Bronchiolitis

IND2025主会场授课已被预定，大会第一天下午茶歇前授课时间段预定开始，咨询热线：177 0186 0390。点击图片，查看IND2024会后报告 文章来源：分子诊断实验室 儿童呼吸道感染病原包括病毒、细菌、真菌等。《儿童呼吸道感染病原体核酸检测专家共识》作为全球首个以儿童为主、涵盖全面的呼吸道感染病原学诊断应用标准，对这些病原体作了详细全面的介绍。 常见呼吸道病毒 病毒是儿童呼吸道感染的主要病原体，儿童呼吸道感染病毒种类至少涉及7个病毒科共200多个型别的病毒。 1.1 人呼吸道合胞病毒(human respiratory syncytial virus，HRSV) HRSV是全球引起5岁以下儿童急性下呼吸道感染(acute lower respiratory tract infection，ALRTI)最重要的病毒病原体，占所有儿童ALRTI的22%。据估计，全球每年大约有270万~380万5岁以下儿童因HRSV感染住院，引起约4.8万~7.5万人死亡。 HRSV属于肺炎病毒科，正肺病毒属，为非节段性单股负链RNA病毒。目前，ON1和BA9基因型为我国及全球很多国家的优势流行基因型。 HRSV感染呈全球广泛流行，其流行受地理位置、温度和湿度等因素影响。在北半球国家和地区，HRSV的流行存在明显的流行季，主要集中于11月至次年2月的冬季和早春季节；在热带和亚热带，HRSV在潮湿的雨季感染率出现明显增高。我国北方地区HRSV流行季开始于第41周(10月中旬)，结束于次年第20周(5月中旬)，持续33周。 HRSV感染在不同年龄人群临床表现差异很大，毛细支气管炎和肺炎是婴幼儿HRSV感染的重要疾病，严重者可发生呼吸衰竭，甚至死亡，年长儿HRSV感染可表现为症状轻微的上呼吸道感染或中耳炎。 1.2 人流感病毒(human influenza virus，HIFV) HIFV是急性呼吸道感染的重要病原，全人群人普遍易感，儿童和老年人感染后危害最为严重，每年可引起季节性流行，亦可引起暴发疫情。 HIFV可分为甲、乙、丙，共3型。甲型流感病毒依据其血凝素(hemagglutinin，HN)和神经氨酸酶(neuraminidase，NA)的亚型组合可进一步分为多种亚型，目前HN有18个亚型(H1~H18)，NA有11个亚型(N1~N11)。乙型流感病毒根据HA的抗原性可分为Victoria和Yamagata两个种系。引起季节性流行的HIFV主要有甲型H1N1、H3N2亚型和乙型的Victoria和Yamagata系4个亚型HIFV。 HIFV在全球呈广泛流行，但不同地区的HIFV型别和流行规模有所不同。我国甲型HIFV在北方省份以冬季为流行高峰，南方省份每年4-6月份出现流行高峰，而中部省份则呈现每年1-2月和6-8月双流行峰。 HIFV感染后引起的临床表现轻重不一，包括无症状感染、上下呼吸道感染，重症病例可以迅速进展为肺炎，亦可并发心肌炎、脑膜炎或脑炎，甚至危及生命。 1.3 人副流感病毒(human parainfluenza virus，HPIVs) HPIVs主要导致儿童和青少年呼吸道感染性疾病，是仅次于HRSV的第二大引起儿童呼吸道感染住院的病原体。 HPIVs属于副黏病毒科(Paramyxoviridae)，有4个血清型(HPIV1、2、3和4)，HPIV1和HPIV3属于呼吸道病毒属(Respirovirus genus)，HPIV2和HPIV4属于腮腺炎病毒属(Rubulavirus genus)。通常HPIVs的流行是散发的，无明显的季节性。 HPIVs感染可引起鼻炎、咽炎、喉炎、气管支气管炎、细支气管炎和肺炎等，也可引发鼻窦炎和中耳炎。 1.4 人鼻病毒(human rhinovirus，HRV) HRV长期以来被认为是"普通感冒"的主要病原体，主要引起上呼吸道感染。据统计，每年有30%~50%的呼吸道感染疾病与HRV感染有关。儿童是HRV的易感人群，据报道，有60%~80%在急诊科就诊的哮喘发作患儿伴有HRV感染，在3岁以下被诊断为毛细支气管炎的住院儿童病例中，有大约50%的婴儿感染或合并感染HRV，而几乎所有婴儿在出生1年后均会经历至少1次的HRV感染。 HRV属小核糖核酸RNA病毒科，肠道病毒属。截至目前已经发现了A、B、C 3个种共169个型别。HRV在全球范围内流行，一年四季均可发病。 HRV感染后主要表现为普通感冒症状，可引起喘息和哮喘急性加重。引起婴幼儿的支气管炎和毛细支气管炎。 1.5 人腺病毒(human adenovirus，HAdV) HAdV可分为7个种(A~G)和至少104个基因型，其中与呼吸道感染相关的HAdV主要型别为B种(HAdV-3，7，11，14，16，21，50，55)，C种(HAdV-1，2，5，6)和E种(HAdV-4)。HAdV-3和HAdV-7型是引起我国儿童呼吸道HAdV感染最常见的血清型，HAdV-55是引起成人HAdV社区型肺炎最常见的型别。 HAdV感染一年四季均可发生，在我国北方以冬春季节多见，南方以春夏季节常见。HAdV传染性较强，常可引起暴发流行。 HAdV感染可表现为上下呼吸道感染。HAdV是儿童重症肺炎的重要病原体，导致危重患者出现休克、呼吸衰竭、弥散性血管内凝血等，甚至导致死亡。 1.6 人偏肺病毒(human metapneumovirus，HMPV) HMPV是导致儿童呼吸道感染的重要病毒病原之一。在急性呼吸道感染住院患者中，HMPV感染约为6.24%。 2017年国际病毒分类委员会将HMPV种属划分为肺病毒科(Pneumoviridae)，偏肺病毒属。根据HMPV F、G蛋白基因序列的差异，将HMPV分为A1、A2a、A2b、A2c、B1和B2共6个基因型。 HMPV在热带地区全年活跃，在温带气候地区，HMPV季节性流行发生在冬季和春季，在3月和4月达到顶峰，其流行高峰与HRSV重叠或稍晚于后者。 HMPV感染患者临床症状与HRSV感染相似，严重者可发展为细支气管炎和肺炎。有研究表明儿童HMPV感染可能与中枢神经系统疾病相关，如癫痫、脑炎等。 1.7人冠状病毒(human coronavirus，HCoV) HCoV是人类上呼吸道感染常见病原体。普通感冒中有15%~30%是由HCoV引起的。HCoV属于套式病毒目(Nidovirales)，冠状病毒科(Coronaviridae)，冠状病毒属(Coronavirus)，分为4个属：α-HCoV、β-HCoV、γ-HCoV和δ-HCoV。HCoV可分为普通人冠状病毒(HCoV-NL63、HCoV-HUK1、HCoV-OC43、HCoV-N229E)及高致病性冠状病毒[严重急性呼吸综合征(severe acute respiratory syndrome，SARS)-CoV、中东呼吸综合征(Middle East respiratory syndrome，MERS)-CoV和严重急性呼吸综合征冠状病毒2 (severe acute respiratory syndrome coronavirus 2，SARS-CoV-2)等]。 1.7.1普通HCoV 引起儿童呼吸道感染的常见普通HCoV有4种，分别为α属的HCoV-229E、HCoV-NL63，β属的HCoV-OC43、HCoV-HKU1。 HCoV感染呈全年流行。不同型别的HCoV在不同地区流行特点具有差异性，流行高峰随地理区域有所不同，有一定的季节差异。北京地区HCoV-OC43感染多发于春季(4月和5月)，HCoV-229E的流行高峰是在2月。在上海地区HCoV-OC43感染多发于夏秋季，HCoV-NL63感染多发生于秋冬季节。在中国香港地区HCoV-OC43感染主要发生在秋冬季，HCoV-HKU1在冬季检出更多，HCoV-229E多发生于冬春季节，HCoV-NL63感染多发生于夏秋季节。 这4种HCoV通常引起上呼吸道感染，多为自限性，但在婴幼儿、老年人或免疫缺陷患者也可引起严重的下呼吸道感染，表现为喘息、气促等。 1.7.2高致病性冠状病毒 SARS是由SARS-CoV感染引起的一种严重的致死性传染病，于2002年11月，在我国广东省首次报道。随后，SARS病例数在我国大幅增加，并在全球蔓延，超过30个国家和地区相继出现病例。2003年7月，世界卫生组织(World Health Organization，WHO)宣布其流行结束。全球SARS病例数达到8 437例，死亡813例，病死率约为10%。SARS-CoV感染起病迅速，常见的早期症状包括发热、畏寒、咳嗽、身体不适、肌肉疼痛和头痛等，可发展为进行性呼吸困难和低氧血症，严重者可造成急性呼吸窘迫综合征(ARDS)，患者常因肺部损伤导致呼吸衰竭而死亡。与成人相比，儿童发病率低，且多为散发，患儿一般与SARS成人有密切接触史，未见在学校、托幼机构内流行；临床表现较轻，预后较好，一般没有远期严重并发症，未见死亡病例报道。 MERS是由MERS-CoV引起的一种严重的致死性传染病，于2012年9月在沙特阿拉伯王国首次报道。截至2020年，全球约27个国家报道过该疾病，其中沙特阿拉伯、阿拉伯联合酋长国和韩国疫情最为严重。截至2019年11月30日，全球总计2 494例实验室确诊病例和858例死亡病例。我国于2015年5月29日确诊了首例由韩国输入的病例。MERS-CoV的潜伏期为2~14 d，平均5~7 d，起病急，病情进展迅速；早期主要表现为发热、畏寒、乏力、头痛、肌痛等，随后出现咳嗽、胸痛、呼吸困难，部分病例还可出现呕吐、腹痛、腹泻等症状；重症病例多在7 d内进展为重症肺炎，可发生ARDS、急性肾衰竭，甚至多脏器功能衰竭等危及生命。MERS致死率较高，死亡率约为37%。老年人、免疫力较差或有基础疾病的患者病情较重，病程进展较快，预后较差。儿童发病率低，且大多数为无症状感染，死亡率较低，预后较好。 SARS-CoV-2是引起新型冠状病毒肺炎(coronavirus disease 2019，COVID-19)的病毒病原体。自2020年3月11日，WHO宣布COVID-19大流行，至今已1.5年的时间。目前，全球正处于第3次高峰的高位平台期。截至2021年11月29日，全球累计报告确诊病例超过2.5亿，死亡病例515万多例，病死率约为2.1%。 SARS-CoV-2属于冠状病毒科，β冠状病毒属。依据SARS-CoV-2的流行程度，WHO于2021年2月25日提出了关切变异株(variant of concern，VOC)和关注变异株(variant of interest，VOI)的定义。