目前尚无针对 MERS 的特异性治疗方法;但许多药物具有较好的治疗前景,可能是未来很有价值的治疗药物。因此,治疗方式为支持性治疗,应侧重于缓解症状,以及预防或治疗并发症。具体的治疗取决于临床表现和患者因素(例如,年龄以及是否患有共病)。
感染预防和控制措施
应对所有疑似或确诊的 MERS 病例启动隔离程序。建议加强感染控制预防措施。具体而言,世界卫生组织 (WHO) 建议实施标准、飞沫和接触传播预防措施,以及在执行产气溶胶操作时,同时实施空气传播预防措施。[82]World Health Organization. Infection prevention and control during health care for probable or confirmed cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Interim guidance. June 2015 [internet publication].
http://apps.who.int/iris/bitstream/10665/174652/1/WHO_MERS_IPC_15.1_eng.pdf?ua=1
疑似或确诊感染的患者,应居住于通风条件良好的单人间,并尽可能与其他患者照护区域明确的进行隔离。应尽量减少医务工作者和访客人数。除了标准预防措施外,所有医务工作者和访客在与疑似或确诊病例密切接触(距离约 1 米)时,应始终穿戴:
医用口罩
眼部防护用品
洁净、但无需无菌的长袖长服
手套。
在接触患者及其周围环境前后,以及在取下个人防护用品后,应立即进行手部卫生。除非有医疗必要性,否则应避免患者在隔离照护间或区域外活动。
这些预防措施应在症状性疾病持续期间实施,并在症状消失后继续实施 24 小时。[82]World Health Organization. Infection prevention and control during health care for probable or confirmed cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Interim guidance. June 2015 [internet publication].
http://apps.who.int/iris/bitstream/10665/174652/1/WHO_MERS_IPC_15.1_eng.pdf?ua=1
应使用推荐的实时逆转录聚合酶链反应 (RT-PCR) 检测对患者的感染清除情况进行监测,直到至少间隔 24 小时采集的样本有 2 个阴性结果。[86]Ministry of Health (Saudi Arabia). Middle East respiratory syndrome coronavirus; guidelines for healthcare professionals, version 5.1. May 2018 [internet publication].
https://www.moh.gov.sa/CCC/StaffRegulations/Corona/Documents/MERS-CoV%20Guidelines%20for%20Healthcare%20Professionals%20-%20April%202018%20-%20v5.pdf
[89]World Health Organization. Clinical management of severe acute respiratory infection when Middle East respiratory syndrome coronavirus (MERS-CoV) infection is suspected. Interim guidance. July 2015 [internet publication].
http://apps.who.int/iris/bitstream/10665/178529/1/WHO_MERS_Clinical_15.1_eng.pdf
当非通气患者(例如,家庭隔离患者)无症状,且单个 RT-PCR 结果为阴性时,可停止感染控制措施。[86]Ministry of Health (Saudi Arabia). Middle East respiratory syndrome coronavirus; guidelines for healthcare professionals, version 5.1. May 2018 [internet publication].
https://www.moh.gov.sa/CCC/StaffRegulations/Corona/Documents/MERS-CoV%20Guidelines%20for%20Healthcare%20Professionals%20-%20April%202018%20-%20v5.pdf
疾病预防控制中心 (CDC) 和 WHO 提供了详细的感染预防和控制建议:
样本采集
应对所有患者采集以下样本,供诊断检测:[89]World Health Organization. Clinical management of severe acute respiratory infection when Middle East respiratory syndrome coronavirus (MERS-CoV) infection is suspected. Interim guidance. July 2015 [internet publication].
http://apps.who.int/iris/bitstream/10665/178529/1/WHO_MERS_Clinical_15.1_eng.pdf
血培养:用于检测同样可能引起肺炎或脓毒症的潜在细菌性病原体。
下呼吸道样本(例如痰、气管抽吸物、支气管肺泡灌洗液):用于细菌和病毒检测
上呼吸道样本(例如鼻咽和咽喉拭子):用于分子病毒检测
血清:用于分子和血清学检测。
应根据适当的感染控制措施采集样本。应尽可能在开始抗微生物治疗之前采集血培养。下呼吸道样本优于上呼吸道样本,但如有可能,两者均应采集。对于在家隔离的患者,仅采集上呼吸道样本(例如鼻咽拭子)即可。
样本采集频率取决于当地情况。WHO 建议,应在最初的 2 周内,至少每 2 至 4 天采集呼吸道样本用于 RT-PCR 检测,并持续采集,直到得到 2 个阴性结果,以确认病毒已清除。[89]World Health Organization. Clinical management of severe acute respiratory infection when Middle East respiratory syndrome coronavirus (MERS-CoV) infection is suspected. Interim guidance. July 2015 [internet publication].
