuing DNA replication, they do not divide.
Persistent growth forms have been associated with chronic infections.
Avian chlamydiosis
All known avian strains belong to the species C. psittaci, which comprises six avian serovars(血清型） A to F, and two mammalian isolates, WC and M56
     (The isolates WC and M56 originated from epizootics in cattle and muskrats（麝鼠）, respectively.)
The avian serovars are relatively host-specific.
Serovars A and B are usually associated with psittacine birds and pigeons.
     The natural hosts of the other serovars are more uncertain.
     Serovar C has primarily been isolated from ducks and geese
     Serovar D mainly from turkeys.
     Serovar F was isolated from a psittacine bird and from turkeys.
     The host range of serovar E is the most diverse among these types, as it was isolated from about 20% of pigeons, from many cases of fatal chlamydiosis in ratites, from outbreaks in ducks and turkeys, and occasionally from humans.
All serovars should be considered to be readily transmissible to humans.
Epidemiology流行病学
C. psittaci infections were not limited to psittacine birds, but could also affect other avian species.
   C. psittaci has been demonstrated in about 465 bird species comprising 30 different bird orders .
 The highest infection rates are found in psittacine birds (Psittacidae) and pigeons (Columbiformes).
The  prevalence（感染率） in psittacine birds ranges between 16 and 81%, and a mortality rate of 50% or even higher is not unusual.
Psittacidae are major reservoirs of chlamydiae, especially under captive  conditions, but also among those kept as pets.
Data on the seropositivity of racing pigeons range from 35.9 to 60%.
    Free-living pigeons are present in urban and rural areas all over the world and get in close contact with people in public places.
Thirty-eight studies on the seroprevalence of C. psittaci in feral pigeons conducted from 1966 to 2005 revealed a seropositivity rate ranging from 12.5 to 95.6%
More recent studies performed in feral pigeons in Italy, Bosnia and Herzegovina, and Macedonia showed a seropositivity of 48.5%, 26.5% and 19.2%, respectively
Birds living on sea shores and other waters, such as gees, ducks, gulls and penguins are more frequently infected than hens, pheasants and quails
 Common reservoirs of C. psittaci include wild and feral birds, such as sea gulls, ducks, herons（苍鹭）, egrets（白鹭）, pigeons, blackbirds, grackles（鹩哥）, house sparrows, and killdeer, all of which freely intermingle with domestic birds.
 Highly virulent strains of C. psittaci can be carried and extensively excreted by sea gulls and egrets without any apparent effect on the hosts themselves.
Transmission between birds鸟间传播
排毒方式
Transmission of C. psittaci primarily occurs from one infected bird to another susceptible bird in close proximity.
The agent is excreted in faeces and nasal discharges.
 Faecal shedding occurs intermittently and can be activated through stress caused by nutritional deficiencies, prolonged transport, overcrowding, chilling, breeding, egg laying, treatment or handling.
排毒期
Bacterial excretion periods during natural infection can vary depending on virulence of the strain, infection dose and host immune status.
However, shedding may occur for several months.
Mode of transmission
传播方式 Transmission of chlamydiae occurs mainly through inhalation（吸入） of contaminated material and, sometimes ingestion.
Large numbers of C. psittaci cells can be found in respiratory tract exudate and faecal material of infected birds. The importance of the respiratory exudate has become more apparent.
In turkeys, the lateral nasal glands become infected early and remain infected for more than 60 days.
Choanal/oropharyngeal swabs are more consistent for isolation of the agent than faecal swabs, especially during early stages of infection.
 Direct aerosol transmission through aerosolization of respiratory exudate must be considered as the primary method of transmission.
Avian species, including domestic poultry sharing aquatic or moist soil habitats with wild infected aquatic birds may become infected via contaminated water.
Birds like pigeons, doves, pheasants and house sparrows may become infected by dust inhalation in faeces contaminated barnyards and grain storage sites.
The consumption of infected carcasses may transmit C. psittaci to host species that are predators or scavengers of otherbirds.
病鸟主要表现为精神沉郁、羽毛蓬乱、厌食、消瘦、呼吸困难和腹泻
康复鸟带菌率约10%
分泌物和排泄物排出大量病菌污染羽毛、粉尘等。
人感染：
发达国家感染很大程度上与鹦鹉有关
观赏鸟
家鸭、鹦鹉和鸽 （中国）
哺乳动物（羊、牛表现为流产、死胎、肺炎或无症状）
Transmission of C. psittaci in the nest is possible.
transmission from parent to young may occur through feeding, by regurgitation,  contamination of the nesting site with infective exudates or faeces may be important in other species, such as snow geese, gulls and shorebirds.
Furthermore, C. psittaci can be transmitted from bird to bird by blood-sucking ectoparasites such as lice, mites and flies or, less commonly, through bites or wounds.
Transmission of C. psittaci by arthropod vectors would be facilitated in the nest environment.
Vertical transmission（垂直感染） has been demonstrated in turkeys, chickens, ducks, parakeets, seagulls and snow geese, although the frequency appears to be fairly low
Clinical disease
Depending on the chlamydial strain and the avian host.
Chlamydiae cause pericarditis, air sacculitis, pneumonia, lateral nasal adenitis, peritonitis, hepatitis, and splenitis.
     Generalized infections result in fever, anorexia, lethargy, diarrhoea and occasionally shock and death.
Chlamydiosis is a very common chronic infection of psittacine birds.
     Infections cause conjunctivitis, enteritis, air sacculitis, pneumonitis, and hepatosplenomegaly.
     Droppings are often green to yellow-green.
 Many of the birds become chronically infected, but show no clinical signs until stressed. These birds often shed chlamydiae intermittently and serve as a source of infection of humans and other birds.
Pigeon infection
Chlamydiosis is also a common chronic infection of pigeons.
Clinical signs include conjunctivitis, blepharitis, and rhinitis. Survivors can become asymptomatic carriers.
Turkey infection
Infected turkeys show vasculitis, pericarditis, pneumonitis, air sacculitis, and hepatosplenomegaly, and lateral nasal adenitis at necropsy.
    Mortality rates of 5–40% may occur unless early antibiotic treatment is introduced
Chlamydiosis in ducks is a serious economic and occupational health problem in Europe.
Trembling, conjunctivitis, rhinitis, and diarrhea are observed in infected ducks. Mortality ranges to up to 30%.
Public health significance
传播途径
流行特征
     地区分布—广泛存在
     时间分布 无明显季节性，但某些情况例外
    人群分布--职业
     流行形式—散发或爆发
人类   经呼吸道吸入病鸟粪便、分泌物或羽毛的气雾或尘埃。(Humans most often become infected by inhaling the organism when urine, respiratory secretions or dried faeces of infected birds are dispersed in the air as very fine droplets or dust particles.)
紧密接触( include mouth-to-beak contact, a bite from an infected bird or handling the plumage and tissues of infected birds.)
人-人传播(Person-to-person transmission of psittacosis is possible, but is believed to be rare
The incubation period(潜伏期） is usually 5–14 days, but longer incubation periods are known.
 Human infections vary from inapparent to severe systemic disease with interstitial pneumonia and occasionally encephalitis.
The disease is rarely fatal in properly treated patients; therefore, awareness of the danger and early diagnosis are important.
Infected humans typically develop headache, chills, malaise and myalgia, with or without signs of respiratory involvement. While pulmonary involvement is common,auscultatory findings may appear to be normal.
A number of severe cases of human psittacosis, i.e., atypical pneumonia, were reported recently
As in birds, the carrier status might be common, as well as pathogenic synergies with other respiratory pathogens
Diagnosis of C. psittaci infection can indeed be difficult and is usually accomplished through testing paired sera, or only one serum sample, using the micro-immunofluorescence (MIF) test, which is more sensitive and specific than the complement fixation test.
 Highly sensitive nucleic acid amplification assays can be used to specifically detect C. psittaci.
Culture is also possible, but technically rather difficult for requiring biosafety level 3 laboratories.
Like in birds, tetracyclines are the drugs of choice for treating human psittacosis. Doxycycline or tetracycline is usually administered, unless contraindicated, like in the case of pregnant women and children under 9 years, where erythromycin can be used. The length of treatment will vary with the drug, but should be continued for at least 14 days for tetracycline.
Antigen detection
Smears
For C. psittaci infectionin birds,smears can be prepared from faeces, cloacal swabs, conjunctival scrapings, although pharyngeal or nasal swabs are preferred
Impression smears can also be prepared from tissue samples obtained from liver, spleen, kidney, lung and pericardium.
In cats and koalas, organisms may be detectedfrom conjunctival, urogenital or genital swabs.