目前，WHO界定的VOC为4种，分别为Alpha(B.1.1.7及其亚分支)、Beta(B.1.351及其亚分支)、Gamma(P.1及其亚分支)和Delta(B.1.617.2及其亚分支)变异株；VOI为5种，分别为Eta(B.1.525)、Iota(B.1.526)、Kappa(B.1.617.1)、Lambda(C.37和C.37.1)和Mu(B.1.621和B.1.621.1)变异株。目前，Delta变异株为全球优势流行毒株。 SARS-CoV-2主要传播途径为呼吸道飞沫和密切接触传播，接触病毒污染的物品也可造成感染，在相对封闭的环境中暴露于高浓度气溶胶情况下存在经气溶胶传播可能。病毒在宿主外不能繁殖，但可在短期内存活，存活时间主要与湿度、温度和材质有关。在相同的材质下，低温干燥的环境有利于病毒的存活。因此，污染了SARS-CoV-2的冷链产品可通过国际贸易远距离跨国、跨地区和跨大洋传播。 SARS-CoV-2感染的临床表现差异很大，从无症状到死亡。确诊病例临床可分为轻型、普通型、重型、危重型。轻型患者症状很轻微，无肺炎表现；普通型有发热和呼吸道症状，影像有肺炎证据；重症患者气促、缺氧、肺部影像学进展迅速；危重型会出现呼吸衰竭、休克或合并其他脏器衰竭。 1.8人博卡病毒(human bocavirus，HBoV) HBoV属于细小病毒科，细小病毒亚科，博卡病毒属。目前为止发现4个基因型HBoV(HBoV1~4)。 HBoV所引起的呼吸道感染疾病四季均可发生，季节性不明显。 HBoV呼吸道感染所致临床表现与呼吸道其他病毒相比无特异性，轻者可无症状，或发热、流涕、咳嗽等，重者可致喘息、呼吸困难等，甚至死亡。 1.9人肠道病毒(human enterovirus，HEV) HEV在急性呼吸道感染中阳性检出率为4.7%~16.2%，EV-D68是公共卫生关注的一种肠道病毒病原体。 HEV属小核糖核酸RNA病毒科，肠道病毒属。基因组结构为单股正链RNA，可分为HEV-A(n＝25)，HEV-B(n＝63)、HEV-C(n＝23)和HEV-D(n＝5)4组。 HEV全年散发，各月份均有检出。但在急性呼吸道感染中，HEV在我国流行具有明显的季节性，高峰期主要集中在4-7月，年龄分布主要在5岁以下。 HEV大多数血清型对人类可致病，既可表现为无症状或上下呼吸道感染，也可引起包括急性出血性结膜炎、病毒性脑炎、急性迟缓性麻痹、病毒性心肌炎等严重疾病。 常见细菌      引起儿童呼吸道感染的常见细菌有A族链球菌、肺炎链球菌、金黄色葡萄球菌、流感嗜血杆菌、百日咳鲍特菌、大肠埃希菌、肺炎克雷伯菌、结核分枝杆菌、铜绿假单胞菌等。这些常见细菌性呼吸道感染季节性并不明显，可能多见于季节变换的时期。 2.1 A族链球菌 具有β溶血性特点，也称为A组β溶血性链球菌，是致病力最强的链球菌。其主要致病因子包括链球菌M蛋白、溶血素和胞外酶等。在呼吸系统主要引起上呼吸道感染，包括咽扁桃体炎、化脓性中耳炎、鼻窦炎等，较少引起肺炎和胸膜炎。该菌可致链球菌感染后肾小球肾炎和急性风湿热。 2.2 肺炎链球菌 定植在人上呼吸道，可通过飞沫传播，其侵袭力主要为荚膜，溶血毒素(haemolysin，HL)和NA也是其主要致病因子，多引起呼吸道疾病；根据肺炎链球菌表面荚膜多糖抗原的差异，可分为不同血清型，目前已知有100种血清型，目前引起我国儿童感染的主要有19F、19A、23F、14、6A和6B型等；可以引起上下呼吸道感染，是儿童社区获得性肺炎最常见的细菌性病原。WHO建议将肺炎链球菌疫苗纳入婴儿常规免疫计划，对所有<2岁的儿童进行肺炎链球菌疫苗接种，以预防由该菌引起的多种感染。 2.3 流感嗜血杆菌 是一种多形性革兰阴性杆菌，常定植于人上呼吸道，有3种主要抗原成分，型特异性荚膜多糖抗原(M抗原)、型特异性菌体抗原(S抗原)和种特异性菌体抗原(R抗原)，分为可分型(有荚膜)和不可分型(无荚膜)两类菌株，有荚膜流感嗜血杆菌分为a、b、c、d、e、f 6个血清型，其中b血清型致病力最强，f型次之。目前全球范围内致病型别以无荚膜型最为常见，是急性中耳炎、急性上颌窦炎、迁延性细菌性支气管炎、肺炎的重要病因。疫苗可以预防b型流感嗜血杆菌疾病。 2.4 金黄色葡萄球菌 金黄色葡萄球菌在显微镜下排列成葡萄串状，无芽孢、鞭毛，大多数无荚膜，常见于皮肤表面和上呼吸道黏膜，约30%的人可在鼻腔，特别是鼻前庭后部携带该细菌；产生并分泌外毒素休克综合征毒素1(toxic shock syndrome toxin-1，TSST-1)和肠毒素，特别是杀白细胞素(panton-valentine leukocidin，PVL)，是一种具有强效细胞溶解及炎症活性的打孔毒素，另外HL、表皮剥脱素和耐热核酸酶也是金黄色葡萄球菌的毒力因子。金黄色葡萄球菌致病特点之一是引起化脓，造成组织坏死和脓肿。除了可以引起上呼吸道感染外，还可以导致支气管炎、肺炎、肺脓肿、肺大疱、胸膜炎等。由于广泛使用抗生素，耐药性(mecA)的传播越来越受到医疗机构的重视。 2.5 百日咳鲍特菌 是百日咳的病原体，人类是其唯一宿主，通过呼吸道飞沫传播，传染性强，易感人群主要集中在1岁以下婴儿，其致病物质包括荚膜、菌毛、内毒素和多种生物活性物质。百日咳毒素是主要的致病毒素。细菌附着在上呼吸道的纤毛上，释放毒素，从而损害纤毛并导致气道肿胀。尽管全球范围常年维持较高的疫苗接种率，近一二十年来多个国家地区出现了明显的百日咳再现。百日咳鲍特菌导致肺炎的比例为25%~88%，部分合并肺不张，极少见侵袭致胸膜炎。 2.6 大肠埃希菌 为革兰阴性杆菌，是一大群多样的细菌，大多数位于肠道内的大肠埃希菌为非致病性菌株，部分大肠埃希菌群含有毒力因子，可发生胃肠道外传播及致病；目前基于主要表面抗原可分为约190个血清群，某些种类的大肠埃希菌会导致腹泻，部分种类可致尿路感染，在呼吸系统常致新生儿和小婴儿肺炎，可伴有脓胸，较少致肺脓肿，多在医院环境下发生。 2.7 肺炎克雷伯菌 是肠杆菌科克雷伯杆菌属的一种细菌，属于人类口腔和肠道正常菌群，在致病性克雷伯杆菌中，肺炎克雷伯杆菌感染最为多见，是社区和医院获得性肺炎的重要细菌性病原，尤其是碳青霉烯耐药和高毒力肺炎克雷伯菌，肺部可形成空洞、单个或多个脓腔，与其他细菌比较，并发菌血症机会多。临床实验室分离的肺炎克雷伯菌主要分为3个亚种，分别为肺炎克雷伯菌肺炎亚种、肺炎克雷伯菌硬鼻亚种和肺炎克雷伯菌臭鼻亚种。 2.8 结核分枝杆菌 结核病是由一群关系密切的分枝杆菌引起的，统称为结核分枝杆菌复合群，包含至少13个成员，最常见的为人型、牛型、非洲型及鼠型，对人致病主要为人型，其次为牛型，在呼吸道主要导致原发性肺结核、血型播散性肺结核、支气管内膜结核及胸膜炎等。耐多药结核分枝杆菌是由至少对异烟肼和利福平这两种最有效的结核病药物有抗药性的病菌引起，成为危害人类健康的重要病原。 2.9 铜绿假单胞菌 是一种非发酵革兰阴性杆菌，在自然界分布广泛，各种水、空气、正常人的皮肤、呼吸道和肠道等均有本菌存在。为条件致病菌，是医院内感染的主要病原菌之一。主要的致病因子包括绿脓菌素、脂多糖、弹性蛋白酶和外毒素A，外毒素A是最主要的致病因子，经常引起术后伤口感染，也可引起褥疮、脓肿、化脓性中耳炎等；亦是呼吸机相关性肺炎的常见原因。 非典型病原 儿童呼吸道感染的非典型病原体主要包括肺炎支原体(Mycoplasma pneumoniae，MP)、肺炎衣原体(Chlamydia pneumonia，CP)、沙眼衣原体(Chlamydia trachomatis)及嗜肺军团菌(Legionella pneumophila，LP)。 3.1 支原体 是一类无细胞壁、多形性、可通过滤菌器的原核细胞型微生物。是目前所知的能在无生命培养基中繁殖的最小的微生物。其属于柔膜体纲支原体目下的支原体属。其中MP是呼吸道感染的常见病原体之一。全球感染率达9.6%~66.7%，且有逐年增高的趋势。全年发病，冬季更多见，每3~7年发生一次大流行。MP感染以学龄儿童多见，潜伏期为2~3周，突出表现为阵发性刺激性咳嗽，以夜间为重，咳少量黏痰或黏液脓性痰，有时痰中带血，也可有呼吸困难、胸痛。发热可持续2~3周，体温正常后仍可遗有咳嗽。严重MP感染可出现肺内肺外并发症的重症肺炎。 3.2 衣原体 是一群体积较小，能通过细菌滤器，细胞内专性寄生，并有独特发育周期的原核细胞型微生物，属于衣原体目衣原体科衣原体属。根据衣原体的抗原构造和DNA同源性的特点，将衣原体属分为4个种，包括沙眼衣原体、CP、鹦鹉热衣原体和家畜衣原体。能引起人类致病的主要是前3种。其中沙眼衣原体可分3个生物亚种，可引起结膜炎和婴幼儿肺炎。CP只有1个血清型，即TWAR组，CP传播方式主要是人与人之间经飞沫或呼吸道分泌物传播，常可呈地方性、散发性流行。CP引起的呼吸道感染约70%是无症状的或仅具有轻度症状，约30%为社区获得性肺炎。 3.3 军团菌 系需氧革兰阴性杆菌，广泛存在于湖泊和河流等天然水源及土壤中，也可在冷热水管道等人造水系统中繁殖。目前已知军团菌属有58个种和3个亚种，70个血清型，能引起人类疾病的约有30种，其中与人类疾病关系最密切的是LP，已确认有15个血清型，其中l型和6型最为常见，在欧美国家感染病例中，1型占80%。LP在自然界存活时间长，常在宿主免疫能力下降时依靠胞内寄生功能产生致病性，全年均可发病，夏秋季多，各年龄段均可以发病，成人发病高于儿童，男多于女。LP能引起社区获得性肺炎，特别是重症肺炎，还可引起医院内感染和旅游性肺炎，其潜伏期大约为2~14 d。可能出现前驱疾病，症状包括头痛、肌痛、虚弱和厌食。除了一些免疫功能低下的患者外，通常会出现发热，并且通常伴有相对的心动过缓。肺炎患者出现胃肠道和神经系统表现应提示军团病。胃肠道症状可能很突出，包括腹泻、恶心、呕吐和腹痛。约50%的患者咳嗽时会产生脓痰，并可能出现胸膜炎性胸痛。头痛可能很突出，并伴有意识模糊、癫痫发作和局灶性神经系统表现。 非典型病原 真菌是一种具有真核、能产孢、无叶绿体的真核生物。目前儿童呼吸道真菌感染的常见种类为假丝酵母菌属(Candida)、荚膜组织胞浆菌(Histoplasma capsulatum)、皮炎芽生菌(Blastomyces dermatitidis)、球孢子菌属(Coccidioides)、曲霉菌(Aspergillus)和新型隐球菌(Cryptococcus neoformans)等。真菌侵袭性感染常见于免疫功能受损时，尤其是各种免疫功能缺陷病、中性粒细胞减少、接受长期免疫抑制治疗及人类免疫缺陷病毒(HIV)感染的儿童；某些特殊情况下，如糖尿病酮症酸中毒患者的血清可刺激毛霉菌的生长。呼吸道真菌感染无明显季节特点。 由于全球气候变化和人类活动范围的扩大，真菌感染的流行病学也在发生变化。组织胞浆菌病和球孢子菌病在北美比较多见，芽生菌病和孢子丝菌病在北美和世界其他地区引起散发性病例，东南亚地区马尔尼菲青霉菌(Penicillium marneffei)病在免疫缺陷(如获得性免疫缺陷综合征)患儿中比较常见，而在南美洲，副球孢子菌经常引起皮肤和骨关节的感染。 