死亡率
主要死亡原因为急性呼吸窘迫综合征(acute respiratory distress syndrome, ARDS)引发的呼吸衰竭。[927]Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 May;46(5):846-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080116/
http://www.ncbi.nlm.nih.gov/pubmed/32125452?tool=bestpractice.com
COVID-19 患者 ARDS 导致的总体死亡率为 39%;但是,各个国家之间有显著差异(例如中国为 69%,伊朗为 28%,法国为 19%,德国为 13%)。[928]Hasan SS, Capstick T, Ahmed R, et al. Mortality in COVID-19 patients with acute respiratory distress syndrome and corticosteroids use: a systematic review and meta-analysis. Expert Rev Respir Med. 2020 Jul 31 [Epub ahead of print].
https://www.tandfonline.com/doi/full/10.1080/17476348.2020.1804365
http://www.ncbi.nlm.nih.gov/pubmed/32734777?tool=bestpractice.com
呼吸衰竭危险因素包括年龄、性别为男性、心血管疾病,实验室指标(例如乳酸脱氢酶、淋巴细胞计数和 C-反应蛋白),以及入院时病毒载量过高。[929]de la Calle C, Lalueza A, Mancheño-Losa M, et al. Impact of viral load at admission on the development of respiratory failure in hospitalized patients with SARS-CoV-2 infection. Eur J Clin Microbiol Infect Dis. 2021 Jan 7 [Epub ahead of print].
https://link.springer.com/article/10.1007/s10096-020-04150-w
http://www.ncbi.nlm.nih.gov/pubmed/33409832?tool=bestpractice.com
对于 <65 岁的人群,即使在大流行震中,死亡风险也很小,而对于 <65 岁且无任何基础疾病的人群,死亡率极低。[930]Ioannidis JPA, Axfors C, Contopoulos-Ioannidis DG. Population-level COVID-19 mortality risk for non-elderly individuals overall and for non-elderly individuals without underlying diseases in pandemic epicenters. Environ Res. 2020 Sep;188:109890.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327471/
http://www.ncbi.nlm.nih.gov/pubmed/32846654?tool=bestpractice.com
尽管患者特征稳定,但死亡率却随时间下降。大流行前 6 个月,美国死亡率急剧下降。[931]Asch DA, Sheils NE, Islam MN, et al. Variation in US hospital mortality rates for patients admitted with COVID-19 during the first 6 months of the pandemic. JAMA Intern Med. 2020 Dec 22 [Epub ahead of print].
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2774572
http://www.ncbi.nlm.nih.gov/pubmed/33351068?tool=bestpractice.com
[932]Nguyen NT, Chinn J, Nahmias J, et al. Outcomes and mortality among adults hospitalized with COVID-19 at US medical centers. JAMA Netw Open. 2021 Mar 1;4(3):e210417.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777028
http://www.ncbi.nlm.nih.gov/pubmed/33666657?tool=bestpractice.com
在一项美国某一教育研究型卫生系统对收入重症监护病房危重患者进行的研究发现,研究期间死亡率从 43.5% 下降至 19.2%。[933]Anesi GL, Jablonski J, Harhay MO, et al. Characteristics, outcomes, and trends of patients with COVID-19-related critical illness at a learning health system in the United States. Ann Intern Med. 2021 Jan 19 [Epub ahead of print].
https://www.acpjournals.org/doi/10.7326/M20-5327
http://www.ncbi.nlm.nih.gov/pubmed/33460330?tool=bestpractice.com
在英国另一项研究中,调整后住院死亡率从 2020 年 3 月第一周的 52.2% 降至 2020 年 5 月最后一周的 16.8%。[934]Navaratnam AV, Gray WK, Day J, et al. Patient factors and temporal trends associated with COVID-19 in-hospital mortality in England: an observational study using administrative data. Lancet Respir Med. 2021 Feb 15 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906650/
http://www.ncbi.nlm.nih.gov/pubmed/33600777?tool=bestpractice.com
这可能反映出医院策略和临床处理变化的影响,随着时间进展,危重患者对于诸如给予高流量鼻套管吸氧从而避免气管插管、俯卧位通气以及减少使用机械通气等循证标准诊疗具有更佳的依从性。需行进一步研究证实此类结果,并研究因果机制。
感染死亡率(infection fatality rate, IFR)
定义为所有感染个体(包括确诊病例、未诊断病例 [例如无症状或轻症病例])以及未报告病例中的死亡比例。与病死率相比,IFR 可以更准确的描述疾病致死性。
到 2020 年 10 月,全球约 10% 人群可能已受到感染,估计整体 IFR 为 0.15% 至 0.2%(<70 岁人群为 0.03% 至 0.04%)。[935]Ioannidis JPA. Global perspective of COVID-19 epidemiology for a full-cycle pandemic. Eur J Clin Invest. 2020 Oct 7:e13421.