Prepared smears can be stained for detection of chlamydiae using one of several staining procedures, for example, modified Machiavello, modified Gimenez, Giemsa, or modified Ziehl-Neelsen (MZN)
Fluorescent antibody tests using Chlamydiaceae-specific anti-LPS antibodies or species-specific mAbs to MOMP,
Pathological specimens
Following the submission of tissue samples to the  diagnostic laboratory for analysis, chlamydiae can be demonstrated in histological preparations using a variety of staining procedures.
Immunohistochemical staining procedures that utilise mAbs directed against chlamydial surface antigens, such as LPS or MOMP, are more sensitive and produce more striking results in comparison to histochemical staining.
Immunoassays
Most of the commercially available antigen detection tests that have been developed over the last 25 years are used primarily and extensively for the detection of Chlamydia trachomatis infections in human clinical specimens based on the family-specific LPS antigen.
These immunoassays include direct fluorescent antibody (DFA) tests (for example IMAGEN, Celltech; Chlamydia-Direct IF, BioMerieux; Vet-IF, Cell Labs),
plate-based ELISAs (Chlamydiazyme, Abbott; IDEIA, Dako; IDEIA PCE, Dako; Pathfinder, Kallestad; Chlamydia-EIA, Pharmacia)
And solid-phase ELISAs (Clearview Chlamydia MF, Unipath; Surecell, Kodak).
Isolation
Suitable antibiotics include streptomycin (200 mg/ml), gentamicin (50 mg/ml), vancomycin (75 mg/ml) and nystatin (25 units/ml),
penicillin, tetracycline and chloramphenicol inhibit chlamydial growth and should not be used.
Yolk-sacs of 6–8-day-old embryos are inoculated with 10% sample suspensions and embryos die between 4 and 14 days after infection. Smears prepared from yolk-sac membranes at the time of death, or from surviving eggs on completion of the experiment, can be stained, using a variety of procedures, such as MZN, modified Machiavello or Giemsa to reveal EBs, thus confirming chlamydial infection.
Most cell types are susceptible to C.  psittaci infection, but the direct inoculation into cultures of BGMK, African green  monkey kidney (Vero), McCoy and L cells are commonly used
Infection of chlamydiae in cell culture can be enhanced by centrifugation and/or by chemical treatment of cultured cells, before or during infection, using for example cycloheximide (1 mg/ml), cytochalasin B (2 mg/ml), emetine (1 mg/ml), diethylaminoethyl-dextran (20 mg/ml) or 5-iodo-2-deoxyuridine (80 mg/ml)
Antibody detection
The detection of antibodies in animal chlamydial infections has multiple purposes, i.e. confirmation of clinical disease or confirmation of the presence or absence of infection, performance of epidemiological surveys to estimate the prevalence of infection, or the determination of immune status after vaccination to name some.
Detection of the bound antibody is achieved by fluorescent, i.e. indirect immunofluorescence test and MIF, or otherwise tagged secondary antibodies, i.e. indirect ELISA, or by estimating the consumption or fixation of complement,
DNA amplification methods
Conventional PCR
Real-time PCR
Treatment and Prevention
Like in birds, tetracyclines are the drugs of choice for treating human psittacosis.
Doxycycline or tetracycline is usually administered, unless contraindicated, like in the case of pregnant women and children under 9 years, where erythromycin can be used.
The length of treatment will vary with the drug, but should be continued for at least 14 days for tetracycline.
鼠疫Plague, Black Death ,Bubonic plague
黑死病对于文明来说 是一剂几乎使人类灭绝的猛药。
由鼠疫耶尔森菌引起的，主要由媒介蚤类传播，在温血动物（啮齿类动物为主）间流行的自然疫源性疾病。
Plague is a zoonotic disease circulating mainly among small animals and their fleas.
The bacteria Yersinia pestis can also infect humans. It is transmitted between animals and humans by the bite of infected fleas, direct contact, inhalation and rarely, ingestion of infective materials.
Plague can be a very severe disease in people, with a case-fatality ratio of 30%-60% if left untreated.
烈性传染病也有历史，也是历史的一部分，但它的历史常常被历史学家忽略。
科学家们在寻找预防治疗方法,努力将其消灭的时候，也很少认真考虑其来龙去脉。
烈性传染病史的关键问题是，该病自古就存在，由于某种环境的改变而光顾人类社会？还是由于某种变异而出现新的品种 (Black Death、AIDS、SARS） ？
疾病对人类社会的影响有两种，一种是长期的病害折磨，人类渐渐麻木了，几十年下来，人们开始习惯和病魔共存，衍生出来的 是更多的迷信乃至邪教。而短期的病害则对人类社会造成强大的震动，尤其是精神上的。
鼠疫的三次大流行-世纪瘟疫
第一次大流行：查士丁尼鼠疫
541-542年的查士丁尼鼠疫是历史上第一次纪录的大流行。541年，鼠疫沿着埃及的培鲁沁(Pelusium)侵袭罗马帝国。鼠疫荼毒培鲁沁后，迅速蔓延至亚力山卓，再继续水陆贸易网扩散到首都君士坦丁堡与整个拜占庭帝国。此次流行导致帝国至少1/3人口死亡。严重影响该帝国经济税基与军制兵源，削弱了拜占庭帝国实力。
查士丁尼鼠疫爆发后，从541-717年，鼠疫沿着海陆贸易网扩散到西欧与不列颠。首先是法国，543年法国西南部亚耳爆发鼠疫病情，接着547年鼠疫传染至爱尔兰与不列颠西部，588-590年的一次鼠疫横扫马赛、亚威农(Avignon)，以及法国北部里昂地区的隆河流域(the Rhone Valley)，造成2500万人死亡，鼠疫不止波及英法等国，它使当时整个地中海贸易衰退。更造成许多昔日王国的势力因此消失，并改写整个欧洲的历史。
由于缺乏详细历史记录，时间及病因有一定的推测成分
第二次鼠疫大流行（黑死病）
14世纪30年代始于蒙古草原，先传入中国，据估计杀死30%的中国人口，然后经过蒙古商路传入欧洲和非洲。在欧洲被称为黑死病。三年间杀死欧洲30%到60%的人口。1400年全球人口有4.5亿下降到3.5亿。
这一轮鼠疫流行到1700年才结束，期间定期在欧洲流行，每次流行中死者以10万计。
第二次大流行：黑死病
在1346年到1350年大規模襲擊歐洲，导致欧洲人口急剧下降，死亡率高达30%。黑死病被認為是蒙古人帶來的。約1347年，往來克里米亞與墨西拿（西西里島）間的熱那亞貿易船隻帶來了被感染的黑鼠或跳蚤，不久便漫延到熱那亞與威尼斯，1348年疫情又傳到法國、西班牙和英國，1348—1350年再東傳至德國和斯堪的納維亞，最後在1351年傳到俄羅斯西北部。估計歐洲有約2500萬人死亡，而歐、亞、非洲則共約5,500萬—7,500萬人在這場疫病中死亡。當時無法找到治療藥物，只能使用隔離的方法阻止疫情漫延。此後在十五、十六世紀黑死病多次再次侵襲歐洲；但死亡率及嚴重程度逐漸下降。
有人認為，這場黑死病嚴重打擊了歐洲傳統的社會結構，削弱封建與教會勢力，間接促成了後來的文藝復興與宗教改革。
1352年，黑死病离开欧洲去了中东，其后150年里，每隔6-12年，某个地方就会流行一次。
1500年以后每15-20年出现一次。
1630-1631 威尼斯人口从142804降至98244
1651-1653 巴塞罗那杀死45%的居民
1665年伦敦 死亡55797人 占17%，一场大火结束欧洲的大流行。
1720年法国马赛最后一次鼠疫余波
鼠疫的离去，解除了欧洲文明的最后锁链。1760年开始的工业革命，70年间让欧洲跨入现代社会
1770莫斯科大鼠疫死亡超过10万
。
在中國，明代万历和崇祯二次的大疫相信是這次全球大流行的一部份。据估计，华北三省人口死亡总数至少达到了1000万人以上，崇祯“七年八年，兴县盗贼杀伤人民，岁馑日甚。天行瘟疫，朝发夕死。至一夜之内，百姓惊逃，城为之空”。“朝发夕死”、“一家尽死孑遗”。一些史學家相信，李自成入北京之前，明朝的京營兵士就正遭受鼠疫侵襲，谷應泰在《明史纪事本末》卷78中说“京师内外城堞凡十五万四千有奇，京营兵疫，其精锐又太监选去，登陴诀羸弱五六万人，内阉数千人，守陴不充”。“上天降灾，瘟疫流行，自八月至今（九月十五日），传染至盛。有一二日亡者，有朝染夕亡者，日每不下数百人，甚有全家全亡不留一人者，排门逐户，无一保全。……一人染疫，传及阖家，两月丧亡，至今转炽，城外遍地皆然，而城中尤甚，以致棺蒿充途，哀号满路。”
明朝（1368年1月23日－1644年4月25日[1]）是中国历史上最后一个由汉族建立并长期统治的君主制皇朝，历经十二世、十六位皇帝。明朝初期定都于应天府（今南京），号京师。永乐十九年（1421年），明成祖朱棣迁都至顺天府（今北京），而应天府改称为南京。
明朝建立始于1368年朱元璋推翻蒙古人建立的元朝，在南京建都称帝，国号大明[2]。因明朝的皇帝姓朱，故又称朱明。
明朝初年比较强盛，经过明太祖的洪武之治，精励图强并逐步恢复国力，到明成祖时期国力到达顶峰，是为永乐盛世。其后的明仁宗和明宣宗时期仍处于兴盛时期，史称仁宣之治。虽于明武宗、明世宗开始逐渐中衰，面临社会矛盾与外患，仍有隆庆新政与万历中兴中兴气象。但万历与崇祯年间连年灾荒与战事，各地爆发民变，至1644年明思宗遭受李自成的大顺军队攻占顺天府，明思宗自缢，随后清朝军队击败大顺军并入主中原，至此明朝享国祚276年。但后继南明与明郑政权仍延续了数十年，直到1683年清军占领台湾，明廷宗室才被清军完全灭绝。
明朝的领土曾囊括今日内地十八省之范围。东北初年抵日本海、鄂霍次克海、乌地河流域，后改为辽河流域；初年北达 西喇木伦河一带，后改为今长城；西北至新疆哈密，后改为嘉峪关；并曾在今东北地区、新疆东部、西藏等地设有羁縻机构。明成祖时期甚至短暂征服并统治安南（今越南北部）。
中国的1644年，北京“城头变幻大王旗”
王朝：大明、大顺、大清
人物：朱由检 (崇祯）
