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Virological Characteristics of the Omicron Variant: Key Mutations, Pathogenicity, and Immune Escape
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摘要: 新型冠状病毒(severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) Omicron变异株首次在博茨瓦纳被检出, 随后造成了全世界范围内的感染人数激增。截至目前, Omicron是需要关注的SARS-CoV-2变异株中突变数量最多的毒株, 已在整个基因组中发生至少50次突变。Omicron基因组发生的突变赋予病毒一定的适应性优势, 如受体结合域与人类血管紧张素转换酶2受体亲和力增强导致病毒传播能力增强; 与先前变异株相比, 病毒复制能力减弱导致在COVID-19患者中引起的症状相对较轻。此外, 该变异株具有较高的环境稳定性, 部分逃脱了来自疫苗接种或先前感染诱导的宿主免疫反应, 且对大多数治疗性抗体具有较高的耐药性。本文对Omicron变异株的关键突变、病毒学特征、致病性和免疫逃逸能力进行总结, 以期为完善疫情防控策略和公共卫生举措提供科学参考。Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant was first detected in Botswana and subsequently led to a worldwide surge in infections. Until now, Omicron and its lineages, the most highly mutated strains among variants of concern (VOC), have contained at least 50 mutations in the entire genome. Mutations give the virus certain adaptive advantages, such as the enhanced affinity between receptor binding domain (RBD) and human angiotensin-converting enzyme 2 (ACE2) receptors leading to enhanced transmission of the virus, and the weakened ability of virus replication leading to mild symptoms in patients with COVID-19. In addition, given its high environmental stability, Omicron can partially escape the host immune response induced by vaccination or prior infection, and is highly resistant tomost therapeutic antibodies.In this paper, key mutations, virological characteristics, pathogenicity, and immune escape of the Omicron variant are summarized, in order to provide scientific reference for coping with the new situation of the pandemic, as well as improving pandemic prevention and control strategy and public health measures.
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Keywords:
- Omicron variant /
- mutations /
