拉沙熱研究進展

邵楠，曹玉璽，王環(huán)宇

中國疾病預防控制中心病毒病預防控制所，北京 102206

·特約專稿·

拉沙熱研究進展

邵楠，曹玉璽，王環(huán)宇

中國疾病預防控制中心病毒病預防控制所，北京 102206

拉沙熱(Lassa fever，LF)由拉沙病毒(Lassa virus，LASV)引起，是一種通過鼠類傳播給人的急性出血性動物源性傳染病，病死率高。主要在西非地區(qū)流行，但在全球多個國家發(fā)現(xiàn)輸入性病例。本文主要針對拉沙病毒的病原學特點、疾病流行現(xiàn)狀、臨床特征、實驗室檢測、治療及預防進展進行綜述。同時，建議在全球經(jīng)濟一體化的大形勢下，加強對拉沙熱國際防控的關注度，建立國際聯(lián)防聯(lián)控防治策略和措施，并將其納入全球防控體系。

拉沙熱；流行病學；防控

拉沙熱(Lassa fever，LF)由拉沙病毒(Lassa virus，LASV)引起，是一種急性出血性動物源性傳染病，主要通過鼠類傳播給人。目前，拉沙熱的流行區(qū)域已從西非擴散到非洲內(nèi)陸，且在歐洲(英國、德國)、美洲(美國、加拿大)、亞洲(日本)等國均有輸入性病例的報道。

首例拉沙熱病例發(fā)現(xiàn)于20世紀50年代[1-2]。1969年，兩名尼日利亞東北部地區(qū)拉沙鎮(zhèn)教會醫(yī)院的醫(yī)護人員被1名美國護士傳染后死亡，最終從死亡病例的血液標本中成功分離出該病毒，并以分離地點命名[2]。自1969年以后，拉沙熱在尼日利亞納薩拉瓦州、塔拉巴州、約貝州等多個地區(qū)暴發(fā)[3-5]。與2014年西非大規(guī)模暴發(fā)的埃博拉疫情地區(qū)分布類似，拉沙熱主要在西非塞拉利昂、幾內(nèi)亞、尼日利亞、利比里亞等地區(qū)暴發(fā)流行[6-7]，且發(fā)病率和病死率較高。據(jù)估計，西非每年有30萬～50萬人感染拉沙病毒，死亡5 000～10 000例[1,6-11]。此外，由于多乳鼠(Mastomysnatalensis)在西非地區(qū)廣泛分布，對主要流行區(qū)的周邊國家存在一定的潛在安全性威脅[7]。近年來，不斷有拉沙熱病例報道。2014年，貝寧確診首例拉沙熱病例；加納自2011年首次報道拉沙熱病例后，于2013年出現(xiàn)2例輸入性病例[12-13]；英國于2009年由馬里輸入首例拉沙熱病例[14]；在靠近幾內(nèi)亞灣的科特迪瓦、多哥及西非內(nèi)陸國家布基納法索均有拉沙熱病例報道[15-19]。然而，由于疾病高發(fā)地區(qū)醫(yī)療條件落后，缺乏有效疫苗和抗病毒藥物及實驗室精密檢測儀器，導致患者接受治療時間滯后，進一步加劇了西非地區(qū)國家的經(jīng)濟負擔。