                     职业：皇帝                    
           李自成（闯王）
                     职业：造反                  
           吴三桂 （明朝将军）
                      职业：军人
           多尔衮 (清朝实际领导人）
                       职业：造反
  明朝后期大疫病在北方多次流行，山西、河间府、通州、昌平、保定等。
       原因：土地兼并严重，老百姓丢掉土地: 成为流寇或经山西去草原垦荒与草原鼠争夺地盘。
  明朝亡于民不聊生、李闯亡于鼠疫，天下归清也要归功于耗子和它们身上的 小小细菌
1944年郭沫若《甲申三百年祭》
第三次大流行
1855年中國雲南首先發生了大型鼠疫，1894年在廣東爆發，並傳至香港，經過航海交通，最終散佈到所有有人居住的大陸，估計在中國和印度便導致約1200萬人死亡。此次全球大流行一直維持至1959年，全球死亡人數少於250人方才正式結束。
第三次鼠疫大流行
1855年始于中国，1955年结束。首波流行于中国和印度 ，死亡1200万人。
1894年印度大鼠疫，1910-1911年中国东北大鼠疫。
1860年前后战乱中的中国，瘟疫已遍地流行，除霍乱外，安徽等地发生鼠疫，远离战乱的云南也爆发鼠疫，死亡200多万。
    关内民众东北大迁移。
科学家发现鼠疫细菌的竞赛
Louis Pasteur
Born December 27, 1822)Dole, Jura, Franche-Comté, France
Died  Sept. 28, 1895 (aged 72)Marnes-la-Coquette, Hauts-de-Seine, FranceNationality French
Fields ChemistryMicrobiology
InstitutionsUniversity of StrasbourgUniversité Lille Nord de FranceÉcole Normale Supérieure
Alma materÉcole Normale Supérieure
Notable students Charles Friedel
Heinrich Herman Robert Koch
Born      11 December 1843)         Clausthal, Kingdom of Hanover
Died      27 May 1910 (aged 66)          Baden-Baden, Grand Duchy of Baden
Fields     Microbiology
Institutions   Imperial Health Office, Berlin,                        University of Berlin
Alma mater   University of Göttingen
Doctoral advisor  Friedrich Gustav Jakob Henle
Known for       Discovery bacteriology                   Koch's postulates of germ theory
 He became famous for isolating Bacillus anthracis (1877), the Tuberculosis bacillus (1882) and the Vibrio cholera (1883) and for his development of Koch's postulates.
 He was awarded the Nobel Prize in Physiology or Medicine for his tuberculosis findings in 1905. He is considered one of the founders of  microbiology—he inspired such major figures as Paul Ehrlich and Gerhard Domagk.
1894年5月8日香港公立医院代理主管-詹姆斯.劳森确定香港出现鼠疫病例。向欧洲求援
6月31日Alexandre Yersin从河内来到香港
Alexandre Emile Jean Yersin (September 22, 1863–March 1, 1943) was a Swiss physician and bacteriologist. Along with Shibasaburo Kitasato he is remembered as the co-discoverer of the bacillus responsible for the bubonic plague or pest, which was later re-named in his honour (Yersinia pestis).
Yersin was born in 1863 in  Switzerland, to a family originally from France. From 1883 to 1884, Yersin studied medicine at Lausanne, Switzerland; and then at Marburg, Germany and Paris (1884-1886). In 1886, he entered Louis Pasteur's research laboratory at the École Normale Supérieure, by invitation of Emile Roux, and participated in the development of the anti-rabies serum. In 1888 he received his doctorate with a dissertation entitled Étude sur le Développement du Tubercule Expérimental and spent two months with Robert Koch in Germany. He joined the recently-created Pasteur Institute in 1889 as Roux's collaborator, and discovered with him the diphtheric toxin (produced by the Corynebacterium diphtheriae bacillus).
100 years ago, in 1894, Alexandre Yersin discovered the causative agent of plaque in Hong Kong.
Only a few people know that the native Swiss and student of Pasteur and Roux spent nearly 50 years of his life in Vietnam, where he became director of the Pasteur institutes and earned merits by his engagement for the control of communicable diseases in humans and animals.
 He, furthermore, successfully introduced tropical plants such as rubber, cacao, coffee and quinquina tree. In 1943, at the age of 80, Yersin died as a personality venerated by all classes of the vietnamese population.
He studied under Dr. Robert Koch in University of Berlin from 1885 to 1891. In 1889, he was the first person to grow the tetanus bacillus in pure culture, and in 1890 cooperated with Emil von Behring in developing a serum therapy for tetanus using this pure culture. He also worked on antitoxins for diphtheria and anthrax. Kitasato and Behring demonstrated the value of antitoxin in preventing disease by producing a passive immunity to tetanus in an animal that received graded injections of blood serum from another animal infected with the disease.
After returning to Japan in 1891 he founded the Institute for Study of Infectious Diseases with the assistance of Fukuzawa Yukichi. One of his early assistants was August von Wassermann. Kitasato demonstrated how dead cultures can be used in vaccination. He also studied the mode of infection in tuberculosis.
He traveled to Hong Kong in 1894 at the request of the Japanese government during an outbreak of the bubonic plague, and unsuccessfully identified the bacterium causing the disease; his results were not as widely disseminated as Yersin's, however, Yersin was for many years given primary credit for the discovery, and the bacterium was named after him. Four years later, Kitasato and his student Kiyoshi Shiga were able to isolate and describe the organism that caused dysentery.
字联星，祖籍广东新宁县(今台山)，1879年３月10日出生于马来亚槟榔屿（今马来西亚的槟城州
1896—1899年留学英国剑桥大学意曼纽学院。
1899—1902年考入圣玛丽医院实习。
1902—1903年在英国利物浦热带病学院、德国哈勒大学卫生学院及法国巴斯德研究所实习、研究。
1903年，获英国剑桥医学博士学位。后返回原马来亚，在吉隆坡医学研究院从事热带病研究。1904年在马来亚槟榔屿开设私人诊所。1907年应邀赴英国伦敦参加由神学博士文英兰主持的禁鸦片烟会议。
1908年，受清政府邀聘回国任教，担任天津陆军军医学堂副监督（副校长职）。
1910年12月东北发生鼠疫大流行，清政府任命伍连德为东三省防鼠疫全权总医官，到哈尔滨进行调查、防治。
1911年４月出席在奉天（今沈阳）召开的万国鼠疫研究会议，任会议主席。1912年在哈尔滨筹建东三省防疫事务总管理处及附属医院。
1915年建立中华医学会，任书记并兼任《中华医学杂志》总编辑。
1916年任黎元洪总统特医及京汉、京张、京奉、津浦四条铁路总医官。当选为中华医学会会长，并兼任公共卫生部委员。
1918年任北洋政府中央防疫处处长、北京中央医院（今位于白塔寺的北京医科大学人民医院分院）院长。
1919年１月代表外交部到上海监督焚烧鸦片。哈尔滨流行霍乱，伍连德利用防疫医院收治2000余名病人。
1920年去美国约翰·霍普金斯大学进修学校卫生和公共卫生。
1922年受奉天督军张作霖委托，在沈阳创建东北陆军医院。
1923-1924年获美国约翰·霍普金斯大学公共卫生硕士学位、上海圣约翰大学名誉科学博士学位、日本东京帝国大学名誉医学博士学位、苏联科学院名誉院士及苏联微生物学会外国会员。
1926年创办哈尔滨医学专门学校（哈尔滨医科大学前身），任第一任校长。
1927年国际联盟卫生处聘伍连德为该处中国委员，并授予鼠疫专家称号。出席国际联盟在印度召开的第七次远东热带病学会，被选为副主席。
1930年任上海全国海港检疫管理处处长、技监，兼任上海海港检疫所所长。1931年代表南京国民政府卫生署刘瑞恒署长出席国际联盟卫生会议。在上海主持召开第一届检疫学术研究会。1937年４月任中华医学会公共卫生学会会长。
八一三事变，举家重返马来亚，定居怡保市，开设私人诊所。1960年１月21日病逝于马来亚槟榔屿，享年82岁。
东北大鼠疫是人类对旱獭死死相逼的结果。
人类活动无限制的扩张、贪婪地索求引发某些共患病的蔓延和扩散、酿成系列的人间悲剧！
Geographic Distribution: Natural foci of infection persist on nearly all continents. They do not exist in Australia, New Zealand, or New Guinea
China seals off town amid plague outbreak updated 9:42 p.m. ET Aug. 3, 2009 Associated Press
BEIJING - An outbreak of pneumonic plague in a remote farming town in northwestern China has killed a third person, the official Xinhua News Agency said Tuesday, as authorities locked down the town and moved to disinfect the region.