- virological characteristics /
- pathogenicity /
- immune escape /
- COVID-19
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嗜铬细胞瘤原发于肾上腺髓质或肾上腺外嗜铬细胞, 可分泌肾上腺素、去甲肾上腺素和多巴胺[1]。该病罕见[2-3], 发病率仅2~8/100万[4]。有研究显示糖尿病与嗜铬细胞瘤存在一定关联[5-7], 15%~35%的嗜铬细胞瘤患者可出现糖耐量异常[8-9]。嗜铬细胞瘤患者儿茶酚胺水平升高, 致使胰岛素分泌功能受损[10-14]并增加胰岛素抵抗[15-17], 同时儿茶酚胺水平增高也与糖摄入减少、糖异生和糖原分解增加有关[6]。在切除嗜铬细胞瘤后, 上述效应迅速消除甚至反转, 部分术前无糖尿病患者术后会出现短暂的反弹性低血糖[3, 7], 而部分合并糖耐量受损的患者术后短期内可表现为胰岛素敏感性增强[3], 大部分患者术后糖尿病可获得远期缓解甚至治愈[18]。遗憾的是上述均为小样本研究, 我国尚缺乏这方面研究。
本文通过单中心回顾性分析, 探究我国嗜铬细胞瘤并发2型糖尿病患者术后血糖的变化及其可能的预测因素。
1. 对象与方法
1.1 对象
回顾性收集并分析2012年1月至2016年12月在华西医院确诊的129例肾上腺嗜铬细胞瘤并接受根治性手术切除患者的临床资料。
纳入患者需同时满足以下3条标准:(1)通过术后病理检查及术前儿茶酚胺检查明确诊断嗜铬细胞瘤; (2)行嗜铬细胞瘤根治性手术切除; (3)诊断2型糖尿病需口服降糖药物或注射胰岛素控制血糖。符合下列1条即可确诊为并发2型糖尿病:(1)既往有2型糖尿病诊断记录; (2)排除胰岛素绝对缺乏情况后, 胰岛素功能测定符合下列1条者:①正在采用降糖措施控制血糖; ②糖化血红蛋白≥6.5%;③口服葡萄糖耐量试验2 h血糖≥11.1 mmol/L。
排除标准:(1)未接受嗜铬细胞瘤根治性切除手术者; (2)合并糖尿病以外的代谢性疾病。
1.2 分组
根据患者术后糖尿病缓解与否, 将患者分为缓解组与未缓解组。术后糖尿病缓解定义为:在血糖控制良好的基础上, 术后停用降糖药物或降糖方案较术前用药剂量/种类减少, 或术后空腹血糖水平≤6.1 mmol/L[19]。术后糖尿病未缓解定义为:术后降糖方案及空腹血糖水平均较术前无改善。
1.3 临床资料采集
收集患者术前相关资料, 包括年龄、性别、体质量指数(body mass index, BMI)、肿瘤直径、血浆儿茶酚胺水平(去甲肾上腺素、肾上腺素和多巴胺)、影像学检查、术前3 d内及术后第2天空腹血糖水平及降糖方案; 术后长期随访并记录术后1年空腹血糖水平。
1.4 统计学方法
计数资料如性别、术后糖尿病缓解例数使用卡方检验进行比较; 计量资料如年龄、BMI、肿瘤直径、血糖等结果以均数±标准差形式表达并通过t检验进行统计学分析; 血浆儿茶酚胺水平使用中位数及四分位数表示, 采用秩和检验进行比较; 使用单因素Logistic回归分析可能影响术后血糖水平的因素。以上统计分析由SPSS 16.0软件计算完成, P＜0.05为差异具有统计学意义。
2. 结果
2.1 一般资料
共129例嗜铬细胞瘤患者接受根治性手术切除治疗, 影像学表现如图 1所示; 其中33例并发2型糖尿病, 发生率为25.6%(33/129)。33例患者中27例随访资料完整, 男性8例, 女性19例, 平均年龄(51±9)岁(表 1)。
表 1 27例嗜铬细胞瘤并发2型糖尿病患者基本信息分组 性别[n(%)] 年龄(x±s, 岁) BMI(x±s, kg/m2) 肿瘤直径(x±s, cm) 术前血浆去甲肾上腺素[M(Q), ng/L] 术前血浆肾上腺素(ng/L) 空腹血糖(x±s, mmol/L) 男 女 术前 术后 缓解组(n=21) 8(38.1) 13(61.9) 50±10 22±4 5.27±2.31 1804 (908, 5544) 182 (49, 635) 8.90±6.70 4.90±1.38* 未缓解组(n=6) 0(0) 6(100) 53±4 23±2 4.17±1.81 1218 (598, 8188) 138 (44, 240) 7.92±1.59 5.97±1.01 P值 0.092 0.511 0.606 0.296 0.457 0.355 0.728 0.090 BMI:体质量指数; 与术前血糖比较, *P＜0.01 2.2 糖尿病缓解情况