http://apps.who.int/iris/bitstream/10665/178529/1/WHO_MERS_Clinical_15.1_eng.pdf
沙特阿拉伯卫生部建议在诊断后一周再次检测,然后每 3 天进行一次检测。[86]Ministry of Health (Saudi Arabia). Middle East respiratory syndrome coronavirus; guidelines for healthcare professionals, version 5.1. May 2018 [internet publication].
https://www.moh.gov.sa/CCC/StaffRegulations/Corona/Documents/MERS-CoV%20Guidelines%20for%20Healthcare%20Professionals%20-%20April%202018%20-%20v5.pdf
肺炎或合并症患者的管理
对于肺炎或呼吸窘迫患者,应立即收入适当的医疗机构接受治疗,并采取感染预防和控制措施。
所有具备下列征象的患者均应收住入院:
呼吸频率≥30 次/分
低氧血症(室内空气 SpO2<90%)
重症呼吸窘迫
具有肺炎的临床和/或放射学证据。
这些患者可能迅速发展为重症肺炎或呼吸衰竭;因此,务必要注意此类临床征象。[78]Arabi YM, Arifi AA, Balkhy HH, et al. Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection. Ann Intern Med. 2014;160:389-397.
http://annals.org/aim/article/1817260/clinical-course-outcomes-critically-ill-patients-middle-east-respiratory-syndrome
http://www.ncbi.nlm.nih.gov/pubmed/24474051?tool=bestpractice.com
患有共病(例如,糖尿病、心脏病、慢性肾衰竭、肥胖)、吸烟和年龄≥50 岁会增加发生严重感染的风险,这些患者也应入院治疗。
应立即开始支持性治疗:[89]World Health Organization. Clinical management of severe acute respiratory infection when Middle East respiratory syndrome coronavirus (MERS-CoV) infection is suspected. Interim guidance. July 2015 [internet publication].
http://apps.who.int/iris/bitstream/10665/178529/1/WHO_MERS_Clinical_15.1_eng.pdf
[86]Ministry of Health (Saudi Arabia). Middle East respiratory syndrome coronavirus; guidelines for healthcare professionals, version 5.1. May 2018 [internet publication].
https://www.moh.gov.sa/CCC/StaffRegulations/Corona/Documents/MERS-CoV%20Guidelines%20for%20Healthcare%20Professionals%20-%20April%202018%20-%20v5.pdf
氧:对于存在重症呼吸窘迫、休克或低氧血症征象的患者,应立即开始氧疗。开始为 5 L/分钟,逐渐调整,使 SpO2≥90%
液体:建议根据需要对患者进行谨慎的液体管理,前提是无任何休克迹象(有休克现象的患者可能需要更积极的复苏治疗)
抗菌药物:应对疑似 MERS 肺炎的住院患者开始经验性抗菌治疗(包括抗生素和抗病毒药物),如疑似有脓毒症,则应在一小时内开始。这样做的目的在于覆盖所有可能的社区获得性或医院获得性(如果患者入院治疗时间>48 小时)病原菌。确诊之前,抗生素的选择应基于当地流行病学、易感性数据和指南,然后根据结果调整经验性治疗
解热药物/镇痛药:建议用于控制发热和疼痛。
对于即将发生或已经出现呼吸衰竭的患者,应当收治于 ICU 病房。如果患者病情恶化,并且无法通过氧疗将 SpO2 保持≥90%,建议进行插管和机械通气。无创机械通气、机械通气或体外膜肺氧合 (extracorporeal membrane oxygenation, ECMO) 已用于 MERS 患者的治疗。[78]Arabi YM, Arifi AA, Balkhy HH, et al. Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection. Ann Intern Med. 2014;160:389-397.
http://annals.org/aim/article/1817260/clinical-course-outcomes-critically-ill-patients-middle-east-respiratory-syndrome
http://www.ncbi.nlm.nih.gov/pubmed/24474051?tool=bestpractice.com
[107]Al-Hameed F, Wahla AS, Siddiqui S, et al. Characteristics and outcomes of Middle East respiratory syndrome coronavirus patients admitted to an intensive care unit in Jeddah, Saudi Arabia. J Intensive Care Med. 2016;31:344-348.
http://www.ncbi.nlm.nih.gov/pubmed/25862629?tool=bestpractice.com
不过,应避免无创通气,因为产生气溶胶的风险很高,并且与气管内插管和机械通气相比,它缺乏疗效证据。[86]Ministry of Health (Saudi Arabia). Middle East respiratory syndrome coronavirus; guidelines for healthcare professionals, version 5.1. May 2018 [internet publication].
