综述
新型冠状病毒肺炎重症及死亡的影响因素研究进展
国际病毒学杂志, 2020,27(6) : 516-520. DOI: 10.3760/cma.j.issn.1673-4092.2020.06.019
摘要

新型冠状病毒肺炎是由新型冠状病毒感染引起的急性呼吸道传染病,新型冠状病毒感染人体后,很大比例人群表现为无症状或轻微的症状,如发热、咳嗽、呼吸急促、嗅觉或味觉丧失、胃肠道症状等,一部分表现为重症,需要住院或进入重症监护室(ICU)。本文通过对新冠病毒不良结局相关的影响因素进行综述,分析人群特征、社会因素及病毒特征等与新冠肺炎不良结局的关联,为新冠肺炎疫情应对、疫情发展和医疗卫生服务需求预测、病例识别和救治策略改进提供证据支持。

引用本文: 任敏睿, 刘凤凤, 孙军玲, 等.  新型冠状病毒肺炎重症及死亡的影响因素研究进展 [J] . 国际病毒学杂志, 2020, 27(6) : 516-520. DOI: 10.3760/cma.j.issn.1673-4092.2020.06.019.
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新型冠状病毒肺炎(以下简称"新冠肺炎")是由新型冠状病毒(以下简称"新冠病毒")感染引起的急性呼吸道传染病。目前,新冠病毒已在全球范围内传播,据世界卫生组织(World Health Organization,WHO)公布数据显示,截至2020年8月30日,全球累计确诊2 400万人,逾83万名患者死亡,目前疫情依然呈现持续上升趋势[1]。我国采取积极的围堵策略(Containment)使国内疫情得到有效控制,全国逐渐转向常态化防控阶段。但目前仍面临国内残存传染源和境外输入传染源引起本地疫情传播以及秋冬季其它呼吸道病毒流行叠加加剧新冠肺炎疫情传播的风险,且我国人群免疫水平较低,尚无有效疫苗和药物预防和治疗。大量研究表明,高龄、男性、肥胖和基础疾病(如高血压、糖尿病等)是导致新冠肺炎不良结局最主要的危险因素,大多数死亡被认为与存在一种或多种合并症有关[2,3,4,5]。在实践中掌握和控制这些因素,可为医疗卫生服务需求预测、病例识别和救治策略改进提供科学依据,对于新冠肺炎疫情应对尤为重要,本文从宿主因素和社会因素两个方面对新冠病毒感染导致重症和死亡的影响因素进行综述。

1 新冠肺炎重症及死亡的影响因素
1.1 宿主因素
1.1.1 年龄

国内外大量研究均显示高龄是新冠病毒感染预后不良的重要危险因素,与住院死亡独立相关[2,3]。我国截至2月11日的分析显示,60岁以上死亡数占总病例数的81.04%,≥80岁老年人病死率最高(14.8%)[6]。Robert等人基于模型估计≥60岁组的病死率(6.4%)明显高于<60岁组(0.32%),≥80岁组病死率高达13.4%、住院比例高达18.4%,而且住院比例和感染死亡率随年龄的增长而增加[7]。同样,在美国2020年2月12日至3月16日的数据中,80%的死亡发生在≥85岁的老年人中(病死率:10%~27%)[8]。此前,高龄也被报道为SARS和MERS死亡的重要独立预测因素[9,10]。国内外养老院和其他长期护理机构曾多次暴发疫情[11,12,13],此类场所人员密集、与外界接触频繁,一旦出现病例,可广泛传播。加上老年人多伴有基础疾病,免疫能力弱,易产生不良结局。

1.1.2 性别

多项研究表明,各年龄段,男性比女性更可能住院、入住ICU和死亡[4,14,15]。我国基于44 672例确诊病例分析显示,男性病死率为2.8%,女性为1.7%[16]。欧盟CDC的数据显示,住院、ICU或需呼吸支持、死亡的病例中男性病例较女性多,男女性别比分别为1.2、2.1和1.4[17]。既往有关MERS和SARS相关研究中也发现男性是死亡的危险因素[18,19],可能与男性和女性在吸烟行为、免疫和内分泌系统方面存在的差异有关[20,21,22,23]。男性吸烟者居多[22],吸烟会引起多种健康问题,削弱人体的免疫力和肺功能[24]。血管紧张素转换酶2(Angiotensin-converting enzyme 2,ACE2)受体在男性体内的浓度也更高[23],而新冠病毒主要通过与ACE2结合进入细胞[25],女性免疫系统抵御病毒能力更强[20,21]等,均导致临床结局的性别差异。