4.1 假丝酵母菌感染 假丝酵母菌属菌体呈圆形或卵圆形，直径3~6 μm，革兰阳性，着色不均匀。可形成芽生孢子和假菌丝，经培养假菌丝中间或顶端可形成厚膜孢子。具有侵袭性的菌株在体内易形成假菌丝。 多种假丝酵母菌都能引起临床症状，但儿童以白色假丝酵母菌(Candida albicans)感染最常见。临床表现不一，可表现为局部黏膜感染，也可表现为广泛性播散，累及多系统器官。口咽假丝酵母菌病(鹅口疮)常见于小婴儿，也可见于使用抗菌药物、吸入性糖皮质激素(治疗哮喘或鼻炎)、化疗或放疗的年龄较大儿童以及有细胞免疫缺陷的儿童。侵袭性假丝酵母菌病尚与气管插管、中心静脉置管等有关。 4.2 荚膜组织胞浆菌感染 荚膜组织胞浆菌在自然界广泛分布，在被鸟类或蝙蝠粪便污染的土壤中最容易增殖。35 ℃培养时，可见直径3~5 μm，大小均匀的梨形孢子，人体感染荚膜组织胞浆菌后，一般可在巨噬细胞内或其周围发现其孢子，直径约2~4 μm，卵圆形，大小均一。 大多数病例是在较大量的暴露后数周发病，临床表现较轻，除发热外，体格检查通常无明显异常，但也可能发现啰音或实变证据。某些急性组织胞浆菌病患者可表现出流感样症状，伴呼吸道症状和影像学异常。症状通常在数周内缓解，但疲劳和乏力可能持续数月，尤其是病情更严重者。X线影像学通常显示局灶性浸润及纵隔或肺门淋巴结大。组织胞浆菌病经常被误诊为社区获得性肺炎，只有在经验性抗菌药物治疗无效后才会考虑该诊断。 4.3 隐球菌属感染 隐球菌在世界范围内广泛分布，其中新型隐球菌感染最为多见，其为圆形或卵圆形，单芽，厚壁，有宽阔、折光性的胶质样荚膜。隐球菌大小相差很大，一般直径多为4~7 μm，有些直径可达20 μm。周围荚膜由黏多糖组成，厚约3~5 μm。 隐球菌已成为一个重要的真菌感染病原体，可见于免疫功能正常的儿童。中枢神经系统和肺部是两个最常受累的器官，可表现为致命性脑膜脑炎和/或肺炎。咳嗽、呼吸困难和胸痛是最常见的肺部感染症状，但胸部影像学显示肺部结节或隐球菌性肉芽肿的儿童也可能无呼吸道症状。除了累及中枢神经系统和肺部，隐球菌还可累及皮肤、软组织、骨、关节、骨髓和淋巴结等，腹腔内隐球菌病少见。 4.4 曲霉菌感染 曲霉菌是一种典型的丝状菌，主要以枯死的植物、动物的排泄物及动物尸体为营养源。曲霉菌丝有隔膜，直径3~6 μm，分支呈锐角45°，菌丝两侧平行。 曲霉菌感染多见于宿主免疫抑制情况下。侵袭性曲霉菌病最常累及肺部。患儿表现出多种症状和体征，包括发热、胸痛、呼吸急促、咳嗽和/或咯血。中性粒细胞减少的肺曲霉菌病患儿存在典型三联征：发热、胸痛和咯血。胸部影像学检查常见肺结节和/或浸润影。烟曲霉亦可引起变应性支气管肺曲霉病(allergic bronchopulmonary aspergillosis，ABPA)，急性期主要为咳嗽、喘息、咯痰、咯血及发热。可咯出棕色痰栓。曲霉尚可以引起中枢神经系统感染。 4.5 毛霉菌(Mucor)感染 毛霉菌在土壤、粪便、禾草及空气等环境中存在。菌丝粗大不规则，无隔、多核、分枝状，直径约5~60 μm，不产生定形菌落。 毛霉菌感染在儿童中发病率逐渐升高，与免疫受损或其他免疫抑制患儿生存率的提高有关。毛霉菌病的特征为菌丝侵犯血管系统导致宿主组织梗死和坏死。糖尿病酮症患儿容易发生鼻脑型毛霉菌病或肺毛霉菌病，这是一种罕见但通常致死的真菌感染。鼻脑型毛霉菌病表现为急性鼻窦炎，伴发热、鼻充血、脓性鼻分泌物、头痛和鼻窦区疼痛。所有鼻窦均受累，并蔓延至邻近结构。肺毛霉菌病主要表现为发热伴咯血，亦有肺梗死及血栓形成。 4.6 马尔尼菲蓝状菌感染 马尔尼菲蓝状菌，原名马尔尼菲青霉菌，是双相型真菌，在30 ℃时呈现为菌丝形态，而在37 ℃时则为酵母形态。在细胞内菌体呈卵圆形、椭圆形，其大小形状一致，直径约2 μm。而游离于组织细胞外的菌则具有多形性，大小形差异大，直径为1~8 μm。 马尔尼菲蓝状菌可引起全身性真菌感染，主要来自东南亚和中国南方，在免疫功能低下者中会发生蓝状菌病。马尔尼菲蓝状菌的传播方式仍不明确。症状和体征不一，轻则为单纯性皮肤病变，重则发生呼吸衰竭和循环衰竭，儿童和成人的表现相似。呼吸系统受累患儿可出现咳嗽、发热、呼吸困难和胸痛，胸片可显示弥漫性网状结节浸润、局限性或弥漫性肺泡浸润。 END 免责声明：本文仅作知识交流与分享及科普目的，不涉及商业宣传，不作为相关医疗指导或用药建议。文章如有侵权请联系删除。 TDS2025检测自动化建设与应用论坛主会场，大会第一天下午茶歇前授课时间段预定开始，咨询热线：177 0186 0390。点击图片，查看TDS2024会后报告

Approval of SELARSDI 130 mg/26 mL in a single-dose vial for intravenous infusion expands label to include treatment of adults with Crohn’s disease and ulcerative colitis The FDA previously approved SELARSDI 45 mg/0.5 mL and 90 mg/mL in a single-dose prefilled syringe for subcutaneous injection in April 2024SELARSDI’s U.S. launch for all indications is expected in Q1 2025 REYKJAVIK, Iceland & PARSIPPANY, N.J., Oct. 22, 2024 (GLOBE NEWSWIRE) -- Alvotech (NASDAQ: ALVO) and Teva Pharmaceuticals, a U.S. affiliate of Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA), today announced that the U.S. Food and Drug Administration (FDA) has approved SELARSDI (ustekinumab-aekn) in a new presentation, 130 mg/26 mL (5 mg/mL) solution in a single-dose vial for intravenous infusion. This approval paves the way for SELARSDI to further align its label with the indications of the reference product Stelara® (ustekinumab) in the U.S. at launch, which is expected in the first quarter of 2025. “We welcome this step which is fully in line with our plan to align the SELARSDI label with the indications of the reference product, prior to launch next year,” said Robert Wessman, Chairman and CEO of Alvotech. “We are looking forward to the U.S. launch, after very successful launches of the first biosimilar ustekinumab in Canada, Japan and Europe. This demonstrates our commitment to increasing availability and access to ustekinumab, and other biosimilars in our growing pipeline, for patients worldwide.” “We are thrilled with the expansion of SELARSDI's indications, marking another significant milestone in Teva’s commitment to increasing access to biosimilars in the U.S.,” said Thomas Rainey, Senior Vice President, U.S. Biosimilars. “This development allows us to serve patients battling gastrointestinal diseases as the U.S. launch of SELARSDI approaches in early 2025. Teva’s dedication to increasing uptake of biosimilars remains steadfast, and we are proud to continue this partnership with Alvotech across a portfolio of nine partnered products.” In April 2024, the FDA approved SELARSDI 45 mg/0.5 mL and 90 mg/mL injection in a prefilled syringe for subcutaneous use, for the treatment of moderate to severe plaque psoriasis and for active psoriatic arthritis in adults and pediatric patients 6 years and older. In June 2023, Alvotech and Teva announced that they had reached a settlement and license agreement with the manufacturer of the reference biologic, granting a license entry date for SELARSDI in the United States no later than February 21, 