https://www.moh.gov.sa/CCC/StaffRegulations/Corona/Documents/MERS-CoV%20Guidelines%20for%20Healthcare%20Professionals%20-%20April%202018%20-%20v5.pdf
一项小型观察性研究发现,ECMO 与患有难治性低氧血症的 MERS 患者死亡率的降低相关。[108]Alshahrani M, Sindi A, Alahmadi B, et al. Extracorporeal membrane oxygenation for severe MERS-CoV: a retrospective observational study. 46th critical care congress of the Society of Critical Care Medicine, United States 2016; abstract 958. Crit Care Med. 2016;44(12 Suppl 1):315.
http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/165/CN-01295165/frame.html
通常不建议使用皮质类固醇;但可以根据需要给予应激剂量(例如,肾上腺功能抑制患者)。由于出现不良反应风险高、存在发生机会性感染的风险以及治疗 MERS 缺乏经证实的疗效,不应长期大剂量使用。[89]World Health Organization. Clinical management of severe acute respiratory infection when Middle East respiratory syndrome coronavirus (MERS-CoV) infection is suspected. Interim guidance. July 2015 [internet publication].
http://apps.who.int/iris/bitstream/10665/178529/1/WHO_MERS_Clinical_15.1_eng.pdf
[109]Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med. 2018 Mar 15;197(6):757-767.
http://www.ncbi.nlm.nih.gov/pubmed/29161116?tool=bestpractice.com
应密切监测患者恶化征象和并发症的发展情况,包括呼吸衰竭、急性呼吸窘迫综合征、急性肾衰竭、脓毒性休克和多器官功能衰竭。如果需要,应立即启动支持性治疗(例如,血液透析、升压药治疗、液体复苏、抗菌药物)。[5]Shalhoub S, Farahat F, Al-Jiffri A, et al. IFN-alpha-2a or IFN-beta-1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J Antimicrob Chemother. 2015;70:2129-2132.
http://www.ncbi.nlm.nih.gov/pubmed/25900158?tool=bestpractice.com
[8]Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, et al. Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. Lancet Infect Dis. 2013;13:752-761.
http://www.ncbi.nlm.nih.gov/pubmed/23891402?tool=bestpractice.com
[25]Omrani AS, Saad MM, Baig K, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis. 2014;14:1090-1095.
http://www.ncbi.nlm.nih.gov/pubmed/25278221?tool=bestpractice.com
[78]Arabi YM, Arifi AA, Balkhy HH, et al. Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection. Ann Intern Med. 2014;160:389-397.
http://annals.org/aim/article/1817260/clinical-course-outcomes-critically-ill-patients-middle-east-respiratory-syndrome
http://www.ncbi.nlm.nih.gov/pubmed/24474051?tool=bestpractice.com
[107]Al-Hameed F, Wahla AS, Siddiqui S, et al. Characteristics and outcomes of Middle East respiratory syndrome coronavirus patients admitted to an intensive care unit in Jeddah, Saudi Arabia. J Intensive Care Med. 2016;31:344-348.
http://www.ncbi.nlm.nih.gov/pubmed/25862629?tool=bestpractice.com
有关孕妇方面的数据有限。考虑到妊娠期生理变化,对于孕妇可以使用以上详述的支持性疗法(布洛芬除外,不建议孕妇使用,尤其是在妊娠晚期)。
无肺炎或共病患者的管理
年轻健康且无共病的患者发生并发症的风险较低,可根据情况考虑实行家庭隔离。[86]Ministry of Health (Saudi Arabia). Middle East respiratory syndrome coronavirus; guidelines for healthcare professionals, version 5.1. May 2018 [internet publication].
https://www.moh.gov.sa/CCC/StaffRegulations/Corona/Documents/MERS-CoV%20Guidelines%20for%20Healthcare%20Professionals%20-%20April%202018%20-%20v5.pdf
[83]Centers for Disease Control and Prevention. Preventing MERS-CoV from spreading to others in homes and communities. September 2017 [internet publication].
http://www.cdc.gov/coronavirus/mers/hcp/home-care-patient.html
[110]World Health Organization. Home care for patients with Middle East respiratory syndrome coronavirus (MERS-CoV) infection presenting with mild symptoms and management of contacts. Interim guidance. June 2018 [internet publication].
http://apps.who.int/iris/bitstream/handle/10665/272948/WHO-MERS-IPC-18.1-eng.pdf?ua=1
这些患者通常伴有轻度非特异性症状,例如发热、头痛、不适、咳嗽、咽痛,也可能伴有胃肠道症状。胸部 X 线检查结果正常。[10]Memish ZA, Zumla AI, Assiri A. Middle East respiratory syndrome coronavirus infections in health care workers. N Engl J Med. 2013;369:884-886.