https://onlinelibrary.wiley.com/doi/abs/10.1111/eci.13423
http://www.ncbi.nlm.nih.gov/pubmed/33026101?tool=bestpractice.com
美国疾病预防控制中心目前根据年龄对 IFR 的最佳估值为(截至 2020 年 9 月 10 日):[141]Centers for Disease Control and Prevention. COVID-19 pandemic planning scenarios. 2020 [internet publication].
https://www.cdc.gov/coronavirus/2019-ncov/hcp/planning-scenarios.html
0 至 19 岁 – 0.003
20 至 49 岁 – 0.02
50 至 69 岁 – 0.5
≥70 岁 – 5.4%。
根据这些数据,对于 <70 岁的人群,整体 IFR 约为 0.18%。
IFR 在不同地点可能有所不同。一项 meta 分析报告指出,IFR 在整个人群中的点估值为 0.68%,异质性很高(截至 2020 年 7 月)。各地区比率从 0.17% 到 1.7% 不等。[936]Meyerowitz-Katz G, Merone L. A systematic review and meta-analysis of published research data on COVID-19 infection-fatality rates. Int J Infect Dis. 2020 Sep 29 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524446/
http://www.ncbi.nlm.nih.gov/pubmed/33007452?tool=bestpractice.com
钻石公主号游轮登船者中 IFR 为 0.85%,这是可对被隔离人群 IFR 进行准确评估的独特情况。但是,所有死亡都发生于 >70 岁患者,年轻、健康人群死亡率远远更低。[937]Rajgor DD, Lee MH, Archuleta S, et al. The many estimates of the COVID-19 case fatality rate. Lancet Infect Dis. 2020 Jul;20(7):776-7.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270047/
http://www.ncbi.nlm.nih.gov/pubmed/32224313?tool=bestpractice.com
此类估值有局限性,并且可能随着大流行的发展有更多数据出现而发生变化。
血清流行病学研究
病死率(case fatality rate, CFR)
定义为报告的总死亡数除以报告的检出病例总数。CFR 受选择偏倚的影响,因为更严重/住院病例更有可能接受检测。
世界卫生组织目前对全球 CFR 估值为 2.2%(截至 2021 年 2 月 28 日)。[942]World Health Organization. Coronavirus disease (COVID-19) weekly epidemiological updates. 2021 [internet publication].
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/
这远低于报告的严重急性呼吸综合征(severe acute respiratory syndrome, SARS) CFR(10%)以及中东呼吸综合征(Middle East respiratory syndrome, MERS) CFR(37%)。[51]Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30183-5/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/31986264?tool=bestpractice.com
各个国家/地区之间 CFR 差异相当显著。
在中国,据报道,总体 CFR 为 1.4%-2.3%(在无合并症的患者中为 0.9%)。[4]Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China [in Chinese]. Zhonghua Liu Xing Bing Xue Za Zhi. 2020 Feb 17;41(2):145-51.
http://weekly.chinacdc.cn/en/article/id/e53946e2-c6c4-41e9-9a9b-fea8db1a8f51
http://www.ncbi.nlm.nih.gov/pubmed/32064853?tool=bestpractice.com
[943]Verity R, Okell LC, Dorigatti I, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020 Jun;20(6):669-77.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158570/
http://www.ncbi.nlm.nih.gov/pubmed/32240634?tool=bestpractice.com
CFR 随年龄增长而升高。
在美国,大多数死亡患者年龄 ≥65 岁。≥85 岁患者 CFR 最高(10% 至 27%),其次为 65 至 84 岁(3% 至 11%),然后是 55 至 64 岁(1% 至 3%),最后是 20 至 54 岁(<1%)。[7]CDC COVID-19 Response Team. Severe outcomes among patients with coronavirus disease 2019 (COVID-19): United States, February 12 - March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020 Mar 27;69(12):343-6.
https://www.cdc.gov/mmwr/volumes/69/wr/mm6912e2.htm?s_cid=mm6912e2_w
http://www.ncbi.nlm.nih.gov/pubmed/32214079?tool=bestpractice.com
在中国,大多数死亡患者年龄 ≥60 岁。[4]Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China [in Chinese]. Zhonghua Liu Xing Bing Xue Za Zhi. 2020 Feb 17;41(2):145-51.