2025. Alvotech developed and produces SELARSDI using Sp2/0 cells and a continuous perfusion process, which are the same type of host cell line and process used in the production of the reference product Stelara.1 Ustekinumab is a human monoclonal antibody that selectively targets the p40 protein, a component common to both interleukin (IL)-12 and IL-23 cytokines, which play crucial roles in treating immune-mediated diseases like psoriasis, psoriatic arthritis, ulcerative colitis and Crohn’s disease. In August 2020, Alvotech and Teva entered into a strategic partnership for the exclusive commercialization of five of Alvotech’s biosimilar product candidates, including SELARSDI. The partnership has since expanded and now includes a total of nine products. Alvotech handles development and manufacturing using its purpose-built end-to-end platform, while Teva is responsible for commercialization in the U.S., which leverages Teva’s experience and extensive sales and marketing infrastructure. Two biosimilars developed under the partnership have been given FDA approval: SELARSDI, and in February 2024, the FDA approved SIMLANDI® (adalimumab-ryvk), the first high-concentration, citrate-free interchangeable biosimilar to Humira® (adalimumab). SIMLANDI was launched in the U.S. in May 2024. About SIMLANDI® (adalimumab-ryvk) SIMLANDI is a monoclonal antibody and has been approved as a biosimilar to Humira® (adalimumab) in over 50 countries globally, including the U.S., Europe, Canada, Australia, Egypt, Saudi Arabia and South Africa. The biosimilar is currently marketed in the U.S. as SIMLANDI and under private label as adalimumab-ryvk, in Europe as HUKYNDRA, in Canada as SIMLANDI and in Australia as ADALACIP. Applications are also under review in multiple countries globally. About SELARSDI™ (ustekinumab-aekn) SELARSDI is a monoclonal antibody and a biosimilar to Stelara® (ustekinumab). Ustekinumab binds to two cytokines, IL-12 and IL-23, that are involved in inflammatory and immune responses.2 The biosimilar has been launched in Canada as JAMTEKI, in Europe as UZPRUVO and in Japan as USTEKINUMAB BS (F). It has been approved in the U.S. as SELARSDI. Applications are also under review in multiple countries globally. Use of TrademarksStelara® is a registered trademark of Johnson & Johnson. Humira® is a registered trademark of AbbVie Biotechnology Ltd. About AlvotechAlvotech is a biotech company, founded by Robert Wessman, focused solely on the development and manufacture of biosimilar medicines for patients worldwide. Alvotech seeks to be a global leader in the biosimilar space by delivering high quality, cost-effective products, and services, enabled by a fully integrated approach and broad in-house capabilities. Two biosimilars to Humira® (adalimumab) and Stelara® (ustekinumab) are already approved and marketed in multiple global markets. The current development pipeline includes nine disclosed biosimilar candidates aimed at treating autoimmune disorders, eye disorders, osteoporosis, respiratory disease, and cancer. Alvotech has formed a network of strategic commercial partnerships to provide global reach and leverage local expertise in markets that include the United States, Europe, Japan, China, and other Asian countries and large parts of South America, Africa, and the Middle East. Alvotech’s commercial partners include Teva Pharmaceuticals, a US affiliate of Teva Pharmaceutical Industries Ltd. (US), STADA Arzneimittel AG (EU), Fuji Pharma Co., Ltd (Japan), Advanz Pharma (EEA, UK, Switzerland, Canada, Australia and New Zealand), Dr. Reddy’s (EEA, UK and US), Biogaran (FR), Cipla/Cipla Gulf/Cipla Med Pro (Australia, New Zealand, South Africa/Africa), JAMP Pharma Corporation (Canada), Yangtze River Pharmaceutical (Group) Co., Ltd. (China), DKSH (Taiwan, Hong Kong, Cambodia, Malaysia, Singapore, Indonesia, India, Bangladesh and Pakistan), YAS Holding LLC (Middle East and North Africa), Abdi Ibrahim (Turkey), Kamada Ltd. (Israel), Mega Labs, Stein, Libbs, Tuteur and Saval (Latin America) and Lotus Pharmaceuticals Co., Ltd. (Thailand, Vietnam, Philippines, and South Korea). Each commercial partnership covers a unique set of product(s) and territories. Except as specifically set forth therein, Alvotech disclaims responsibility for the content of periodic filings, disclosures and other reports made available by its partners. For more information, please visit https://www.alvotech.com. None of the information on the Alvotech website shall be deemed part of this press release. For