本文主要針對拉沙病毒的病原學特點、疾病流行現(xiàn)狀、臨床特點、實驗室檢測、治療及預防進展等進行綜述，以期進一步增加對拉沙熱的認識，提高防控意識。

1 病原學特征

拉沙病毒屬沙粒病毒科，基因組由2節(jié)段單負鏈RNA組成[20-21]，與淋巴細胞脈絡叢腦膜炎病毒(lymphocytic choriomeningitis virus，LCMV)同屬舊世界群(LCM族)，而新世界群主要包括塔卡里伯病毒(Tacaribe virus)、胡寧病毒(Junin virus)、馬丘波病毒(Machupo virus)、阿馬帕里病毒(Amapari virus)等[22]。病毒大小60～280 nm，呈非對稱性，有包膜[22-23]。核內(nèi)為單負鏈RNA，分別為S RNA和L RNA。S RNA(22S)約3 400個堿基，編碼主要結構蛋白[24]：核衣殼蛋白(nuclocapsid protein，N)；糖蛋白(glycoprotein，G)，進一步切割為G1和G2，參與構成病毒的包膜和刺突，為病毒特異性中和抗原。L RNA(31S)約7 200個堿基，編碼RNA依賴的RNA聚合酶(RNA-dependent RNA polymerase，RdRP)和調節(jié)蛋白Z[25]。研究顯示，Z蛋白可通過直接作用于翻譯起始因子eIF4E，阻止mRNA翻譯網(wǎng)織紅細胞溶解產(chǎn)物；此外，在感染時，Z蛋白通過作用于早幼粒細胞性白血病(promyelocytic leukemia，PML)蛋白而避免宿主細胞凋亡[26]。

2 流行病學特征

2.1 病毒儲存宿主及感染途徑

鼠類為拉沙病毒的主要儲存宿主，包括多乳鼠、家鼠、草鼠等[27]。在西非地區(qū)主要是多乳鼠[28-32]，該鼠繁殖能力較強，常出沒于食物儲藏地及住房環(huán)境擁擠、衛(wèi)生條件差的鄉(xiāng)村地區(qū)。McCormick等的早期研究顯示，在拉沙熱流行地區(qū)約30%多乳鼠自然攜帶病毒[9]。人群主要因密切接觸帶有病毒的嚙齒類動物而感染。感染方式包括吸入帶病毒的氣溶膠、接觸被感染動物的分泌物(血液、尿液及糞便)或食入被污染的食物及帶病毒的鼠肉等[33-34]。在西非部分經(jīng)濟落后地區(qū)，當?shù)鼐用褚恢北３植妒蟮挠螒蚧顒雍褪呈笕獾娘L俗習慣[33,35]。相關研究表明，在食鼠肉感染者中神經(jīng)性耳聾癥狀更常見，約為無此飲食習慣感染者的3.7倍[35]。因此，與鼠類密切接觸且食用鼠肉的風俗是拉沙熱在西非地區(qū)流行不可忽視的潛在危險因素。

2.2 病毒傳播方式

拉沙病毒可在人與人之間傳播，主要通過接觸被感染者的血液、尿液、糞便及分泌液(如精液等)[34,36]。有研究顯示，可從感染者血、尿、咽部、嘔吐物、分泌物及精液中分離到拉沙病毒[31,33,36-38]，該病毒從感染者尿液中排出可持續(xù)3～9周，在精液中甚至長達3個月[1,39]。此外，接觸被污染的醫(yī)療器械和反復利用針具等是造成醫(yī)院內(nèi)感染的主要因素[32]。雖然早期研究顯示通過簡單防護措施能明顯減少病毒通過人傳人的方式傳播[40-42]，但Lo Iacono等通過建立模型對塞拉利昂凱內(nèi)馬公立醫(yī)院(Kenema Government Hospital，KGH)出現(xiàn)的拉沙熱患者進行綜合分析時發(fā)現(xiàn)，在住院患者中病毒以人傳人的方式傳播，5%拉沙熱患者引起的二代發(fā)病率高達20%[34]。目前，性傳播方式感染雖有報道，但尚不明確。此外，實驗室研究表明該病毒在氣溶膠中穩(wěn)定存在，嚙齒類動物之間可通過空氣傳播方式感染[28,43]。