http://weekly.chinacdc.cn/en/article/id/e53946e2-c6c4-41e9-9a9b-fea8db1a8f51
http://www.ncbi.nlm.nih.gov/pubmed/32064853?tool=bestpractice.com
≥80 岁患者 CFR 最高(13.4%),其次是 60 至 79 岁(6.4%),然后是 <60 岁(0.32%)。[943]Verity R, Okell LC, Dorigatti I, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020 Jun;20(6):669-77.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158570/
http://www.ncbi.nlm.nih.gov/pubmed/32240634?tool=bestpractice.com
在意大利,≥80 岁患者 CFR 最高(52.5%),其次是 70 至 79 岁(35.5%),然后是 60 至 69 岁(8.5%)。[944]Sorbello M, El-Boghdadly K, Di Giacinto I, et al. The Italian COVID-19 outbreak: experiences and recommendations from clinical practice. Anaesthesia. 2020 Jun;75(6):724-32.
https://onlinelibrary.wiley.com/doi/full/10.1111/anae.15049
http://www.ncbi.nlm.nih.gov/pubmed/32221973?tool=bestpractice.com
儿童极少出现死亡。[7]CDC COVID-19 Response Team. Severe outcomes among patients with coronavirus disease 2019 (COVID-19): United States, February 12 - March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020 Mar 27;69(12):343-6.
https://www.cdc.gov/mmwr/volumes/69/wr/mm6912e2.htm?s_cid=mm6912e2_w
http://www.ncbi.nlm.nih.gov/pubmed/32214079?tool=bestpractice.com
[21]Castagnoli R, Votto M, Licari A, et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review. JAMA Pediatr. 2020 Sep 1;174(9):882-9.
https://jamanetwork.com/journals/jamapediatrics/fullarticle/2765169
http://www.ncbi.nlm.nih.gov/pubmed/32320004?tool=bestpractice.com
在一项研究中,70% 的死亡病例处于 10-20 岁这一年龄段,20% 处于 1-9 岁年龄段,10% 处于 1 岁以下年龄段。[945]Bixler D, Miller AD, Mattison CP, et al. SARS-CoV-2–associated deaths among persons aged <21 years: United States, February 12–July 31, 2020. MMWR Morb Mortal Wkly Rep. 2020 Sep 18;69(37):1324-9.
https://www.cdc.gov/mmwr/volumes/69/wr/mm6937e4.htm
http://www.ncbi.nlm.nih.gov/pubmed/32941417?tool=bestpractice.com
CFR 随合并症存在而升高。
CFR 随病情严重程度增加而升高。
危重症患者 CFR 最高,研究显示此类患者 CFR 为 26%-67%。[4]Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China [in Chinese]. Zhonghua Liu Xing Bing Xue Za Zhi. 2020 Feb 17;41(2):145-51.
http://weekly.chinacdc.cn/en/article/id/e53946e2-c6c4-41e9-9a9b-fea8db1a8f51
http://www.ncbi.nlm.nih.gov/pubmed/32064853?tool=bestpractice.com
[946]Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020 Apr 6;323(16):1574-81.
https://jamanetwork.com/journals/jama/fullarticle/2764365
http://www.ncbi.nlm.nih.gov/pubmed/32250385?tool=bestpractice.com
[947]Arentz M, Yim E, Klaff L, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington State. JAMA. 2020 Mar 19;323(16):1612-4.
https://jamanetwork.com/journals/jama/fullarticle/2763485
http://www.ncbi.nlm.nih.gov/pubmed/32191259?tool=bestpractice.com
IFR/CFR 局限性
在大流行早期阶段 IFR 和 CFR 估值存在很大的不确定性,并且随着更多数据出现,估值可能会发生变化。这些比率在大流行开始时往往很高,随着获得数据越来越多,呈下降趋势。[948]Centre for Evidence-Based Medicine; Oke J, Heneghan C. Global COVID-19 case fatality rates. 2020 [internet publication].
https://www.cebm.net/global-covid-19-case-fatality-rates/
确诊病例当前没有固定的病例定义,且病例定义各不相同。聚合酶链反应(polymerase chain reaction, PCR)阳性结果有时是识别病例的唯一标准;然而,PCR 检测结果阳性不一定等同于确诊患有 COVID-19,也不意味着某人受到了感染或具有传染性。[949]Mahase E. Covid-19: the problems with case counting. BMJ. 2020 Sep 3;370:m3374.