more information, please visit our investor portal, and our website or follow us on social media on LinkedIn, Facebook, Instagram, X and YouTube. About TevaTeva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) is a global pharmaceutical leader with a category-defying portfolio, harnessing our generics expertise and stepping up innovation to continue the momentum behind the discovery, delivery, and expanded development of modern medicine. For over 120 years, Teva's commitment to bettering health has never wavered. Today, the company’s global network of capabilities enables its 37,000 employees across 58 markets to push the boundaries of scientific innovation and deliver quality medicines to help improve health outcomes of millions of patients every day. To learn more about how Teva is all in for better health, visit www.tevapharm.com. SELARSDI INDICATIONS AND SAFETY INFORMATION INDICATIONS SELARSDI™ (ustekinumab-aekn) Injection, is a human interleukin-12 and -23 antagonist indicated for:• the treatment of adults and pediatric patients 6 years of age and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. • the treatment of adults and pediatric patients 6 years of age and older with active psoriatic arthritis.• the treatment of adult patients with moderately to severely active Crohn's disease.• the treatment of adult patients with moderately to severely active ulcerative colitis. IMPORTANT SAFETY INFORMATION SELARSDI™ (ustekinumab-aekn) injection is contraindicated in patients with clinically significant hypersensitivity to ustekinumab products or to any of the excipients in SELARSDI. InfectionsUstekinumab products may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab products. Serious infections requiring hospitalization or otherwise clinically significant infections were reported. In patients with plaque psoriasis, these included diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis, and urinary tract infections. In patients with psoriatic arthritis, this included cholecystitis. In patients with Crohn’s disease, these included anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and Listeria meningitis. In patients with ulcerative colitis, these included gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis. Treatment with SELARSDI should not be initiated in patients with a clinically important active infection until the infection resolves or is adequately treated. Consider the risks and benefits of treatment prior to initiating use of SELARSDI in patients with a chronic infection or a history of recurrent infection. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on treatment with SELARSDI and discontinue SELARSDI for serious or clinically significant infections until the infection resolves or is adequately treated. Theoretical Risk for Vulnerability to Particular InfectionsIndividuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), Salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with ustekinumab products may be susceptible to these types of infections. Consider diagnostic testing, e.g., tissue culture, stool culture, as dictated by clinical circumstances. Pre-Treatment Evaluation of Tuberculosis (TB)Evaluate patients for TB prior to initiating treatment with SELARSDI. Do not administer SELARSDI to patients with active TB infection. Initiate treatment of latent TB before administering SELARSDI. Consider anti-tuberculosis therapy prior to initiation of SELARSDI in patients with a history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Closely monitor patients receiving SELARSDI for signs and symptoms of active TB during and after treatment. MalignanciesUstekinumab products are immunosuppressants and may increase the risk of malignancy. Malignancies were reported among patients who received ustekinumab in clinical trials. The safety of ustekinumab products has not been evaluated in patients who have a history of malignancy or who have a known malignancy. There have been post-marketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving ustekinumab products who had pre-existing risk factors for developing non-melanoma skin cancer (NMSC). All patients receiving SELARSDI, especially those greater than 60 years of age or those with a history of Psoralen plus ultraviolet A (PUVA) or prolonged immunosuppressant treatment, should be monitored for the appearance of NMSC. Hypersensitivity ReactionsHypersensitivity reactions, including anaphylaxis and angioedema, have been reported with ustekinumab products. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue SELARSDI. Posterior Reversible Encephalopathy Syndrome (PRES)Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), were reported in clinical trials. Cases have also been reported in postmarketing experience in patients with psoriasis, psoriatic arthritis, and Crohn’s disease. Clinical presentation included headaches, seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after ustekinumab product initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab products. Monitor all patients treated with SELARSDI for signs and symptoms of PRES. If PRES is suspected, promptly administer appropriate treatment and discontinue SELARSDI. ImmunizationsPrior to initiating therapy with SELARSDI, patients should receive all age-appropriate immunizations as recommended by current immunization guidelines. Patients being treated with SELARSDI should not receive live vaccines. Avoid administering BCG vaccines during treatment with SELARSDI or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving SELARSDI because of the potential risk for shedding from the household contact and transmission to patient. Non-live vaccinations received during a course of SELARSDI may not elicit an immune response sufficient to prevent disease. Concomitant TherapiesThe safety of ustekinumab products, in combination with other biologic immunosuppressive agents or phototherapy has not been evaluated in clinical trials of psoriasis. Ultraviolet-induced skin cancers developed earlier and more frequently in mice. In psoriasis studies, the relevance of findings in mouse models for malignancy risk in humans is unknown. In psoriatic arthritis studies, concomitant methotrexate use did not appear to influence the safety or efficacy of ustekinumab. Noninfectious PneumoniaCases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during post-approval use of ustekinumab products. Clinical presentations included cough, dyspnea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and, in certain cases, administration of corticosteroids. If diagnosis is confirmed, discontinue SELARSDI and institute appropriate treatment. Allergen ImmunotherapyUstekinumab products have not been evaluated in patients who have undergone allergy immunotherapy. Ustekinumab products may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis. Most Common Adverse ReactionsThe most common adverse reactions for plaque psoriasis (greater than or equal to 3%) were nasopharyngitis, upper respiratory tract infection, headache, and fatigue. The safety profile in pediatric patients with plaque psoriasis was similar to that of adults with plaque psoriasis. The most common adverse reaction for Crohn's disease induction (greater than or equal to 3%) was vomiting. The most common adverse reactions for Crohn's disease maintenance (greater than or equal to 3%) were nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis. The most common adverse reaction for ulcerative colitis induction (greater than or equal to 3%) was nasopharyngitis. The most common adverse reactions for ulcerative colitis maintenance (greater than or equal to 3%) were nasopharyngitis, headache, abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, and nausea. Please click here for full Prescribing Information for SELARSDI. Alvotech Forward Looking StatementsCertain statements in this communication may be considered “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements generally relate to future events or the future financial operating performance of Alvotech and may include, for example, Alvotech’s expectations regarding competitive advantages, business prospects and opportunities including pipeline product development, future plans and intentions, results, level of activities, performance, goals or achievements or other future events, regulatory submissions, review and interactions, the potential approval and commercial launch of its product candidates, the timing of regulatory approval, and market launches. In some cases, you can identify forward-looking statements by terminology such as “may”, “should”, “expect”, “intend”, “will”, “estimate”, “anticipate”, “believe”, “predict”, “potential”, “aim”, or “continue”, or the negatives of these terms or variations of them or similar terminology. Such forward-looking statements are subject to risks, uncertainties, and other factors which could cause actual results to differ materially from those expressed or implied by such forward-looking statements. These forward-looking statements