2.3 發(fā)病年齡

多項研究結果顯示，拉沙熱總體病死率高達1%～2%，住院患者病死率高達15%，疾病暴發(fā)期間住院患者病死率高達50%[1,3,9,13,44-46]。各年齡段人群均可感染拉沙病毒。西非利比里亞地區(qū)2008—2012年以醫(yī)院為基礎的監(jiān)測結果表明，拉沙熱病例主要為20～39歲群體，女性較男性多(56.2%vs. 43.8%)；且病例主要在8月下旬至9月出現(xiàn)[47]。同期，塞拉利昂2002—2012年監(jiān)測結果表明，患者(Ag+/IgM±)發(fā)病年齡呈雙峰分布，分別為0～9歲和15～39歲；實驗室檢測發(fā)現(xiàn)Ag+/IgM±患者的發(fā)病高峰主要在3月，而Ag-/IgM±患者具有兩段高峰時期，分別是旱季的3月和雨季的10月[48]。此外，對感染期孕婦的調查顯示，流產(chǎn)是拉沙熱的嚴重并發(fā)癥，特別是妊娠晚期，孕婦和胎兒死亡率較高[9,49-50]。醫(yī)療工作者往往在護理拉沙熱患者期間因缺乏適當?shù)膫€人防護用品(personal protective equipment，PPE)及醫(yī)院傳染病管理規(guī)范和防控措施不健全而被感染[3,36,51]。

2.4 病毒感染的擴大趨勢

隨著全球各國之間人員往來越來越密切，拉沙熱也隨著旅游人群向其他地區(qū)播散。目前，美國、德國、英國、日本、以色列、加拿大均有拉沙熱輸入性病例的報道[14,17,52-54]。早期，輸入性病例主要來自西非高發(fā)區(qū)(塞拉利昂、尼日利亞、利比里亞和幾內(nèi)亞等)[54]，隨著病毒在西非廣大地區(qū)出現(xiàn)，已有來自加納、馬里、布基納法索或科特迪瓦等原拉沙熱低發(fā)地區(qū)的輸入性病例報道[14,54-55]。Branco等對1例拉沙熱孕婦體內(nèi)毒株進行分離，發(fā)現(xiàn)該毒株與原型株(Josiah strain)的核苷酸同源性僅為89%，提示塞拉利昂分離的新病毒流行株的基因出現(xiàn)明顯變異，表明此變異株的地理分布范圍具有潛在擴大的可能性[50]。

3 致病性與免疫

3.1 發(fā)病機制

目前拉沙病毒的免疫發(fā)病機制尚不完全清楚[56]，但基本認為病毒主要通過呼吸道、消化道和皮膚及黏膜等途徑侵入機體，在單核-巨噬細胞和內(nèi)皮細胞中生長和繁殖，暫時不引起細胞損傷。病毒直接侵犯細胞，在細胞內(nèi)復制時能抑制某些促炎癥因子的作用，因此拉沙熱患者中很少見到炎癥反應。但由于拉沙病毒的受體α dystroglycan(α-DG)廣泛分布于機體各組織[57]，病毒可侵入多種器官，引起肺部疾病、消化道出血、心肌炎、肝脾細胞壞死、腎臟疾病等，從而導致機體多器官功能衰竭而引發(fā)死亡。

3.2 病毒抗體

拉沙熱血癥期達20 d左右，由于中和抗體出現(xiàn)晚，且抗體效價低，T細胞在病毒感染早期發(fā)揮重要抵抗作用。若細胞免疫受損或延遲，血液中高病毒血癥將導致病情惡性發(fā)展[58-59]，一般4～9 d后病毒血癥達高峰[21]。對于幸存者，體內(nèi)病毒滴度在癥狀出現(xiàn)3周后開始逐漸降低，最終從血循環(huán)中清除，患者開始恢復[44,60-62]。中和抗體一般在急性感染后幾個月才產(chǎn)生，且抗體效價持續(xù)上升，甚至有研究顯示在感染后40年人體內(nèi)仍有較高效價的IgG抗體[63]。目前，中和抗體在急性恢復中的作用尚不明確，而在被動免疫中則顯示保護作用與中和抗體效價相關。