https://www.bmj.com/content/370/bmj.m3374
http://www.ncbi.nlm.nih.gov/pubmed/32883657?tool=bestpractice.com
[950]Centre for Evidence-Based Medicine; Spencer E, Jefferson T, Brassey J, et al. When is Covid, Covid? 2020 [internet publication].
https://www.cebm.net/covid-19/when-is-covid-covid/
由于存在与死亡报道相关的延误,在特定日期报道的死亡例数,可能无法准确反映前一天的死亡例数。因此很难知道死亡例数是否会在短期内随时间而下降。[951]Centre for Evidence-Based Medicine; Oke J, Heneghan C. Reconciling COVID-19 death data in the UK. 2020 [internet publication].
https://www.cebm.net/covid-19/reconciling-covid-19-death-data-in-the-uk/
在某些国家/地区,“患”COVID-19 而后死亡的患者和“死于”COVID-19 的患者可能均计入死亡人数。例如,在意大利,只有 12% 的死亡证明报告了与 COVID-19 的直接因果关系,而 88% 的死亡患者至少有一种合并症。[948]Centre for Evidence-Based Medicine; Oke J, Heneghan C. Global COVID-19 case fatality rates. 2020 [internet publication].
https://www.cebm.net/global-covid-19-case-fatality-rates/
[952]Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA. 2020 Mar 23 [Epub ahead of print].
https://jamanetwork.com/journals/jama/fullarticle/2763667
http://www.ncbi.nlm.nih.gov/pubmed/32203977?tool=bestpractice.com
各国死亡率
预后因素
与重症和死亡风险增加相关的预后因素包括:[954]Izcovich A, Ragusa MA, Tortosa F, et al. Prognostic factors for severity and mortality in patients infected with COVID-19: a systematic review. PLoS One. 2020;15(11):e0241955.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671522/
http://www.ncbi.nlm.nih.gov/pubmed/33201896?tool=bestpractice.com
[955]Booth A, Reed AB, Ponzo S, et al. Population risk factors for severe disease and mortality in COVID-19: a global systematic review and meta-analysis. PLoS One. 2021 Mar 4;16(3):e0247461.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247461
http://www.ncbi.nlm.nih.gov/pubmed/33661992?tool=bestpractice.com
患者因素
合并症的发生
高血压
心血管病
心衰
脑血管疾病
痴呆
糖尿病
慢性肺疾病
慢性阻塞性肺疾病 (COPD)
活动性恶性肿瘤
免疫抑制
慢性肾病
症状/征象
肌痛
痰液产生
畏寒
恶心
呼吸困难
呼吸急促
低氧血症
呼吸衰竭
低血压
心动过速
检查
死亡患者中最常见基础疾病为高血压、糖尿病和心血管疾病。[956]Javanmardi F, Keshavarzi A, Akbari A, et al. Prevalence of underlying diseases in died cases of COVID-19: a systematic review and meta-analysis. PLoS One. 2020 Oct 23;15(10):e0241265.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584167/
http://www.ncbi.nlm.nih.gov/pubmed/33095835?tool=bestpractice.com
氧动脉分压与吸入氧分数比率(PaO₂/FiO₂)≤200 mmHg,以及入院时呼吸衰竭亦与院内死亡风险增加独立相关。[957]Santus P, Radovanovic D, Saderi L, et al. Severity of respiratory failure at admission and in-hospital mortality in patients with COVID-19: a prospective observational multicentre study. BMJ Open. 2020 Oct 10;10(10):e043651.
https://bmjopen.bmj.com/content/10/10/e043651
http://www.ncbi.nlm.nih.gov/pubmed/33040020?tool=bestpractice.com
几乎半数接受有创机械通气的患者遭遇死亡。>80 岁的老年患者死亡率(84%)高于 ≤40 岁的年轻患者死亡率(48%)。[958]Lim ZJ, Subramaniam A, Reddy MP, et al. Case fatality rates for COVID-19 patients requiring invasive mechanical ventilation: a meta-analysis. Am J Respir Crit Care Med. 2020 Oct 29 [Epub ahead of print].
https://www.atsjournals.org/doi/pdf/10.1164/rccm.202006-2405OC
http://www.ncbi.nlm.nih.gov/pubmed/33119402?tool=bestpractice.com
再次入院
在超过 106,000 例患者中,有约 9% 患者初次住院出院后 2 个月内再次入住同一家医院。1.6% 患者经历多次再入院。从出院到第一次再入院中位时长为 8 天。不足 0.1% 患者在再入院期间死亡。再入院危险因素包括:[959]Lavery AM, Preston LE, Ko JY, et al. Characteristics of hospitalized COVID-19 patients discharged and experiencing same-hospital readmission: United States, March–August 2020. MMWR Morb Mortal Wkly Rep. 2020 Nov 13;69(45):1695-9.