1.1.3 基础疾病

大量研究表明,各年龄段患有某些基础疾病的人群感染新冠病毒后重症的风险均较高[2,3,5,26,27]。高血压、糖尿病是住院患者最常见的合并症[2,3,5]。有高血压的新冠肺炎患者患重症的风险可能会增加,全球高血压患病率较高,而且长期的高血压患者因存在多种并发症,感染新冠病毒后重症风险较高,应进一步研究不同程度的高血压与疾病严重程度的关联。但目前证据尚不清楚仅患高血压是否为预后不良的危险因素,未来的调查应阐明这一问题。糖尿病此前已被确定为影响SARS、H1N1和MERS重症和死亡的主要因素[28,29,30]。迄今为止的临床观察表明,糖尿病与增加新冠肺炎严重程度和死亡风险相关。糖尿病或血糖控制不良的患者,患新冠肺炎重症和死亡风险比血糖正常患者和非糖尿病患者高[31,32],而维持血糖变化范围在3.9~10.0 mmol/L,死亡风险将大大降低[33]。另一方面,有研究发现新冠病毒可使健康人患糖尿病或使既往糖尿病患者出现严重代谢并发症[34,35]。病毒通过入侵胰岛组织直接或间接损伤胰岛β细胞、加重免疫功能失调、炎症风暴和内分泌失衡等对血糖产生不良影响[36,37],但目前新冠病毒影响葡萄糖代谢的确切机制、新冠肺炎患者中新发糖尿病患者的病情严重程度和转归等问题仍不清楚,需进一步研究。肥胖可通过引发呼吸系统功能障碍、增加基础疾病风险和影响代谢等机制,增加新冠肺炎患者的重症风险[27]。研究显示,新冠肺炎严重程度随着体重指数(BMI)的增加而增加,BMI≥35 kg/m2与有创机械通气风险增加相关[38],超重及肥胖患者患重症肺炎的风险分别是正常体重的1.84倍和3.4倍[39],但是肥胖与新冠肺炎联系的确切机制及肥胖对儿童新冠病毒感染或疾病进展的影响尚不清楚,未来应多关注。

1.1.4 遗传因素

研究发现,遗传因素与新冠病毒感染后的疾病进展相关,如ACE2基因、ABO血型等。人群中ACE2具有高度遗传多态性,有助于解释不同国家或地区、不同人群中,新冠病毒的临床发展进程存在的差异[40,41]。此外,多国研究人员对意大利和西班牙1 980名新冠重症患者和2 381名对照组人群进行了全基因组关联分析,发现A型血相对其他血型在感染新冠病毒后出现呼吸衰竭的风险更高,而O型血出现呼吸衰竭的风险相对较低。研究人员解释可能与不同血型人群的N-聚糖中和抗体差异、基因变异等因素有关[42]。美国和伊朗的研究也发现了相似的结果[43,44]。未来有必要对更大规模的数据进行跟踪研究,以探究遗传因素如何影响病情的严重程度以及其潜在的病理生理机制。

1.2 社会因素
1.2.1 医疗水平

新冠肺炎的临床结局受医疗水平和经济条件的影响较大。在中国,暴发早期阶段的病死率较高(12月31日前为14.4%),2月1日—2月11日降至0.8%[16]。湖北省粗病死率为5.91%,湖北以外为0.98%[45]。武汉及湖北新冠肺炎疫情暴发期间,医疗系统崩溃,暂时性的疾病负担超出了医疗机构的能力,病例数激增给医疗系统带来压力,医疗系统过载可导致更多的死亡。而湖北以外地区疫情发生较晚,病例识别能力随着经验累积有所提升,病例发现和救治更加及时。在缺乏药物干预措施(包括疫苗、抗病毒药物)的情况下,加强公共卫生干预措施和提升医疗系统救治能力对降低患者病死率具有至关重要的意义。