http://www.nejm.org/doi/full/10.1056/NEJMc1308698
http://www.ncbi.nlm.nih.gov/pubmed/23923992?tool=bestpractice.com
CDC 建议只有在医护人员咨询地方或国家卫生部后,认为居住环境合适,并且患者能够遵守建议的感染控制预防措施时,本管理方案才适用。[111]Centers for Disease Control and Prevention. Implementing home care and isolation or quarantine of people not requiring hospitalization for MERS-CoV. September 2017 [internet publication].
https://www.cdc.gov/coronavirus/mers/hcp/home-care.html
WHO 建议,应尽可能在医院中隔离和监测有症状的确诊病例;但是,如果住院治疗不可行或不安全,可以考虑对某些症状轻微且无潜在疾病(例如心脏病、肾衰竭)或不存在免疫功能低下情况的患者实施家庭隔离。需要谨慎作出临床判断,并通过评估患者家庭环境的安全性了解背景情况,然后再作决定。[110]World Health Organization. Home care for patients with Middle East respiratory syndrome coronavirus (MERS-CoV) infection presenting with mild symptoms and management of contacts. Interim guidance. June 2018 [internet publication].
http://apps.who.int/iris/bitstream/handle/10665/272948/WHO-MERS-IPC-18.1-eng.pdf?ua=1
仍建议对这些患者采取感染控制措施,包括单独使用一个房间和一个浴室(如果条件允许),尽量减少与其他家庭成员的接触,以及有接触必要时,佩戴医用口罩。[86]Ministry of Health (Saudi Arabia). Middle East respiratory syndrome coronavirus; guidelines for healthcare professionals, version 5.1. May 2018 [internet publication].
https://www.moh.gov.sa/CCC/StaffRegulations/Corona/Documents/MERS-CoV%20Guidelines%20for%20Healthcare%20Professionals%20-%20April%202018%20-%20v5.pdf
[83]Centers for Disease Control and Prevention. Preventing MERS-CoV from spreading to others in homes and communities. September 2017 [internet publication].
http://www.cdc.gov/coronavirus/mers/hcp/home-care-patient.html
建议采用支持性治疗,包括使用解热药物和镇痛药(例如对乙酰氨基酚、布洛芬),用于缓解疼痛和发热。患者应保持充足水分,但不应摄入过多的液体,因为这可能会使氧合变差。[89]World Health Organization. Clinical management of severe acute respiratory infection when Middle East respiratory syndrome coronavirus (MERS-CoV) infection is suspected. Interim guidance. July 2015 [internet publication].
http://apps.who.int/iris/bitstream/10665/178529/1/WHO_MERS_Clinical_15.1_eng.pdf
WHO 和 CDC 提供了详细的家庭隔离指南:
试验性治疗
目前没有确切的证据可推荐对疑似或确诊感染患者进行任何病毒特异性治疗。然而,基于结果积极的体外研究和动物研究,当前已研究出许多治疗方法(例如,干扰素-β、干扰素-α、洛匹那韦、利巴韦林、麦考酚酯和环孢素)用于治疗 MERS。[112]Hart BJ, Dyall J, Postnikova E, et al. Interferon-beta and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J Gen Virol. 2014;95:571-577.
http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/vir.0.061911-0#tab2
http://www.ncbi.nlm.nih.gov/pubmed/24323636?tool=bestpractice.com
[113]Chan JF, Chan KH, Kao RY, et al. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect. 2013;67:606-616.
http://www.ncbi.nlm.nih.gov/pubmed/24096239?tool=bestpractice.com
到目前为止,尚未证明这些治疗方法有效。这在一定程度上由于缺乏随机对照试验,以及回顾性研究中的患者数量有限。
一些国家,例如韩国,已发布指南,允许医生谨慎使用一些经过研究的治疗方法。[114]Chong YP, Song JY, Seo YB, et al. Antiviral treatment guidelines for Middle East respiratory syndrome. Infect Chemother. 2015;47:212-222.
https://synapse.koreamed.org/DOIx.php?id=10.3947/ic.2015.47.3.212
http://www.ncbi.nlm.nih.gov/pubmed/26483999?tool=bestpractice.com
这些疗法通常仅用于患有广泛性肺炎、病情不稳定的患者。如果使用试验性药物,WHO 建议仅在标准研究性治疗方案中,以及研究试验的背景下使用这些药物。[89]World Health Organization. Clinical management of severe acute respiratory infection when Middle East respiratory syndrome coronavirus (MERS-CoV) infection is suspected. Interim guidance. July 2015 [internet publication].
http://apps.who.int/iris/bitstream/10665/178529/1/WHO_MERS_Clinical_15.1_eng.pdf
需要进一步的研究来评估这些药物对 MERS 患者的安全性和有效性。
如需了解具体试验药物的更多详细信息,请参阅“新兴疗法”。