https://www.cdc.gov/mmwr/volumes/69/wr/mm6945e2.htm
http://www.ncbi.nlm.nih.gov/pubmed/33180754?tool=bestpractice.com
再感染
关于再次感染的信息还很有限。研究表明康复后 1-60 天的患者出现 RT-PCR 再次阳性的概率为 7%-23%,总再次阳性率估计为 12%。[960]Mattiuzzi C, Henry BM, Sanchis-Gomar F, et al. SARS-CoV-2 recurrent RNA positivity after recovering from coronavirus disease 2019 (COVID-19): a meta-analysis. Acta Biomed. 2020 Sep 7;91(3):e2020014.
https://www.mattioli1885journals.com/index.php/actabiomedica/article/view/10303
http://www.ncbi.nlm.nih.gov/pubmed/32921710?tool=bestpractice.com
病史较长、年龄较小的患者更有可能出现 RT-PCR 阳性复发,而重症、糖尿病和淋巴细胞计数较低的患者则较为少见。[961]Azam M, Sulistiana R, Ratnawati M, et al. Recurrent SARS-CoV-2 RNA positivity after COVID-19: a systematic review and meta-analysis. Sci Rep. 2020 Nov 26;10(1):20692.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691365/
http://www.ncbi.nlm.nih.gov/pubmed/33244060?tool=bestpractice.com
目前尚不清楚其是否由再感染引发;是否由诸如样本采集类型和拭子检测相关性技术误差、变异 SARS-CoV-2 感染或持续性病毒脱落等因素引发;或检测结果是否在出院时呈假阴性。[962]SeyedAlinaghi S, Oliaei S, Kianzad S, et al. Reinfection risk of novel coronavirus (COVID-19): a systematic review of current evidence. World J Virol. 2020 Dec 15;9(5):79-90.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747024/
http://www.ncbi.nlm.nih.gov/pubmed/33363000?tool=bestpractice.com
研究已反复报道了直至初次感染后 90 天为止都可出现 RT-PCR 检测阳性;因此,最有可能的原因是这类病例实际上并未康复、仍处于初次感染期。重要的是要意识到尽管有报道称持续病毒脱落可持续至感染发生后 90 天,在症状发作 10-20 天(取决于疾病严重程度)后就已经无法分离出具有复制能力的病毒了。[963]Arafkas M, Khosrawipour T, Kocbach P, et al. Current meta-analysis does not support the possibility of COVID-19 reinfections. J Med Virol. 2020 Sep 8 [Epub ahead of print].
http://www.ncbi.nlm.nih.gov/pubmed/32897549?tool=bestpractice.com
一项对 200 名既往感染患者进行的队列研究发现,尽管咽部 RT-PCR 检测在康复后长达 90 天呈持续阳性,但未观察到密切接触者传播,表明此类患者在感染症状后阶段并无传染性。[964]Vibholm LK, Nielsen SS, Pahus MH, et al. SARS-CoV-2 persistence is associated with antigen-specific CD8 T-cell responses. EBioMedicine. 2021 Jan 30;64:103230.
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(21)00023-2/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/33530000?tool=bestpractice.com
香港、印度、厄瓜多尔和比利时已报道了真正的再感染病例(其定义为两次感染发作间隔至少 3 个月,由不同基因组序列病毒株感染所致)。[965]Parry J. Covid-19: Hong Kong scientists report first confirmed case of reinfection. BMJ. 2020 Aug 26;370:m3340.
https://www.doi.org/10.1136/bmj.m3340
http://www.ncbi.nlm.nih.gov/pubmed/32847834?tool=bestpractice.com
[966]Gupta V, Bhoyar RC, Jain A, et al. Asymptomatic reinfection in two healthcare workers from India with genetically distinct SARS-CoV-2. Clin Infect Dis. 2020 Sep 23 [Epub ahead of print].
https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1451/5910388
http://www.ncbi.nlm.nih.gov/pubmed/32964927?tool=bestpractice.com
[967]Van Elslande J, Vermeersch P, Vandervoort K, et al. Symptomatic SARS-CoV-2 reinfection by a phylogenetically distinct strain. Clin Infect Dis. 2020 Sep 5 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499557/
http://www.ncbi.nlm.nih.gov/pubmed/32887979?tool=bestpractice.com
[968]Prado-Vivar B, Becerra-Wong M, Guadalupe JJ, et al. A case of SARS-CoV-2 reinfection in Ecuador. Lancet Infect Dis. 2020 Nov 23 [Epub ahead of print].