Police set up checkpoints around Ziketan in Qinghai province after the outbreak was first detected last Thursday. The lung infection can kill a human in 24 hours if left untreated. Townspeople reached by The Associated Press by phone said the streets were largely deserted and most shops shut.
The latest victim was a 64-year-old man named Danzhi, Xinhua said. He was a neighbor of a 32-year-old herdsman in Ziketan and a 37-year-old man who died earlier. A further nine people — mainly relatives of the herdsman — are infected and in a hospital, according to the local health bureau.
Of those, one is in a serious condition and one other has developed symptoms of coughing and chest pain, but there have been no reports of new infections, Xinhua said.
The local government has sealed off the town, and medical staff are disinfecting the region and tracking down those who have been in close contact with those affected, it said.
Authorities urged anyone who had visited the town of 10,000 people since mid-July and has developed a cough or fever to seek hospital treatment..
病原 Causative agent
日本学者Kitassato和法国学者Alexandre J. Yersin于1894年在香港分离到病原
分类归属
    肠杆菌科、耶尔森菌属、鼠疫耶尔森菌种
     两个亚种：Yersinia pseudotuberculosis pestis
                       Y. pseudotuberculosis pseudotuberculosis
 形态： 卵圆形短杆菌 1-2 um x 0.5-0.7 um,
              有荚膜， G-
鼠疫菌的抗原与毒力因子
封套抗原（ F1, Fraction 1) 位于菌体周围的多糖蛋白复合物。
   温度（37C）、CO2、甘氨酸、人血液促进其产生、毒力强产量高。
V和W 抗原  毒力抗原的一种
菌体抗原  非特异性性抗原
鼠疫菌毒力决定因子：
    F+/F-
   VW+/VW-
    依赖钙离子或嘌呤化合物作营养源
    产色素能力
    产鼠疫毒素能力
鼠疫菌毒素：
   鼠毒素(murine toxin)   一种可熔性毒蛋白（外毒素）
   作用于血管及淋巴管内皮细胞引起炎症、坏死、出血、致死性休克、毒血症而导致器官衰绝。对鼠心肌线粒体有选择性毒性作用。
  内毒素
流行病学
流行病学
动物鼠疫流行病学
   自然疫源地判定标准：
   1）具有适宜于各类鼠疫疫源地存在的相应景观；
   2）在该景观内有连续成片分布的主要动物宿主，其种群覆盖度通常占该景观20%以上，其密度高且稳定；
  3）主要宿主的主要媒介，蚤指数应≥1；
  4）在该景观内的主要宿主或其主要体外寄生虫体内检出鼠疫菌。
鼠疫自然疫源地世界分布
   我国鼠疫自然疫源地的分布特点：
    鼠疫自然疫源地分布在19 个省区273 个县(旗),各疫源地疫情发生发展差异不一。
1、疫情稳定性疫源地:
    呼伦贝尔高原蒙古旱獭疫源地：1910-1921年间东北两次鼠疫大流行时被波及。建国后至今，在疫源地进行细菌学检验旱獭11550 余只，均为阴性，未发生人、动物鼠疫，疫源地疫情处于静息状态。但这块疫源地的俄罗斯和蒙古的部分地区，仍有动物鼠疫发生流行，为此，今后要加强监测，密切注视疫情，防止疫源传入，防患于未然。
2 、疫情活跃性疫情地
1） 青藏高原喜马拉雅旱獭疫源地
1966 年西藏在日喀则地区仲巴县首次确诊人间鼠疫后到2000 年共发生#18 起人间鼠疫，腺鼠疫，传播途径为食肉和剥皮。新的疫源县不断出现，疫源地面积也在扩大增加。
2）内蒙古高原长爪沙鼠疫源地
内蒙古杭锦后旗、陕西定边、宁夏灵武
3）锡林郭勒高原布氏田鼠疫源地
4）滇西居民区黄胸鼠疫源地
5）天山山地灰旱獭、长尾黄鼠疫源地
6）松辽平原达乌尔黄鼠疫源地
7）青藏高原青海田鼠疫源地
3、疫情偶发性疫源地
阿拉善黄鼠、长尾旱獭和大绒鼠、齐氏姬鼠疫源地，疫情波动不稳，处于疫情稳定的上峰期和疫情活跃的下峰期
青藏高原和天山山地的鼠疫疫源地相对比较活跃，鼠疫动物病每年都有流行。
滇、黔、桂黄胸鼠鼠疫发病有上升趋势。
宿主
主要宿主  在长期保存鼠疫菌中起决定性作用的宿主。优势种、密度高、数量大、分布广、易感。
     达乌尔黄鼠、阿拉善黄鼠、长尾黄鼠、蒙古旱獭、灰旱獭、红旱獭、喜马拉雅旱獭、黄胸鼠、长沙沙鼠、大绒鼠、齐氏姬鼠、布氏田鼠和青海田鼠。
次要宿主  在疫源地中经常参加鼠疫动物病的流行，但对保持鼠疫疫源地中的长期存在不起主要作用的温血动物。家栖或半家栖鼠类：褐家鼠、小家鼠、黑家鼠等
偶然宿主 疫源地中有些数量比较少的啮齿类和食肉动物。跳鼠、野兔、狐、鼬、貂、猫等偶尔可感染鼠疫
223种啮齿类动物
媒介
在鼠疫疫源地，鼠疫菌主要通过蚤类在宿主动物间传播。
我国已发现59种节肢动物可以自然感染鼠疫菌
51种蚤类、4种蜱类、2种螨类、2种虱类
动物鼠疫流行病学特点及影响因素
长时间的间断性以及经过一段时间的间歇期后再次爆发流行的突然性。
影响因素包括：
        宿主和媒介（数量）
        病原体（自然弱毒的出现）
        自然和人为因素
        非生物因素地理因素，如水文、地质、气象和太阳黑子活动等
人类鼠疫流行病学
传染源
    1、野生动物作为传染源 （10-100万CFU/ml血液）
    ★寄生蚤在吸血后，鼠疫菌在蚤的前胃中繁殖形成菌栓，逐渐堵塞消化道而使蚤处于饥饿状态，从而更加频繁吸血，冲刷菌栓，因不能进入后面的消化道而只能反吐回去。栓塞蚤每次反吐可吐出2.5-10万个鼠疫菌。
    ★捕杀旱獭等
  2、家畜作为传染源  藏系绵羊、藏黄羊、山羊、骆驼、家兔、猫和犬。
   3、人作为传染源--鼠疫肺炎咳嗽
流行特征
   ★地域性
   ★季节性及与职业关系
预防、监测与控制
预防
    原则：针对传染病流行的三环节
    灭鼠灭蚤
    卫生检疫
鼠疫的监测
监测类型及标准
动物鼠疫监测在世界上大致分为2 类:
  ★以中国和俄罗斯为代表的主动监测;
 ★以美国为代表的被动监测 ,只有在高危险区啮齿类动物发生变化、出现人间病例或在食肉动物中检出抗体阳性血清时才进行主动监测。
中国制定了《中国动物鼠疫监测标准》[ GB 1688221997 ] ,作 为各类鼠疫疫源地进行动物鼠疫监测依据,规范监测工作。
监测方式
根据全国鼠疫监测工作方案,鼠疫疫源地的动物鼠疫监测以固定监测点和流动监测点相结合的方式进行。在那些地广人稀、但鼠疫又活跃的地区,需要重点加强流动监测,并为这种类型的监测工作设计合理的巡回路线,以扩大监测覆盖面。
监测内容
　宿主动物监测　主要监测啮齿类宿主动物的异常情况、种群结构、密度、季节变动等方面的内容。宿主动物的异常,主要由专业人员和群众目测观察获得。我国的“疫情三报”(包括在监测期间发现自毙鼠及其他自毙动物,疑似鼠疫病例,不明原因的高热急死病例) ,是一项控制人间鼠疫发生及早期发现疫情的有效措施
     媒介监测　动物鼠疫的主要传播媒介为蚤类,蚤类的种群数量、生态习性、季节消长直接关系到动物鼠疫发生、流行的时间和强度。
病原学和血清学监测　是鼠疫监测的重要部分,可为确定或追溯鼠疫发生,探索鼠疫自然疫源地鼠疫菌保存机制和预测预报等服务。
     主要在宿主、媒介、疑似病例、指示动物中进行,将捕获宿主的血清学和病原学及其寄生蚤病原学监测作为重点。国内研究认为鼠疫细菌学监测应以自毙鼠为主。指示动物在我国主要是犬、猫、猪等。
其他监测　鼠疫流行是病原体、宿主、媒介、人文环境和地理环境相互作用的结果,同时生态系的改变直接影响动物鼠疫流行的变化
临床表现
潜伏期1-6天， 多为2-3天
严重的全身中毒症状，发病急剧、恶寒颤栗、高烧39-40C（呈稽留热），头剧疼并可能出现中枢性呕吐、头晕和呼吸急迫很快进入极度虚弱状态。
临床表现型：
     腺鼠疫
     肺鼠疫
     鼠疫败血症
     皮肤鼠疫
     脑膜炎型鼠疫
     眼鼠疫
     肠鼠疫
     扁桃体型鼠疫
诊断
临床诊断
 原则：
  患者有流行病学线索并具有鼠疫临床症状；
  鼠疫细菌学诊断阳性或被动血凝试验（PHA）血清F1抗体诊断阳性。
诊断标准
   发病前10天有与病原接触史；
   突然发病并表现相关症状；
   患者穿刺液或分泌液分离到鼠疫菌；
  患者2次采血清（间隔10天）PHA检测F1抗体呈4倍增长。
CDC Diagnosis:
The typical sign of the most common form of human plague is a swollen and very tender lymph gland, accompanied by pain. The swollen gland is called a "bubo." Bubonic plague should be suspected when a person develops a swollen gland, fever, chills, headache, and extreme exhaustion, and has a history of possible exposure to infected rodents, rabbits, or fleas. A person usually becomes ill with bubonic plague 2 to 6 days after being infected.
When bubonic plague is left untreated, plague bacteria invade the bloodstream. As the plague bacteria multiply in the bloodstream, they spread rapidly throughout the body and cause a severe and often fatal condition. Infection of the lungs with the plague bacterium causes the pneumonic form of plague, a severe respiratory illness. The infected person may experience high fever, chills, cough, and breathing difficulty and may expel bloody sputum. If plague patients are not given specific antibiotic therapy, the disease can progress rapidly to death. About 14% (1 in 7) of all plague cases in the United States are fatal.