3.3 流行區(qū)域

尼日利亞、幾內(nèi)亞和塞拉利昂地區(qū)的人群中，拉沙病毒抗體陽性率分別為21%、4%～55%和8%～52%。據(jù)此估計約有5 900萬人處于拉沙病毒感染的威脅之中，年發(fā)病人數(shù)可達300萬，年死亡人數(shù)可達6.7萬[8,39,64]。2009年Fichet-Calvet等通過模型估計拉沙熱可能覆蓋塞拉利昂和利比里亞近80%的地區(qū)，幾內(nèi)亞和利比里亞地區(qū)分別達50%和40%，貝寧、科迪瓦特和多哥均達30%，加納約10%[6]。最近，Mylne等根據(jù)研究結果預計，西非地區(qū)約14個國家中，共計3 700萬人生活在適宜拉沙病毒傳播的區(qū)域[65]。提示如果未能采取適當防控措施，可能會引起疾病的大規(guī)模暴發(fā)，嚴重威脅周邊國家和地區(qū)人群的健康。

4 臨床癥狀和體征

新生乳鼠感染拉沙病毒后，體內(nèi)可明顯檢測到病毒滴度，但多為持續(xù)性無癥狀感染[66]。人體感染病毒后，潛伏期一般為6～21 d[10,44,46]。疾病初期，80%感染者處于亞臨床癥狀，無明顯臨床癥狀或癥狀輕微(輕度發(fā)熱、無力)，因此診斷困難[2,44,67]；其余20%感染者可最終發(fā)展為嚴重的多系統(tǒng)疾病[68]。潛伏后期，患者病情逐漸加重，出現(xiàn)頭痛、咽痛、胸痛及肌肉痛[8,62,67,69-70]，并伴有惡心、嘔吐、腹瀉、咳嗽、腹痛和耳鳴等癥狀[27]，常出現(xiàn)面頸部腫脹，胸腔積液，口、鼻、胃腸道、陰道出血，蛋白尿等[2,71-73]，甚至發(fā)展為低血壓，有時可出現(xiàn)皮膚斑丘疹。疾病后期，一般在癥狀出現(xiàn)后第10～14天，患者出現(xiàn)休克、癲、震顫、定向障礙和昏迷等嚴重癥狀[55]。最終，因肝、肺及心臟等多器官受損而死亡[74]。拉沙熱患者很少出現(xiàn)神經(jīng)系統(tǒng)癥狀，但神經(jīng)性耳聾是其并發(fā)癥之一，常見于疾病后期和恢復早期[75-76]，約20%感染者出現(xiàn)短暫性或永久性耳聾[8]。兒童與成人的病程相似，嬰兒則表現(xiàn)為“水腫嬰兒綜合征”，出現(xiàn)全身水腫、腹部腫脹、出血等癥狀。

5 診斷與鑒別診斷

5.1 診斷

目前，主要采用酶聯(lián)免疫吸附試驗(enzyme-linked immunosorbent assay，ELISA)檢測拉沙病毒IgM和IgG抗體及抗原來確診疾病，也可采用反轉錄聚合酶鏈反應(reverse transcriptase-polymerase chain reaction，RT-PCR)針對拉沙病毒基因進行檢測，但由于病毒分離培養(yǎng)時間較長，一般不用于臨床診斷。作為拉沙熱篩檢指標，檢測血清中IgM抗體效果并不顯著，靈敏度和特異度分別為55%和57%[77]。雖然RT-PCR的靈敏度和特異度較高，且可用于早期診斷，但西非地區(qū)經(jīng)濟欠發(fā)達，基本不具備先進實驗設備和技術，因此需研發(fā)適用于當?shù)氐母喴妆憬萸铱刹僮鞯目焖俸Y檢方法?？焖倏尚械膶嶒炇以\斷方法有利于早期發(fā)現(xiàn)潛在的病毒攜帶者，給予及時抗病毒治療，從而提高治療效果。與埃博拉病毒類似，拉沙病毒病原學檢測需在生物安全4級(biosafety level 4，BSL-4)實驗室中完成。這意味著，由于實驗條件限制，常規(guī)的病毒分離、培養(yǎng)、檢測等方法不能廣泛應用。