are based upon estimates and assumptions that, while considered reasonable by Alvotech and its management, are inherently uncertain and are inherently subject to risks, variability, and contingencies, many of which are beyond Alvotech’s control. Factors that may cause actual results to differ materially from current expectations include, but are not limited to: (1) the ability to raise substantial additional funding, which may not be available on acceptable terms or at all; (2) the ability to maintain stock exchange listing standards; (3) changes in applicable laws or regulations; (4) the possibility that Alvotech may be adversely affected by other economic, business, and/or competitive factors; (5) Alvotech’s estimates of expenses and profitability; (6) Alvotech’s ability to develop, manufacture and commercialize the products and product candidates in its pipeline; (7) actions of regulatory authorities, which may affect the initiation, timing and progress of clinical studies or future regulatory approvals or marketing authorizations; (8) the ability of Alvotech or its partners to respond to inspection findings and resolve deficiencies to the satisfaction of the regulators; (9) the ability of Alvotech or its partners to enroll and retain patients in clinical studies; (10) the ability of Alvotech or its partners to gain approval from regulators for planned clinical studies, study plans or sites; (11) the ability of Alvotech’s partners to conduct, supervise and monitor existing and potential future clinical studies, which may impact development timelines and plans; (12) Alvotech’s ability to obtain and maintain regulatory approval or authorizations of its products, including the timing or likelihood of expansion into additional markets or geographies; (13) the success of Alvotech’s current and future collaborations, joint ventures, partnerships or licensing arrangements; (14) Alvotech’s ability, and that of its commercial partners, to execute their commercialization strategy for approved products; (15) Alvotech’s ability to manufacture sufficient commercial supply of its approved products; (16) the outcome of ongoing and future litigation regarding Alvotech’s products and product candidates; (17) the impact of worsening macroeconomic conditions, including rising inflation and interest rates and general market conditions, conflicts in Ukraine, the Middle East and other global geopolitical tension, on the Company’s business, financial position, strategy and anticipated milestones; and (18) other risks and uncertainties set forth in the sections entitled “Risk Factors” and “Cautionary Note Regarding Forward-Looking Statements” in documents that Alvotech may from time to time file or furnish with the SEC. There may be additional risks that Alvotech does not presently know or that Alvotech currently believes are immaterial that could also cause actual results to differ from those contained in the forward-looking statements. Nothing in this communication should be regarded as a representation by any person that the forward-looking statements set forth herein will be achieved or that any of the contemplated results of such forward-looking statements will be achieved. You should not place undue reliance on forward-looking statements, which speak only as of the date they are made. Alvotech does not undertake any duty to update these forward-looking statements or to inform the recipient of any matters of which any of them becomes aware of which may affect any matter referred to in this communication. Alvotech disclaims any and all liability for any loss or damage (whether foreseeable or not) suffered or incurred by any person or entity as a result of anything contained or omitted from this communication and such liability is expressly disclaimed. The recipient agrees that it shall not seek to sue or otherwise hold Alvotech or any of its directors, officers, employees, affiliates, agents, advisors, or representatives liable in any respect for the provision of this communication, the information contained in this communication, or the omission of any information from this communication. Teva Cautionary Note Regarding Forward Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, which are based on management’s current beliefs and expectations and are subject to substantial risks and uncertainties, both known and unknown, that could cause our future results, performance or achievements to differ significantly from that expressed or implied by such forward-looking statements. You