Laboratory Test Criteria for Diagnosis of Plague
SUSPECTED PLAGUE SHOULD BE CONSIDERED IF THE FOLLOWING CONDITIONS ARE MET:
1. Clinical symptoms that are compatible with plague, i. e., fever and lymphadenopathy in a person who resides in or recently traveled to a plague-endemic area.
2. If small gram-negative and/or bipolar-staining coccobacilli are seen on a smear taken from affected tissues, e.g.:
Bubo (bubonic plague)
Blood (septicemic plague)
Tracheal/lung aspirate (pneumonic plague)
PRESUMPTIVE PLAGUE SHOULD BE CONSIDERED WHEN ONE OR BOTH OF THE FOLLOWING CONDITIONS ARE MET:
If immunofluorescence stain of smear or material is positive for the presence of Yersinia pestis F1 antigen.
If only a single serum specimen is tested and the anti-F1 antigen titer by agglutination is >1:10.*
CONFIRMED PLAGUE IS DIAGNOSED IF ONE OF THE FOLLOWING CONDITIONS IS MET:
1.If a culture isolated is lysed by specific bacteriophage.
2.If two serum specimens demonstrate a four fold anti-F1 antigen titer difference by agglutination testing.*
3.If a single serum specimen tested by agglutination has a titer of >1:128 and the patient has no known previous plague exposure or vaccination history.*
*Agglutination testing must be shown to be specific to Y. pestis F1 antigen by hemagglutination inhibition.
实验室诊断
细菌学诊断
    取材-  患者的渗出液、血液、脑脊髓液等
               鼠的脾脏、肝脏和血液等
               昆虫
    分离培养
血清学诊断
   间接血凝试验
   细菌凝集反应
   免疫荧光
    ELISA
分子生物学诊断
Human specimens:
Specimens should be obtained from appropriate sites for isolating the bacteria.
The preferred specimen for microscopic examination and isolation from a bubonic case is material from the affected bubo, which should contain numerous organisms.
Blood cultures should be taken whenever possible.
 In cases where live organisms are unculturable, e.g., in specimens taken postmortem, lymphoid tissues, lung and bone marrow samples may yield evidence of plague infection by FA test or by detection of Y. pestis DNA.
Specimens intended for culture should be taken before initiation of antibiotic treatment.
Specimens are inoculated on general laboratory media and into laboratory mice for isolation; a thin smear is made from the remaining materials for examination by fluorescent microscopy. If a specimen is suspected to contain mixed flora, passage of the material through laboratory mice will increase the likelihood of recovery of a pure Y. pestis culture.
Plague bacilli express a unique diagnostic envelope glycoprotein called the Fraction 1 (F1) antigen or capsular antigen at >33°C; this unique envelope antigen is the primary target antigen used for plague diagnostic FA and antibody tests.
Plague bacilli are susceptible to lysis by a specific bacteriophage at both 25°C and 37°C.
 If a patient has been treated with a static antibiotic (e.g., tetracycline) for more than 4 days, bacterial cultures should be incubated for more than 5 days to give organisms a chance to recover.
 In case cultures yield negative results, serologic testing is advised. One serum specimen should be taken as early in the illness as possible to be followed by a second sample 1-4 months after antibiotic therapy has ceased.
Animal/flea specimens:
 Lymphoid tissues should be removed for testing of the presence of F1 antigen by FA and by culture.
Bone marrow from dessicated animal carcasses may yield positive results when other tissues are not available.
 In addition, serum and blood specimens may be taken for detection of antibody by agglutination.
Fleas should be identified and may be placed in pools for tituration and examination. Titurated flea materials may be inoculated into laboratory mice for isolation of plague bacteria and for examination of mouse tissues by FA for expression of F1.
Fleas or flea pool material may be directly examined by FA if the samples are pre-incubated at 37°C for 24 hours to encourage F1 antigen expression.
The serum from inoculated laboratory mice may be examined for presence of antibody to F1.
For serosurveillance of plague in animal populations, blood may be soaked and dried onto filter paper strips and sent to the laboratory for the detection of F1 antibody.
In cases where no cultures or serum specimens are available for testing, both animal and flea material may be tested by polymerase chain reaction (PCR) to determine if plague DNA is present in the specimens.
Vaccines
Current
The existing Killed whole cell vaccines (KWCV)  for plague comprises heat-killed bacteria,in aqueous medium incorporating a preservative such as phenol.
It requires multiple immunising doses and is reactogenic. The primary immunisation schedule comprises an initial sub-cutaneous 0.5 ml dose, followed by a 0.5 ml booster dose at 1–4 weeks and every 6 months thereafter.
Additionally, production of the vaccine involves microbial culture within containment which is costly, hazardous and restricts manufacturing location. These factors have led to research into an improved vaccine.
Recombinant vaccine candidates
the Fraction 1 (F1) and V (virulence) proteins which as virulence factors are pivotal in preventing phagocytosis of, and inregulating type three secretion (TTS) by the bacteria, respectively.