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30910-5/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/33242475?tool=bestpractice.com
美国亦报道了两例再感染可能病例;然而,尽管该两名男性患者两次发作由不同基因变异引发,但感染发生的时间间隔不足 2 个月。[969]Larson D, Brodniak SL, Voegtly LJ, et al. A case of early re-infection with SARS-CoV-2. Clin Infect Dis. 2020 Sep 19 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543357/
http://www.ncbi.nlm.nih.gov/pubmed/32949240?tool=bestpractice.com
[970]Tillett RL, Sevinsky JR, Hartley PD, et al. Genomic evidence for reinfection with SARS-CoV-2: a case study. Lancet Infect Dis. 2020 Oct 12 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550103/
http://www.ncbi.nlm.nih.gov/pubmed/33058797?tool=bestpractice.com
SARS-CoV-2 变体再感染病例在巴西、英国和南非已见诸报道。[971]Zucman N, Uhel F, Descamps D, et al. Severe reinfection with South African SARS-CoV-2 variant 501Y.V2: a case report. Clin Infect Dis. 2021 Feb 10 [Epub ahead of print].
https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab129/6132402
http://www.ncbi.nlm.nih.gov/pubmed/33566076?tool=bestpractice.com
[972]Resende PC, Bezerra JF, de Vasconcelos RHT, et al. Spike E484K mutation in the first SARS-CoV-2 reinfection case confirmed in Brazil, 2020. 2021 [internet publication].
https://virological.org/t/spike-e484k-mutation-in-the-first-sars-cov-2-reinfection-case-confirmed-in-brazil-2020/584
[973]Naveca F, da Costa C, Nascimento V, et al. SARS-CoV-2 reinfection by the new variant of concern (VOC) P.1 in Amazonas, Brazil. 2021 [internet publication].
https://virological.org/t/sars-cov-2-reinfection-by-the-new-variant-of-concern-voc-p-1-in-amazonas-brazil/596
[974]Nonaka, CKV, Franco MM, Gräf, T, et al. Genomic evidence of a Sars-Cov-2 reinfection case with E484K spike mutation in Brazil. Preprints. 2021 Jan 27 [Epub ahead of print].
https://www.preprints.org/manuscript/202101.0132/v1
免疫力
尚未完全了解免疫应答,包括免疫力持续时间。有证据表明,感染 SARS-CoV-2 可能会带来某种抵御再感染的保护性免疫力。[503]Watson J, Richter A, Deeks J. Testing for SARS-CoV-2 antibodies. BMJ. 2020 Sep 8;370:m3325.
https://www.bmj.com/content/370/bmj.m3325
http://www.ncbi.nlm.nih.gov/pubmed/32900692?tool=bestpractice.com
[975]Gudbjartsson DF, Norddahl GL, Melsted P, et al. Humoral immune response to SARS-CoV-2 in Iceland. N Engl J Med. 2020 Sep 1 [Epub ahead of print].
https://www.nejm.org/doi/full/10.1056/NEJMoa2026116
http://www.ncbi.nlm.nih.gov/pubmed/32871063?tool=bestpractice.com
[976]Chandrashekar A, Liu J, Martinot AJ, et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science. 2020 May 20 [Epub ahead of print].
https://science.sciencemag.org/content/early/2020/05/19/science.abc4776
http://www.ncbi.nlm.nih.gov/pubmed/32434946?tool=bestpractice.com
[977]Kirkcaldy RD, King BA, Brooks JT. COVID-19 and postinfection immunity: limited evidence, many remaining questions. JAMA. 2020 May 11 [Epub ahead of print].
https://jamanetwork.com/journals/jama/fullarticle/2766097
http://www.ncbi.nlm.nih.gov/pubmed/32391855?tool=bestpractice.com
[978]Ni L, Ye F, Cheng ML, et al. Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals. Immunity. 2020 Jun 16;52(6):971-7.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196424/
http://www.ncbi.nlm.nih.gov/pubmed/32413330?tool=bestpractice.com
但是,研究质量参差不齐,对结果进行比较亦较为困难。[979]Post N, Eddy D, Huntley C, et al. Antibody response to SARS-CoV-2 infection in humans: a systematic review. PLoS One. 2020;15(12):e0244126.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244126
http://www.ncbi.nlm.nih.gov/pubmed/33382764?tool=bestpractice.com
英格兰公共卫生部一项研究发现,与既往未感染过该疾患者相比,既往感染导致的自然获得性免疫力可对再感染提供 83% 的保护性。保护性似乎可持续至少 5 个月。[980]Public Health England. Past COVID-19 infection provides some immunity but people may still carry and transmit virus. 2021 [internet publication].