can identify these forward-looking statements by the use of words such as “should,” “expect,” “anticipate,” “estimate,” “target,” “may,” “project,” “guidance,” “intend,” “plan,” “believe”, and other words and terms of similar meaning and expression in connection with any discussion of future operating or financial performance. Important factors that could cause or contribute to such differences include risks relating to: our strategic partnership with Alvotech; our ability to successfully develop and commercialize SELARSDI in the U.S.; our ability to successfully commercialize SIMLANDI in the U.S; our ability to commercialize the additional biosimilar product candidates under the strategic partnership with Alvotech once U.S. regulatory approval is obtained; our ability to successfully compete in the marketplace including our ability to develop and commercialize additional pharmaceutical products; our ability to successfully execute our Pivot to Growth strategy, including to expand our innovative and biosimilar medicines pipeline and profitably commercialize the innovative medicines and biosimilar portfolio, whether organically or through business development, and to sustain and focus our portfolio of generics medicines; and other factors discussed in this press release, in our Quarterly Report on Form 10-Q for the second quarter of 2024 and in our Annual Report on Form 10-K for the year ended December 31, 2023, including in the sections captioned “Risk Factors.” Forward-looking statements speak only as of the date on which they are made, and we assume no obligation to update or revise any forward-looking statements or other information contained herein, whether as a result of new information, future events or otherwise. You are cautioned not to put undue reliance on these forward-looking statements.Sources Stelara FDA product label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761044s013lbl.pdf. Accessed on October 18, 2024.Selarsdi FDA product label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761343s000lbl.pdf. Accessed on October 18, 2024. Contacts for the Media and Investor Relations Alvotech IR and PRBenedikt Stefansson, VPalvotech.ir@alvotech.com Teva IR Contacts Ran Meir +1 (267) 468 4475 Yael Ashman +972 (3) 914 8262 Sanjeev Sharma +1 (973) 658 2700 PR Contacts Kelley Dougherty +1 (973) 832-2810 Yonatan Beker +1 (973) 264-7378 Eden Klein +972 (3) 906 2645

▎药明康德内容团队编辑 日前，默沙东（MSD）公布其MK-1654-004临床2b/3期试验的积极结果。分析显示，其在研呼吸道合胞病毒（RSV）预防性单抗clesrovimab（MK-1654）在5个月内分别将RSV相关住院率和RSV相关下呼吸道感染（LRI）住院率降低了84%和90%以上。研究详细数据公布于2024年感染性疾病周（IDWeek）会议当中。新闻稿指出，如果获得批准，clesrovimab将成为通过单次固定剂量给药在婴儿第一个RSV季节中提供快速、持久的保护的首款预防性抗体疗法，无论婴儿的体重如何。 RSV是一种具有传染性的病毒，导致全球范围内婴儿和老年人中普遍的季节性感染。全球范围内，RSV是导致一岁以下健康婴儿住院的主要原因。RSV可引发如细支气管炎和肺炎等严重的呼吸系统疾病，每年在全球五岁以下儿童中导致超过10万人死亡。 MK-1654-004是一项双盲、随机、安慰剂对照的2b/3期临床试验，旨在评估clesrovimab对进入第一个RSV季节的健康早产和足月婴儿（从出生到1岁）的安全性和有效性。该研究招募了3632名受试者，他们按2：1的比例随机分配在第1天接受单次固定剂量clesrovimab（105毫克）或安慰剂的肌肉注射。 图片来源：123RF 该试验的主要疗效终点是评估在接种后150天（5个月）内，clesrovimab与安慰剂相比，减少与RSV相关的需医疗干预的下呼吸道感染（MALRI）发病率的效果。这些MALRI具有至少一项标志下呼吸道感染及其严重程度的症状。分析显示，试验达到主要疗效终点。Clesrovimab的有效性达60.4%（95% CI：44.1-71.9，p<0.001）。此外，clesrovimab还显著减少了RSV相关的住院率（次要终点）和RSV相关的LRI住院率（三级终点），分别达84.2%（95% CI：66.6-92.6，p<0.001）和90.9%（95% CI：76.2-96.5）。同时，clesrovimab在降低严重MALRI（三级终点）发病率方面的效果也显著，达到91.7%（95% CI：62.9-98.1）。 此外，在事后分析中，clesrovimab在减少至少具有两种LRI及其严重程度相关症状的MALRI（比主要终点更严重的MALRI）发病率方面，效果达到了88.0%（95% CI：76.1-94.0），评估期为接种后第150天。 关于MK-1654-004试验中RSV疾病负担的更多数据，按照疾病严重程度递减的终点顺序在下表中进行了详细呈现。 ▲MK-1654-004试验中RSV疾病负担的数据（图片来源：参考资料[1]） 默沙东还公布了MK-1654-007试验的预定中期分析数据，该3期试验评估了clesrovimab与获批的RSV长效抗体疗法Beyfortus（nirsevimab）相比，在高风险婴幼儿中预防严重RSV疾病的安全性和疗效。分析结果显示，clesrovimab的安全性与活性对照组相当，至今未报告与药物相关的严重不良事件。RSV相关的MALRI发病率和RSV相关的住院率（次要终点）在clesrovimab组（分别为3.6%和1.3%）和活性对照组（分别为3.0%和1.5%）在150天观察期内也相当。 Clesrovimab是一款在研的长效单克隆抗体，用于被动免疫预防RSV。Clesrovimab的设计特点是无论婴儿出生体重如何，都可以以相同的单次剂量进行给药，旨在为健康的早产儿、足月婴儿及高风险婴儿提供直接、快速且持久的保护，帮助他们在首个RSV季节抵御轻度、中度和重度RSV感染。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料： [1] Merck’s Clesrovimab (MK-1654), an Investigational Respiratory Syncytial Virus (RSV) Preventative Monoclonal Antibody, Significantly Reduced Incidence of RSV Disease and Hospitalization in Healthy Preterm and Full-term Infants. Retrieved October 18, 2024 from https://www-merck-com.libproxy1.nus.edu.sg/news/mercks-clesrovimab-mk-1654-an-investigational-respiratory-syncytial-virus-rsv-preventative-monoclonal-antibody-significantly-reduced-incidence-of-rsv-disease-and-hospitalization-in-heal/ 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新