土拉杆菌病 tularemia
一、病名定义与历史概述
      土拉杆菌病是由土拉杆菌引起的一种高度传染性的自然疫源性疾病，曾称为“野兔热”。
Synonyms: Francis disease, deer-fly fever, rabbit fever, Ohara’s disease, hare fever
      该病最早由McCoy于1911年正式报道。1914年在美国Ohio确定了首例人感染，到1919年美国科学家Edward  Francis从California的Tulare地区啮齿动物流行爆发中分离到该菌。
      为纪念Edward  Francis在该病研究所作出的先驱性工作以及突出的贡献，后人将该细菌命名为Francisella tularensis。
该病在北美、欧洲和亚洲均有报道，1960年以前一直呈较高的流行态势。
近年来，在欧美各国的发病数呈明显的下降趋势，美国有2000年前的每年感染病例约200-500个下降到目前每年约50个感染病例。
我国于1957年首次在内蒙古通辽地区黄鼠分离到细菌。
1959年首次在黑龙江省哈拉海屯14人因直接和间接接触野兔和鼠而爆发土拉杆菌病。
在青海、西藏和新疆发现多个自然疫点和感染病例，特别是西藏波密县易贡地区居民变态反应阳性率为8.43%，牛血清凝集反应阳性率高达80.9% (72/89) 。
值得注意的是在内陆地区的山东胶南某食品加工厂1986年1月发生一起典型的人间土拉弗氏菌病爆发流行，在短短10天内兔肉加工车间86％（31/36）的操作工人显性感染发病，表现为突然发病和持续高热，平均病程为11天。
由于该菌具有高度的传染性，对人具有很强的致病力，经呼吸道感染10个细菌即可引起发病和死亡，因此一直被用作潜在的生物武器。
1940至1960年代美国和前苏联一直将其作为生物武器储备。第二次世界大战期间，臭名昭著的日本731部队曾在中国对中国公民开展人体试验。
世界卫生组织（WHO）美国疾病控制中心（CDC）曾预测，如果用50公斤土拉杆菌作为生物武器对一个有500万人口的城市发动袭击可造成25万人感染，约19000人死亡。每10万感染者造成的经济损失为54亿美元，其危害可能高于其他生物武器。
美国CDC将其列为A类生物武器病原。
二、病原学
土拉杆菌为革兰氏阴性球杆菌，为严格的细胞内寄生。
属弗朗西丝菌科（Francisellaceae）弗朗西丝菌属。
    目前在该属包括2个种：
        土拉弗朗西丝菌（ Francisella tularensis）
        菲洛米拉弗朗西丝菌(F. philomiragia)。
土拉弗朗西丝菌包括4个亚种：
1）土拉弗朗西丝菌土拉亚种（ F.  tularensis subsp. tularensis）     主要分布于北美、北欧、墨西哥，为毒力最强的亚种。人经呼吸道感染10个细菌即可引起发病，致死率高于30%；少于5个细菌可以100%致死小白鼠，属严格的生物安全3级病原微生物。
      该亚种又进一步分为A1和A2两个亚群。在美国A1亚群菌株主要分布于东部地区，而A2亚群则主要分布于西部。
2）土拉弗朗西丝菌全北区亚种（ F.  tularensis subsp. holarctica）, 主要分布于北美、欧洲、亚洲。对人具有较强的致病性，但比A型菌株毒力低。
3）土拉弗朗西丝菌中亚亚种（ F.  tularensis subsp. mediasatica）。该菌目前仅报道于前苏联的中亚加盟共和国，分自于野兔、沙鼠和蜱，对该菌目前缺乏详细的鉴定资料，但其致病性似乎明显比A型弱。
4）土拉弗朗西丝菌novicida亚种（ F.  tularensis subsp. novicida）。对小鼠具有强的致病力，但对人无致病性。
菲洛洛米拉弗朗西丝菌(F. philomiragia)，或意译为爱蜃景弗朗西丝菌
    主要分自于水、麝鼠和人。鱼类也有感染类似菌的报道
培养特性
土拉弗朗西丝菌为专性需氧菌，最适生长温度为35-37C，5%CO2环境有助于细菌生长。
     该对营养要求相对较高，生长速度缓慢。在普通琼脂培养基上不易生长，采用Mueller-Hinton培养基、胰酶大豆琼脂（TSA）、胱氨酸心琼脂、GC琼脂II做基础培养基，添加1%牛血红蛋白、1% 葡萄糖和0.1%L-半胱氨酸及1% IsoVitalex后生长良好。
     液体培养可采用添加1% 葡萄糖和0.1%L-半胱氨酸及1% IsoVitalex 的MH肉汤或Chamberlain氏培养基。
土拉弗朗西丝菌novicida亚种和菲洛米拉弗朗西丝菌对培养基的营养要求相对较低，易于分离培养。
流行特点 Epidemiology
土拉杆菌的传播模式
流行特点
自然条件下，土拉弗朗西丝菌的宿主范围非常广泛，可感染至少100多种哺乳动物和20多种鸟类。啮齿类和兔形目动物可能是主要的储存宿主和传染来源，包括野兔、田鼠、麝鼠，其中A型多见于兔形目动物，B型多见于啮齿类。
野兔和麝鼠对土拉弗朗西丝菌非常敏感，感染后大部分死亡，因此能否长久带菌仍不能完全确定。
      欧洲一些地区观察发现，野兔流行本病期间，同一地区先有田鼠流行，因此推测多数地区的感染人的主要传染源虽然是野兔，但保菌宿主更可能是鼠类。体表寄生虫在动物之间不断传播细菌对于细菌能在宿主动物群内长时间存在起着很重要的作用，而蜱类很可能是病原体能够在疫源地长期存在的保菌宿主。
在欧洲，多起感染的爆发都与水源污染有关，并且从水和淤泥中检测到土拉弗朗西丝菌
节肢动物，包括虻、跳蚤、虱子、蜱、蚊子和蝇均可传播本病。鼠间和野兔间的流行主要通过这些吸血节肢动物传播，尤其是蜱。疫源地的家畜和家禽也可能被感染。
我国曹务春等对采用PCR技术我国吉林、新疆、黑龙江内蒙古和浙江等地14种啮齿动物样品进行检测发现总体感染率为4.76%，除浙江的样品全部阴性外，阳性率分别为11.65%、10%、 6.54%和1.76%。
吉林省成年革蜱的阳性率为3.67%、黑龙江和内蒙古硬蜱的阳性率分别为2.25%和3.0%。
对20个阳性样品的PCR产物进行序列分析证明，感染的菌株为土拉弗朗西丝菌全北区亚种。
本病可通过多种途径传播给人包括：
1）直接接触感染动物的尸体、排泄物或污染的水体。我国报道的的人间感染病例很多与狩猎和加工野兔有关。
2）经呼吸道和眼结膜感染带有细菌的气溶胶和粉尘。如堆积或加工被污染的干草等可发生呼吸道吸入感染。
3）经吸血昆虫叮咬感染。目前尚未发现有人与人之间直接感染传播的报道。
临床症状
人感染发病的潜伏期为1-15天不等，平均为3-5天。表现为突然发病，体温迅速升高，同时怕冷，全身疼痛和头疼。根据感染途径的不同土拉杆菌病可分为：
腺型和腺溃疡型土拉杆菌病：主要通过吸血昆虫叮咬、直接接触感染动物或通过接触被动物污染的用具或垫料而间接感染。病变主要见于接触细菌的部位，首先形成丘疹，周边有明显的炎性反应带，随后形成脓肿。感染后的几天内，体温升高、局部淋巴结肿大，变硬，表面皮肤发红和水肿。
眼腺型土拉杆菌病：比较少见，主要细菌通过结膜感染引起。除了发热和全身症状外，可见单侧结膜、眼睑红肿，流泪和畏光等。
咽喉型土拉杆菌病：主要通过口腔摄入被污染的饮水和食物感染。主要表现为口炎和咽喉炎，也可能伴有扁桃体炎。有时可见口腔和咽喉黏膜化脓性病变和一侧性淋巴腺炎。
呼吸型土拉杆菌病：为最严重和致命性感染，主要是吸入含有细菌的气溶胶感染。有典型的肺炎症状，如咳嗽、胸痛、呼吸频率增加，也可能仅表现高热和全身性症状，如恶心和呕吐。A型强度感染表现为突然发病、怕冷、高热、呼吸困难、咳嗽、胸部疼痛、头疼、出汗和身体虚弱，表现某些伤寒热的特征，出现神志紊乱。相比较而言，B型呼吸道感染的肺炎症状相对较轻，但X光检查可见肺脏病变。
Human infection
--Ulceroglandular tularemia— infection through the skin or mucous membranes
--Ocularglandular tularemia—direct contamination of eye with the bacterium
--Oropharyngeal tularemia—ingestion of   contaminated water or food
--Typhoidal tularemia—severe systemic infection
--Respiratory tularemia —infection by inhalation
动物感染
诊断
    局部皮肤出现红肿、溃疡、单侧淋巴结重大，结合流行病学资料和职业特点。
    特别是有与野兔或野鼠接触史，或者被吸血昆虫，尤其是蜱叮咬过等对诊断具有重要的参考价值。对可疑病例可采用下面的方法进行确诊。
细菌分离培养  
  1）由于土拉弗朗西丝菌营养要求比较高，生长缓慢，在临床诊断中很少进行细菌分离培养。
  2）在进行实验诊断时应采取严格的实验室生物安全措施。
  3）样品的运送和保存是细菌分离成功与否的关键。
     对新鲜的淋巴结和组织可冻存于-80C，或用改良的Thayer-Martin培养基运送到相关实验室。也可就地将养品，以脾脏和肝脏组织为佳，划线接种到添加了9%巧克力化绵羊血的胱氨酸心琼脂上，密封后在常温下2-3天运送到实验室进行培养。为了减少污染，提高分离率，可以在培养基中添加多黏菌素、林可霉素和两性霉素等抑制杂菌生。
4）对生长的菌落可采用玻片凝集或免疫荧光染色进行鉴定，也可采用PCR技术检测fopA或tul4基因。
血清学诊断 
  ★试管凝集或微量凝集试验具有很高的敏感性和特异性。人在发病后2周抗体效价可达到320-1280。临床康复后血清抗体下降很慢，20年后还能检测到抗体。
  ★作为诊断，应采取双份血清进行检测，一份为发病急性期血清，另一份为3周后血清，如果抗体效价增加4倍即可确诊。
 ★当出现土拉杆菌病的临床症状，而且血清效价高于160，也可以确诊。
 ★血清效价较低时，可能为非特异性的交叉反应，应注意排除布氏杆菌病和耶尔森菌病。此外，还可采用ELISA检测抗体。
直接免疫学方法检测抗原 
   可以采用免疫荧光抗体染色方法检测尸体或剖检样品中的细菌抗原，但该方法不太适合人土拉杆菌病的诊断。但ELISA方法可以用于组织、分泌物和环境（如水和淤泥）中抗原的检测。
分子生物学检测 
    PCR技术目前已广泛用于土拉杆菌病诊断和鉴定，具有很高的敏感性和特异性，可用于多种样品的检测。目标基因有fopA、tul4和16S rRNA基因等。荧光实时PCR还可用于不同亚种的检测。
鹦鹉热 Psittacosis
History
In 1879, psittacosis or parrot fever was documented for the first time when Ritter (1880) described an epidemic of unusual pneumonia associated with exposure to tropical pet birds in seven individuals in Switzerland.