https://www.gov.uk/government/news/past-covid-19-infection-provides-some-immunity-but-people-may-still-carry-and-transmit-virus
根据一项大型回顾性研究,SARS-CoV-2 血清学阳性者未来至少数月内感染风险似乎较低。[981]Harvey RA, Rassen JA, Kabelac CA, et al. Association of SARS-CoV-2 seropositive antibody test with risk of future infection. JAMA Intern Med. 2021 Feb 24 [Epub ahead of print].
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2776810
http://www.ncbi.nlm.nih.gov/pubmed/33625463?tool=bestpractice.com
新兴研究表明,大多数人都会对 CD4+ 和 CD8+ T 细胞产生强烈而广泛的 T 细胞反应,有些人会产生记忆表型。[982]Centre for Evidence-Based Medicine; Plüddemann A, Aronson JK. What is the role of T cells in COVID-19 infection? Why immunity is about more than antibodies. 2020 [internet publication].
https://www.cebm.net/covid-19/what-is-the-role-of-t-cells-in-covid-19-infection-why-immunity-is-about-more-than-antibodies
一项预印本研究发现,刺突免疫球蛋白 G(IgG)在 6 个月内相对稳定,刺突特异性记忆 B 细胞在 6 个月时比 1 个月时更为丰富,COVID-19 恢复成人中(多数为轻度疾病),CD4+ 和 CD8+ T 细胞半衰期为 3 至 5 个月。[983]Dan JM, Mateus J, Kato Y, et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science. 2021 Jan 6 [Epub ahead of print].
https://science.sciencemag.org/content/early/2021/01/06/science.abf4063.long
http://www.ncbi.nlm.nih.gov/pubmed/33408181?tool=bestpractice.com
另一项对超过 12,000 名医护人员进行的研究发现,先前的 SARS-CoV-2 感染可产生抗体反应,感染后 6 个月内为大多数患者提供保护,避免再感染。[984]Lumley SF, O'Donnell D, Stoesser NE, et al. Antibody status and incidence of SARS-CoV-2 infection in health care workers. N Engl J Med. 2020 Dec 23 [Epub ahead of print].
https://www.nejm.org/doi/full/10.1056/NEJMoa2034545
http://www.ncbi.nlm.nih.gov/pubmed/33369366?tool=bestpractice.com
这预示着潜在的长期免疫力。
对 SARS-CoV-2 的免疫应答涉及细胞免疫和抗体产生。研究认为,对 SARS-CoV-2 的适应性免疫发生在感染前 7 至 10 天内。在感染的早期检测到了强烈的记忆 B 细胞和浆母细胞反应,症状发作后第 5 至 7 天分泌 IgA 和 IgM 抗体,第 7 至 10 天分泌 IgG。约 28 天后,IgA 和 IgM 滴度下降,而 IgG 滴度在约 49 天时达到峰值。T 细胞在感染的第一周被同时激活,SARS-CoV-2 特异性记忆 CD4+ 和 CD8+ T 细胞在 2 周内达到峰值,但在 ≥100 天后仍可检测到。个体之间的抗体和 T 细胞反应不同,取决于年龄和疾病严重程度。预印本研究发现,多数成人初次感染后至少 6 至 8 个月可出现 T 细胞反应。[985]Stephens DS, McElrath MJ. COVID-19 and the path to immunity. JAMA. 2020 Sep 11 [Epub ahead of print].
https://jamanetwork.com/journals/jama/fullarticle/2770758
http://www.ncbi.nlm.nih.gov/pubmed/32915201?tool=bestpractice.com
[986]Shrotri M, van Schalkwyk MCI, Post N, et al. T cell response to SARS-CoV-2 infection in humans: a systematic review. PLoS One. 2021;16(1):e0245532.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833159/
http://www.ncbi.nlm.nih.gov/pubmed/33493185?tool=bestpractice.com
尽管有人担心恢复期间 IgG 中和抗体的早期下降,但这并不被视作一个问题,因为在感染急性期过去后抗体水平总是会下降,而感染后的抗体滴度水平才是重要指标,因为这反映了长寿命浆细胞的产生,可防止随后的感染。[985]Stephens DS, McElrath MJ. COVID-19 and the path to immunity. JAMA. 2020 Sep 11 [Epub ahead of print].