5.2 鑒別診斷

拉沙熱的臨床癥狀缺乏特異性，往往易與穿孔性傷寒回腸炎[11,67]、咽炎、瘧疾及其他出血性疾病(如埃博拉病毒病)等混淆[39]。因此，臨床診斷時應慎重，避免延誤疾病治療的最佳時間。

6 藥物與疫苗

目前尚未有經(jīng)許可的藥物或疫苗用于治療拉沙熱。

6.1 藥物

核苷酸類似物利巴韋林被認為是治療拉沙熱的有效抗病毒藥物，但對其抗病毒機制尚存在一定爭議[78-81]。有研究指出，利巴韋林可用于疾病發(fā)展各期[82]，但僅在疾病早期使用時效果明顯，能降低患者包括高?；颊叩牟∷缆蔥83-84]。McCormick等研究表明，如果在出現(xiàn)癥狀后的前6 d內(nèi)靜脈注射利巴韋林，病死率將大幅下降(55%vs. 5%，P=0.000 2)[9,83,85]，與Dahmane等的研究結果相符(50%vs. 29%)[86]。而Asogun等研究顯示，即使對感染者采用利巴韋林進行抗病毒治療，仍有近1/3的感染者不能避免死亡[87]。因此，需尋找更有效的治療藥物。目前具有廣譜抗病毒作用的法匹拉韋被認為是理想的候選藥物[88]。最近一項致死性小鼠實驗發(fā)現(xiàn)，法匹拉韋與利巴韋林對抗拉沙病毒具有協(xié)同作用[89]，提示兩者聯(lián)用有望降低感染者的病死率。

6.2 疫苗

研究表明，滅活拉沙熱疫苗安全性較好，但缺乏有效免疫保護作用[90]。Mopeia病毒和ML29毒株是減毒疫苗的良好候選者[91-96]，但仍需更多臨床試驗支持。重組活載體疫苗(牛痘病毒載體、水皰性口炎病毒載體、黃熱病毒YF17D載體、委內(nèi)瑞拉馬腦炎病毒復制子、病毒樣顆粒)和DNA疫苗等新型疫苗尚處于實驗階段[96-101]。研究顯示，重組黃熱病毒載體疫苗接種的豚鼠雖能避免死亡，但不能防止感染拉沙病毒[97]。此外，考慮到拉沙病毒在不同地理環(huán)境中基因的高度多樣性[92]，開展抵抗不同基因型拉沙病毒疫苗的研究具有重要意義。Safronetz等用水皰性口炎病毒載體疫苗VSV-LASV免疫近交系13的豚鼠及獼猴，證實該疫苗對不同地區(qū)(馬里、尼日利亞及利比里亞等)的分離株均能產(chǎn)生保護作用[99]，提示理想的候選疫苗應對不同血清型拉沙病毒具有交叉保護作用和良好的成本效益。目前，由于實驗動物需求量大、實驗條件要求嚴格(BSL-4實驗室)等限制因素，拉沙熱疫苗研發(fā)存在一定局限性[96]。

7 預防和控制措施

7.1 控制傳染源

在西非地區(qū)，主要加強居室周圍生活環(huán)境中的滅鼠工作。隔離感染者(疑似及確診患者)，防止在醫(yī)院內(nèi)引發(fā)二次感染，嚴格處理患者體液和排泄物，對使用后的醫(yī)療設備進行消毒殺菌及暴露后預防(post-exposure prophylaxis，PEP)等。鑒于已從拉沙熱恢復期患者的尿液或精液中分離到病毒，但尚不清楚排毒時間，故應保證尿液消毒且采取安全的性行為。此外，對密切接觸者應開展20 d的醫(yī)學觀察。

7.2 切斷傳播途徑

在廣泛滅鼠的基礎上，加強在西非某些食鼠肉地區(qū)進行宣傳教育，改變不健康的風俗習慣，減少與多乳鼠接觸的機會。保護食物及水源免受鼠類污染，保持良好的環(huán)境衛(wèi)生，及時清理食物垃圾并保存好未食用的食物。與患者密切接觸者應使用特定防護用品，如防護服、口罩、手套等。