In 1907, Halberstaedter and von Prowazek were the first to make drawings of chlamydia-infected conjunctival cells of trachoma (Chlamydia trachomatis) patients.
In the following years, similar infective agents causing inclusion conjunctivitis of the newborn or infection of the adult genital tract were described. The inability to grow these germs, in fact C. trachomatis organisms, on artificial media made scientists assume that they were viruses.
During the winter of 1929–1930, a pandemic of human psittacosis (occurred in the United States and Europe.
The disease was attributed to the importation of Green Amazon parrots from Argentina. Shortly afterwards, 174 cases of human psittacosis were reported from the Faroe Islands in the period from 1930 to 1938. The human death rate was 20% and was especially high (80%) in pregnant women. Humans contracted the infection while capturing juvenile fulmars (Fulmarus glacialis) and preparing them for cooking.
病原学 etiology
分类 classification
衣原体科(Chlamydiaceae)
    衣原体属(Chlamydia)
         沙眼衣原体(C. trachomatis)
         猪衣原体( C.suis)
         鼠衣原体( C. muridarum)
    嗜性衣原体属(Chlamydophila)
         鹦鹉热嗜性衣原体(C. psittaci)
         肺炎嗜性衣原体( C. pneumoniae)
         反刍动物嗜性衣原体( C. pecorum)
         流产嗜性衣原体( C. abortus)
         猫嗜性衣原体( C. felis)
         豚鼠嗜性衣原体( C. caviae)
Morphology
   Morphologically distinct forms of  Chlamydophila are termed elementary body (EB,始体), The EB is a small, electron-dense, spherical body, of about 0.2–0.3 mm in diameter
The reticulate body (RB 网状体is larger, measuring approximately 0.5–2.0 mm in diameter.
   During this maturation, morphologically intermediate body (IB，中间体measuring about 0.3–1.0 mm in diameter can be observed inside the host cell.
Model of chlamydial cell wall or envelope
衣原体(Chlamydiae) 广泛分布于世界各地,引起动物和 人的多种疾病,特别是鹦鹉热嗜性衣原体( Chlamydophila psittaci , C. p) 和流产嗜性衣原体( C. abortus) ,可由动物传染 给人,导致严重的人兽共患病(zoonotic infections) 。
衣原体 是专性细胞内寄生菌,具有独特的两阶段生活方式,即细胞 外感染期和细胞内寄生期,致使由其所引发的各种病症很难 控制。
感染人的最重要的动 物衣原体病是鹦鹉热(psittacosis) ,该病是鹦鹉鸟类的一种 全身性疾病,可表现为急性、亚急性、慢性或亚临床性。
Infection biology
C. psittaci is an obligate intracellular bacterium（专性细胞内寄生） replicating within a non-acidified vacuole, termed an inclusion（包涵体）.
Within the inclusion, C. psittaci undergoes a unique biphasic developmental cycle alternating between the EB, which guarantees extracellular survival and infection of host cells and RB, which is responsible for intracellular replication and generation of infectious progenitor bacteria.
EBs
Attachment (黏附）
Endocytosis（内吞）
Aggregate at Golgi region
(Microtubule Organizing Center)
Differentiate into RBs（分化）
Replicate by binary fission（二分裂繁殖）
RBs detach from inclusion membrane
     (IBs + RBs)
first few hours: EBs differentiating ( losss infectivity)
20 h PI : active replicating (1:1000)
50 h PI: inclusion lysing
Persistence infection（持续感染）
Persistent chlamydiae fail to complete their development from RBs into infectious EBs, but retain metabolic activity.
Persistent RBs appear morphologically aberrant from oval shaped to strongly enlarged and form small inclusions. While they accumulate chromosomes because of continuing DNA replication, they do not divide.
Persistent growth forms have been associated with chronic infections.
Avian chlamydiosis
All known avian strains belong to the species C. psittaci, which comprises six avian serovars(血清型） A to F, and two mammalian isolates, WC and M56
     (The isolates WC and M56 originated from epizootics in cattle and muskrats（麝鼠）, respectively.)
The avian serovars are relatively host-specific.
Serovars A and B are usually associated with psittacine birds and pigeons.
     The natural hosts of the other serovars are more uncertain.
     Serovar C has primarily been isolated from ducks and geese
     Serovar D mainly from turkeys.
     Serovar F was isolated from a psittacine bird and from turkeys.
     The host range of serovar E is the most diverse among these types, as it was isolated from about 20% of pigeons, from many cases of fatal chlamydiosis in ratites, from outbreaks in ducks and turkeys, and occasionally from humans.
All serovars should be considered to be readily transmissible to humans.
Epidemiology流行病学
C. psittaci infections were not limited to psittacine birds, but could also affect other avian species.
   C. psittaci has been demonstrated in about 465 bird species comprising 30 different bird orders .
 The highest infection rates are found in psittacine birds (Psittacidae) and pigeons (Columbiformes).
The  prevalence（感染率） in psittacine birds ranges between 16 and 81%, and a mortality rate of 50% or even higher is not unusual.
Psittacidae are major reservoirs of chlamydiae, especially under captive  conditions, but also among those kept as pets.
Data on the seropositivity of racing pigeons range from 35.9 to 60%.
    Free-living pigeons are present in urban and rural areas all over the world and get in close contact with people in public places.
Thirty-eight studies on the seroprevalence of C. psittaci in feral pigeons conducted from 1966 to 2005 revealed a seropositivity rate ranging from 12.5 to 95.6%
More recent studies performed in feral pigeons in Italy, Bosnia and Herzegovina, and Macedonia showed a seropositivity of 48.5%, 26.5% and 19.2%, respectively
Birds living on sea shores and other waters, such as gees, ducks, gulls and penguins are more frequently infected than hens, pheasants and quails
 Common reservoirs of C. psittaci include wild and feral birds, such as sea gulls, ducks, herons（苍鹭）, egrets（白鹭）, pigeons, blackbirds, grackles（鹩哥）, house sparrows, and killdeer, all of which freely intermingle with domestic birds.
 Highly virulent strains of C. psittaci can be carried and extensively excreted by sea gulls and egrets without any apparent effect on the hosts themselves.
Transmission between birds鸟间传播
排毒方式
Transmission of C. psittaci primarily occurs from one infected bird to another susceptible bird in close proximity.
The agent is excreted in faeces and nasal discharges.
 Faecal shedding occurs intermittently and can be activated through stress caused by nutritional deficiencies, prolonged transport, overcrowding, chilling, breeding, egg laying, treatment or handling.
排毒期
Bacterial excretion periods during natural infection can vary depending on virulence of the strain, infection dose and host immune status.
However, shedding may occur for several months.
Mode of transmission
传播方式 Transmission of chlamydiae occurs mainly through inhalation（吸入） of contaminated material and, sometimes ingestion.