https://jamanetwork.com/journals/jama/fullarticle/2770758
http://www.ncbi.nlm.nih.gov/pubmed/32915201?tool=bestpractice.com
抗体在感染后长达 8 个月亦可测得。[987]Choe PG, Kim KH, Kang CK, et al. Antibody responses 8 months after asymptomatic or mild SARS-CoV-2 infection. Emerg Infect Dis. 2020 Dec 22;27(3).
https://wwwnc.cdc.gov/eid/article/27/3/20-4543_article
http://www.ncbi.nlm.nih.gov/pubmed/33350923?tool=bestpractice.com
针对纽约市一个恢复期血清捐献者大型队列的分析表明,99.5% 确诊为轻度疾病的患者,患病后 4 周出现血清转阳。IgG 抗体在症状发作后 7-50 天和症状消退后 5-49 天内形成。这表明轻度疾病患者也许能够产生免疫力。[988]Wajnberg A, Mansour M, Leven E, et al. Humoral response and PCR positivity in patients with COVID-19 in the New York City region, USA: an observational study. Lancet Microbe. 2020 Sep 25 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518831/
http://www.ncbi.nlm.nih.gov/pubmed/33015652?tool=bestpractice.com
但是在中国,从轻度疾病中康复的患者,中和抗体滴度差异十分显著。[989]Wu F, Liu M, Wang A, et al. Evaluating the association of clinical characteristics with neutralizing antibody levels in patients who have recovered from mild COVID-19 in Shanghai, China. JAMA Intern Med. 2020 Aug 18 [Epub ahead of print].
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2769741
http://www.ncbi.nlm.nih.gov/pubmed/32808970?tool=bestpractice.com
有数据表明,无症状者对感染的免疫应答较弱;但是,这一点尚未得到证实。[990]Long QX, Tang XJ, Shi QL, et al. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med. 2020 Jun 18 [Epub ahead of print].
https://www.nature.com/articles/s41591-020-0965-6
http://www.ncbi.nlm.nih.gov/pubmed/32555424?tool=bestpractice.com
在 COVID-19 大流行之前采集的血液样本检测结果已表明,一些人已经具有识别 SARS-CoV-2 的免疫细胞。研究报道称,在已知无病毒暴露史的人群中,20%-50% 存在 T 细胞对 SARS-CoV-2 的反应。[991]Doshi P. Covid-19: do many people have pre-existing immunity? BMJ. 2020 Sep 17;370:m3563.
https://www.bmj.com/content/370/bmj.m3563
http://www.ncbi.nlm.nih.gov/pubmed/32943427?tool=bestpractice.com
在一项研究中,约 5% 未感染成人和 62% 未感染儿童(6 岁至 16 岁)拥有可识别 SARS-CoV-2 的抗体。[992]Ng KW, Faulkner N, Cornish GH, et al. Preexisting and de novo humoral immunity to SARS-CoV-2 in humans. Science. 2020 Nov 6 [Epub ahead of print].
https://science.sciencemag.org/content/early/2020/11/05/science.abe1107
http://www.ncbi.nlm.nih.gov/pubmed/33159009?tool=bestpractice.com
这可能是真正的免疫记忆所致,部分由既往感染普通感冒冠状病毒或其他未知动物冠状病毒引起。但是,需要对人类是否已有对 SARS-CoV-2 的免疫力开展进一步研究。
母体 SARS-CoV-2 IgG 抗体被发现在妊娠期无症状性或有症状性感染后,可通过胎盘。[993]Flannery DD, Gouma S, Dhudasia MB, et al. Assessment of maternal and neonatal cord blood SARS-CoV-2 antibodies and placental transfer ratios. JAMA Pediatr. 2021 Jan 29 [Epub ahead of print].
https://jamanetwork.com/journals/jamapediatrics/fullarticle/2775945
http://www.ncbi.nlm.nih.gov/pubmed/33512440?tool=bestpractice.com
预印本研究新兴数据表明,T 细胞应答在很大程度上不受 SARS-CoV-2 变体影响。[994]Tarke A, Sidney J, Methot N, et al. Negligible impact of SARS-CoV-2 variants on CD4+ and CD8+ T cell reactivity in COVID-19 exposed donors and vaccinees. bioRxiv. 2021 Mar 1 [Epub ahead of print].
https://www.biorxiv.org/content/10.1101/2021.02.27.433180v1.full.pdf