随访资料完整的27例患者术前均采用药物控制
血糖, 其中17例注射外源胰岛素, 10例口服降糖药。术后15例患者完全停用降糖治疗(7例术前口服降糖药, 8例术前注射外源胰岛素), 6例药物用量较术前减少(口服降糖药和注射外源胰岛素者各3例), 总体缓解率为78%(21/27);术后降糖方案较术前无变化者6例, 未缓解率为22%(6/27)。两组患者术后总体空腹血糖较术前显著降低[(8.68±5.94) mmol/L比(5.14±1.37) mmol/L, P＜0.01], 未缓解组亦较术前降低但无统计学差异(P=0.111)(表 1)。
2.3 预测因素分析
两组患者在性别、年龄、BMI、肿瘤直径、术前血去甲肾上腺素及血肾上腺素等方面均无统计学差异(P均＞0.05, 表 1)。单因素Logistic回归分析显示, 患者年龄、性别、BMI、肿瘤直径、术前血浆去甲肾上腺素及肾上腺素水平与术后糖尿病缓解无关(表 2)。
表 2 单因素Logistic回归分析影响术后糖尿病缓解的预测指标因素 β值 SE值 Wald值 自由度 P值 OR值 95% CI 年龄 0.034 0.050 0.463 1.000 0.496 1.034 0.939~1.140 性别 -20.430 14 210.361 0.000 1.000 0.999 0.000 - BMI 0.067 0.126 0.284 1.000 0.594 1.070 0.835~1.370 肿瘤直径 -0.274 0.261 1.100 1.000 0.294 0.760 0.455~1.269 血浆去甲肾上腺素 0.000 0.000 0.000 1.000 0.986 1.000 1.000 血浆肾上腺素 -0.002 0.002 0.752 1.000 0.386 0.998 0.994~1.002 BMI:同表 1 3. 讨论
本研究中嗜铬细胞瘤并发2型糖尿病的发生率为25.6%, 与Beninato等[14]的研究结果(23.5%)相近。约15%~35%的嗜铬细胞瘤患者会出现糖耐量受损[8-9], 与本研究结果一致。
患者无论术前是否合并糖耐量受损, 术后血糖均可出现下降[15]。本研究结果亦提示术后空腹血糖较术前显著降低, 其机制可能是切除肿瘤后, 儿茶酚胺水平降低, 对血糖上调作用减弱, 胰岛素分泌增加, 胰岛素抵抗减弱, 患者糖耐量异常得到改善。
遗憾的是, 本研究尚缺失术后儿茶酚胺水平检测数据, 无法进行相关分析, 今后需进一步检测术后儿茶酚胺水平以验证其对术后血糖影响及其可能的机制。
本研究中年龄、性别、BMI、肿瘤大小、血浆肾上腺素和去甲肾上腺素水平均非术后糖尿病缓解的预测因素。但Beninato等[18]的研究却提示, BMI是嗜铬细胞瘤患者术后糖尿病缓解的独立预测因素, BMI越小, 术后糖尿病缓解的可能性越高, 与本研究结论相反。可能由于嗜铬细胞瘤分泌的儿茶酚胺激活脂肪分解, 导致体重降低, 进一步降低BMI; 本研究中患者术前体重数据存在部分缺失, 仅能以术后随访所得数据予以补充, 也可能在一定程度上干扰了对BMI与糖尿病缓解之间关系的判断。此外, Beninato等[18]的研究亦提示肿瘤大小与术后糖尿病缓解相关, 肿瘤体积越大, 术后糖尿病缓解的可能性越大, 这可能与肿瘤体积大的患者儿茶酚胺水平高, 增加糖耐量受损或糖尿病患病风险有关。本研究未显示肿瘤大小及儿茶酚胺水平与术后血糖缓解之间的相关性, 笔者推测可能与血儿茶酚胺水平波动较大有关, 而尿儿茶酚胺水平相对稳定, 但由于尿儿茶酚胺数据缺失, 无法进行单因素分析, 是本文的研究缺陷之一, 今后收集尿儿茶酚胺资料进一步分析可能会得出新的结论。BMI和肿瘤直径是否为独立预测因素尚需大样本前瞻性研究进一步明确。
嗜铬细胞瘤并发2型糖尿病患者在切除肿瘤后, 糖尿病病情可得到明显缓解甚至治愈, 年龄、性别、BMI、肿瘤直径、术前血浆肾上腺素和去甲肾上腺素并非术后糖尿病缓解的预测因素, 这一结论尚需大样本研究进一步验证。
作者贡献：陈玉清负责资料收集和论文撰写；李金明负责选题设计并审阅定稿。利益冲突：所有作者均声明不存在利益冲突 -
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