1.2.2 社会经济地位

社会经济地位可以通过职业、生活条件、健康相关行为和基础病等因素直接或间接地影响疾病的发生发展[46]。研究发现与白人族裔相比,黑人、南亚和混合族裔新冠肺炎死亡风险增加了43%~48%,其原因与较高的基础疾病患病率和贫困有关,而且贫困程度越高,风险增加的趋势越明显[47]。对流感的研究也发现,疾病流行时,贫困和不平等可能会增加住院率和相关并发症的发生[48]。有关新冠肺炎社会经济地位的研究较少,有研究显示,与轻型患者相比,重症患者中农民工人和退休人员占比较高[49]

2 问题与展望

目前有关孕妇、混合感染和毒株变异等因素与新冠肺炎患者临床结局的关联有待进一步探索。此前研究发现孕妇感染流感病毒、SARS病毒或MERS病毒时更易出现重症[50,51,52]。新冠病毒对孕妇或新生儿结局的影响研究较少,但有研究报道孕妇新冠病毒感染可能与早产、先兆子痫、剖宫产和围产期死亡有关[53,54]。Alexandre等人报告了一例经胎盘传播的病例,新生儿具有与新冠病毒感染相关的症状[55],但也有研究未发现围产期母婴垂直传播的证据[53,56,57,58],传播风险来自于接触传播,未来需要更多的证据。

目前已有新冠病毒和流感病毒、人类免疫缺陷病毒和其他呼吸道病原体等合并感染的报道[59,60,61]。混合感染可能会显著抑制宿主的免疫系统,并对疾病的预后不利。秋冬季是流感病毒、肺炎链球菌、呼吸道合胞病毒等各类呼吸道病毒流行季,大量具有相似呼吸道感染症状的就诊病例将增加医疗机构对新冠肺炎病例鉴别诊断的复杂性,对疫情防控和医疗机构诊治将带来很大挑战。目前尚无证据表明混合感染的病人感染新冠病毒后结局是否更严重,需进一步研究。另外,多项研究表明过去感染了某种冠状病毒,可能对新冠病毒产生交叉免疫,从而减轻病情[62,63,64],但这一假设需要未来在队列研究中进一步验证。

毒株的变异可能会影响新冠肺炎患者的临床进程。新冠病毒基因组开放阅读框8(ORF8)区域∆382突变(即382个核苷酸缺失)在大流行早期被检测到。Young等人回顾性分析了新加坡2020年1月22日至3月21日的住院病例,发现相较于野生型病毒组,∆382变异病毒组的患者更年轻,全身炎症反应更轻,需要补充氧气治疗的几率更低,但这一变异毒株在3月之后未能再检测到[65]。另外,研究发现2020年2月份在意大利首次发现的新冠病毒S蛋白的D614G突变株(即新冠病毒刺突蛋白上的第614位氨基酸由天冬氨酸[D]变成甘氨酸[G])传染性更强[66,67,68],但尚没有证据表明其变异会导致更严重的病情,目前需要对新冠病毒基因突变进行监测,以推动疫苗等干预措施的研究。

此外,维生素D的严重缺乏、癌症、免疫低下等都与新冠重症和死亡之间存在着很强的相关性。人体维生素D平均水平低的国家,新冠肺炎发病率和死亡率都比较高,仍需进一步研究缺乏维生素D与加重新冠肺炎的因果关系[69],癌症患者由于年龄较大、ACE2表达较高和更多的基础病[70],感染新冠病毒时出现不良结局风险较高。感染新冠病毒的癌症患者需要机械通气或入住ICU的风险是普通人群的3.5倍[71],病死率高达28.6%[72],远高于一般患者。

本文结果表明,高龄、男性和基础疾病等是导致新冠肺炎不良结局的危险因素。特殊人群、秋冬季混合感染、毒株变异加大了疫情防控的难度。本研究可为今后的新冠疫情应对、病例识别和救治策略及防控策略的改进提供更为合理的科学依据。

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