Large numbers of C. psittaci cells can be found in respiratory tract exudate and faecal material of infected birds. The importance of the respiratory exudate has become more apparent.
In turkeys, the lateral nasal glands become infected early and remain infected for more than 60 days.
Choanal/oropharyngeal swabs are more consistent for isolation of the agent than faecal swabs, especially during early stages of infection.
 Direct aerosol transmission through aerosolization of respiratory exudate must be considered as the primary method of transmission.
Avian species, including domestic poultry sharing aquatic or moist soil habitats with wild infected aquatic birds may become infected via contaminated water.
Birds like pigeons, doves, pheasants and house sparrows may become infected by dust inhalation in faeces contaminated barnyards and grain storage sites.
The consumption of infected carcasses may transmit C. psittaci to host species that are predators or scavengers of otherbirds.
病鸟主要表现为精神沉郁、羽毛蓬乱、厌食、消瘦、呼吸困难和腹泻
康复鸟带菌率约10%
分泌物和排泄物排出大量病菌污染羽毛、粉尘等。
人感染：
发达国家感染很大程度上与鹦鹉有关
观赏鸟
家鸭、鹦鹉和鸽 （中国）
哺乳动物（羊、牛表现为流产、死胎、肺炎或无症状）
Transmission of C. psittaci in the nest is possible.
transmission from parent to young may occur through feeding, by regurgitation,  contamination of the nesting site with infective exudates or faeces may be important in other species, such as snow geese, gulls and shorebirds.
Furthermore, C. psittaci can be transmitted from bird to bird by blood-sucking ectoparasites such as lice, mites and flies or, less commonly, through bites or wounds.
Transmission of C. psittaci by arthropod vectors would be facilitated in the nest environment.
Vertical transmission（垂直感染） has been demonstrated in turkeys, chickens, ducks, parakeets, seagulls and snow geese, although the frequency appears to be fairly low
Clinical disease
Depending on the chlamydial strain and the avian host.
Chlamydiae cause pericarditis, air sacculitis, pneumonia, lateral nasal adenitis, peritonitis, hepatitis, and splenitis.
     Generalized infections result in fever, anorexia, lethargy, diarrhoea and occasionally shock and death.
Chlamydiosis is a very common chronic infection of psittacine birds.
     Infections cause conjunctivitis, enteritis, air sacculitis, pneumonitis, and hepatosplenomegaly.
     Droppings are often green to yellow-green.
 Many of the birds become chronically infected, but show no clinical signs until stressed. These birds often shed chlamydiae intermittently and serve as a source of infection of humans and other birds.
Pigeon infection
Chlamydiosis is also a common chronic infection of pigeons.
Clinical signs include conjunctivitis, blepharitis, and rhinitis. Survivors can become asymptomatic carriers.
Turkey infection
Infected turkeys show vasculitis, pericarditis, pneumonitis, air sacculitis, and hepatosplenomegaly, and lateral nasal adenitis at necropsy.
    Mortality rates of 5–40% may occur unless early antibiotic treatment is introduced
Chlamydiosis in ducks is a serious economic and occupational health problem in Europe.
Trembling, conjunctivitis, rhinitis, and diarrhea are observed in infected ducks. Mortality ranges to up to 30%.
Public health significance
传播途径
流行特征
     地区分布—广泛存在
     时间分布 无明显季节性，但某些情况例外
    人群分布--职业
     流行形式—散发或爆发
人类   经呼吸道吸入病鸟粪便、分泌物或羽毛的气雾或尘埃。(Humans most often become infected by inhaling the organism when urine, respiratory secretions or dried faeces of infected birds are dispersed in the air as very fine droplets or dust particles.)
紧密接触( include mouth-to-beak contact, a bite from an infected bird or handling the plumage and tissues of infected birds.)
人-人传播(Person-to-person transmission of psittacosis is possible, but is believed to be rare
The incubation period(潜伏期） is usually 5–14 days, but longer incubation periods are known.
 Human infections vary from inapparent to severe systemic disease with interstitial pneumonia and occasionally encephalitis.
The disease is rarely fatal in properly treated patients; therefore, awareness of the danger and early diagnosis are important.
Infected humans typically develop headache, chills, malaise and myalgia, with or without signs of respiratory involvement. While pulmonary involvement is common,auscultatory findings may appear to be normal.
A number of severe cases of human psittacosis, i.e., atypical pneumonia, were reported recently
As in birds, the carrier status might be common, as well as pathogenic synergies with other respiratory pathogens
Diagnosis of C. psittaci infection can indeed be difficult and is usually accomplished through testing paired sera, or only one serum sample, using the micro-immunofluorescence (MIF) test, which is more sensitive and specific than the complement fixation test.
 Highly sensitive nucleic acid amplification assays can be used to specifically detect C. psittaci.
Culture is also possible, but technically rather difficult for requiring biosafety level 3 laboratories.
Like in birds, tetracyclines are the drugs of choice for treating human psittacosis. Doxycycline or tetracycline is usually administered, unless contraindicated, like in the case of pregnant women and children under 9 years, where erythromycin can be used. The length of treatment will vary with the drug, but should be continued for at least 14 days for tetracycline.
Antigen detection
Smears
For C. psittaci infectionin birds,smears can be prepared from faeces, cloacal swabs, conjunctival scrapings, although pharyngeal or nasal swabs are preferred
Impression smears can also be prepared from tissue samples obtained from liver, spleen, kidney, lung and pericardium.
In cats and koalas, organisms may be detectedfrom conjunctival, urogenital or genital swabs.
Prepared smears can be stained for detection of chlamydiae using one of several staining procedures, for example, modified Machiavello, modified Gimenez, Giemsa, or modified Ziehl-Neelsen (MZN)
Fluorescent antibody tests using Chlamydiaceae-specific anti-LPS antibodies or species-specific mAbs to MOMP,
Pathological specimens
Following the submission of tissue samples to the  diagnostic laboratory for analysis, chlamydiae can be demonstrated in histological preparations using a variety of staining procedures.
Immunohistochemical staining procedures that utilise mAbs directed against chlamydial surface antigens, such as LPS or MOMP, are more sensitive and produce more striking results in comparison to histochemical staining.
Immunoassays
Most of the commercially available antigen detection tests that have been developed over the last 25 years are used primarily and extensively for the detection of Chlamydia trachomatis infections in human clinical specimens based on the family-specific LPS antigen.
These immunoassays include direct fluorescent antibody (DFA) tests (for example IMAGEN, Celltech; Chlamydia-Direct IF, BioMerieux; Vet-IF, Cell Labs),
plate-based ELISAs (Chlamydiazyme, Abbott; IDEIA, Dako; IDEIA PCE, Dako; Pathfinder, Kallestad; Chlamydia-EIA, Pharmacia)
And solid-phase ELISAs (Clearview Chlamydia MF, Unipath; Surecell, Kodak).
Isolation
Suitable antibiotics include streptomycin (200 mg/ml), gentamicin (50 mg/ml), vancomycin (75 mg/ml) and nystatin (25 units/ml),
penicillin, tetracycline and chloramphenicol inhibit chlamydial growth and should not be used.
Yolk-sacs of 6–8-day-old embryos are inoculated with 10% sample suspensions and embryos die between 4 and 14 days after infection. Smears prepared from yolk-sac membranes at the time of death, or from surviving eggs on completion of the experiment, can be stained, using a variety of procedures, such as MZN, modified Machiavello or Giemsa to reveal EBs, thus confirming chlamydial infection.
Most cell types are susceptible to C.  psittaci infection, but the direct inoculation into cultures of BGMK, African green  monkey kidney (Vero), McCoy and L cells are commonly used
Infection of chlamydiae in cell culture can be enhanced by centrifugation and/or by chemical treatment of cultured cells, before or during infection, using for example cycloheximide (1 mg/ml), cytochalasin B (2 mg/ml), emetine (1 mg/ml), diethylaminoethyl-dextran (20 mg/ml) or 5-iodo-2-deoxyuridine (80 mg/ml)
Antibody detection
The detection of antibodies in animal chlamydial infections has multiple purposes, i.e. confirmation of clinical disease or confirmation of the presence or absence of infection, performance of epidemiological surveys to estimate the prevalence of infection, or the determination of immune status after vaccination to name some.
Detection of the bound antibody is achieved by fluorescent, i.e. indirect immunofluorescence test and MIF, or otherwise tagged secondary antibodies, i.e. indirect ELISA, or by estimating the consumption or fixation of complement,
DNA amplification methods
Conventional PCR
Real-time PCR
Treatment and Prevention
Like in birds, tetracyclines are the drugs of choice for treating human psittacosis.
Doxycycline or tetracycline is usually administered, unless contraindicated, like in the case of pregnant women and children under 9 years, where erythromycin can be used.
The length of treatment will vary with the drug, but should be continued for at least 14 days for tetracycline.