7.3 保護易感人群

目前尚無主動免疫的方法，因此加強自我防護是重中之重。高危人群可口服利巴韋林開展預防。

7.4 加強出入境檢測檢疫及病例監(jiān)測

隨著人與動物之間接觸日益頻繁與密切、居民城鎮(zhèn)化水平的范圍擴大、全球化水平加劇，任一地區(qū)的健康威脅均可能發(fā)展至全球性。對于輸入性病例的管理，第一時間發(fā)現(xiàn)病例是疾病整體預防和控制的關鍵，也是預防工作的重中之重。

8 結語

目前，拉沙熱不僅僅是西非傳統(tǒng)流行地區(qū)及周邊國家面臨的公共衛(wèi)生問題。隨著全球多個國家相繼出現(xiàn)輸入性病例，且病例原發(fā)地已不限于傳統(tǒng)高發(fā)地區(qū)，同時引發(fā)疾病的毒株也出現(xiàn)變化，拉沙熱的傳播與流行已成為潛在的世界性公共衛(wèi)生問題。

拉沙熱的病死率高，無有效疫苗預防，抗病毒藥物效果有限。因此，針對拉沙熱，早發(fā)現(xiàn)、早診斷、早治療仍是最有效的手段。就疾病防控而言，首先，應建立靈敏、快捷且能廣泛應用的檢測方法，第一時間發(fā)現(xiàn)病例；其次，發(fā)現(xiàn)疫情國家應及時進行疫情通報，由世界衛(wèi)生組織(World Health Organization，WHO)及時發(fā)布疫情通報；第三，在出現(xiàn)潛在的世界性流行前，應由WHO建立規(guī)范的國際性聯(lián)防聯(lián)控防治策略和措施，避免潛在感染者將病毒帶入其他國家并控制疫源地發(fā)展趨勢。

隨著我國“一帶一路”新經(jīng)濟戰(zhàn)略的引導，國外居民及旅客人數(shù)持續(xù)增長，特別是在交流頻繁及經(jīng)濟發(fā)展快速的地區(qū)，各種傳染病的輸入風險顯著增加。針對拉沙熱的防控，應借鑒埃博拉病毒病、寨卡病毒病和黃熱病的防控策略；同時，應充分利用我國援建塞拉利昂的BSL-3實驗室，在當?shù)亻_展拉沙熱監(jiān)測，包括病例監(jiān)測、毒株毒力和型別監(jiān)測等，將防控關口前移，真正做到防患于未然，避免引發(fā)類似埃博拉病毒病等嚴重危害人類健康的全球性公共衛(wèi)生問題。

綜上所述，建議在全球經(jīng)濟一體化的大形勢下，加強對拉沙熱國際防控的關注度，建立國際聯(lián)防聯(lián)控防治策略和措施，將其納入全球防控體系。

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s. CAO Yuxi, E-mail: yuxicao@hotmail.com; WANG Huanyu, E-mail: rainoffall@yahoo.com

Research progress on Lassa fever

SHAO Nan, CAO Yuxi, WANG Huanyu

NationalInstituteforViralDiseaseControlandPrevention,ChineseCenterforDiseaseControlandPrevention,Beijing102206,China

Lassa fever (LF) caused by Lassa virus (LASV) is an acute hemorrhagic zoonotic disease transmitted to humans by rodent. The disease has high mortality, and mainly endemic in West Africa. However, the imported cases have been reported in many countries worldwide. In this review, we focus on the etiology of Lassa virus, disease prevalence, clinical features, laboratory testing, treatment and prevention. In light of the global economic integration, it is recommended that the strengthening of prevention and control of Lassa fever, establishment of international strategies on prevention measures, and integration into the global system should be paid more attention.

Lassa fever；Epidemiology；Prevention and control

傳染病預防控制國家重點實驗室課題(2015SKLID505)

曹玉璽, 王環(huán)宇

2016-05-09)