大规模爆发的新型冠状病毒肺炎（Corona Virus Disease 2019,COVID-19）已然成为近年来困扰全球的突发公共卫生事件。COVID-19是由正冠状病毒亚科中的β-冠状病毒属（β-CoV）的新型冠状病毒（2019-nCoV）与宿主细胞膜融合,释放遗传物质进入胞质内所引起的传染性极强的呼吸道疾病。新型冠状病毒的刺突蛋白（S蛋白）是其侵入宿主体内的关键蛋白,在病毒与宿主细胞靠近时,S蛋白受体结合区（receptor binding domains,RBD）与其受体血管紧张素转化酶-2（angiotensin-converting enzyme-2,ACE-2）结合,介导病毒入侵并促进其病毒与宿主细胞的膜结合[1]。ACE-2是病毒进入宿主的关键点,患者出现的呼吸系统症状也正是因为ACE-2在其中的大量表达。目前,COVID-19患者典型的呼吸系统症状（如干咳、乏力等）是进行初步筛查的重要指征,但仅仅通过呼吸系统表现进行筛查是不够完善的。近来研究发现ACE-2受体在近70种人体组织中表达[2],且大量分布于口腔相关组织,如唾液腺,口腔黏膜上皮及舌上皮细胞,COVID-19患者表现出独有的口腔症状,如味觉减退[3]、口干[4]、口臭[5]、唾液腺炎症[6]、坏死性牙周病[7]及念珠菌病[8]、多形性红斑[9]及一些常见的口腔黏膜病[10]等,且部分症状早于发烧、干咳等典型症状,因此,关注患者的口腔表现能够进一步完善COVID-19筛查程序。
1 味觉障碍
味觉障碍是一种以味觉改变为特征的病症,主要表现为无法分辨酸、甜、苦、咸。味觉障碍可能是COVID-19的首发症状之一,现已被世界卫生组织纳入诊断标准当中,同时也是最常见的周围神经系统损害的症状[3]。味觉障碍在欧洲国家的报道较为普遍。一项欧洲多国（比利时,法国,西班牙,意大利）调查研究表明[3],在417名轻中度冠状病毒感染的患者中,有342（88.8%）名报告了味觉障碍。韩国学者[11]报道在3 191名患者中,发生味觉或嗅觉障碍的患者为488例,其中味觉和嗅觉同时出现障碍的情况有254例,仅出现味觉障碍的患者有99例,表明味觉障碍和嗅觉障碍之间存在着一定的相关性。同时,Yan等[12]对比存在类似流感样症状的COVID-19患者和普通肺炎患者,发现59例COVID-19患者中有42例存在味觉改变,而普通患者则为17%（35/203）,证明了味觉障碍与COVID-19之间存在着很强的联系。
ACE-2的受体存在于味蕾和唾液腺上皮,表达ACE-2的细胞与部分味觉相关基因标记细胞（如Ⅱ型和Ⅲ型味觉细胞）共存,因此,2019-nCoV可直接接触味觉受体引起味觉障碍。同时,周围神经系统也是2019-nCoV的靶点,病毒损伤味觉相关神经（脑神经Ⅶ、Ⅸ、Ⅹ）,且口腔黏膜上皮内的ACE-2受体可引发局部炎症反应,导致水肿,阻碍味蕾功能,从而导致味觉改变。另外,对嗅觉上皮中表达ACE-2的细胞的直接损伤也可能导致味觉障碍[13]。
2 口干症
唾液腺中存在着ACE-2受体,病毒侵袭唾液腺,引起炎症和感染,从而影响唾液质量和流量,同时年龄增长及年龄增长伴随的基础疾病的用药均会导致唾液流量减少,如治疗某些自身免疫疾病的氯喹可引起口干症。另外,病毒引起的鼻塞鼻漏会导致口呼吸,引起口干[19]。
不同病因引起的口干症的治疗原则不同。因药物的副作用带来的口干症常常会减少相应药物的使用,同时,唾液替代物（如毛果芸香碱等）,针灸和传统中药治疗（如麦冬、生地黄、甘草等）也是常用的改善口干症的方法[20]。
3 口臭
4 唾液腺炎症
ACE-2存在于滋养腮腺和小唾液腺及口腔黏膜固有层的毛细血管内皮细胞和脂肪细胞中,因此,2019-nCoV可直接传播到唾液腺与ACE-2受体结合,溶解上皮中的腺泡细胞,使唾液淀粉酶释放到外周血液中,引起免疫反应。当免疫反应增强时,机体过度分泌炎性细胞因子反而促进损害唾液腺组织的炎症反应,从而引起急性腮腺炎。而随着免疫反应的减弱,炎症损伤通过肉芽组织和纤维化修复,引起唾液腺导管的狭窄,导致唾液减少,增加慢性阻塞性涎腺炎的风险[24]。
COVID-19伴发的唾液腺炎症以抗炎抗感染治疗为主。临床上常采取口服抗生素或抗炎药物、同时联合皮质类固醇等来改善炎症状态。另外,对于慢性阻塞性涎腺炎,可采用唾液腺按摩,湿热涂抹以及口服唾液剂（如毛果芸香碱等）作为辅助手段[25]。
5 坏死性牙周病
坏死性牙周病是一种较为严重的牙周组织破坏性疾病,发病较急,牙龈组织表现为坏死和溃疡。Patel等[7]报道了1例疑似COVID-19患者出现的急性坏死性牙周病的表现,主要为严重口臭、水肿型牙龈和坏死的牙间乳头。因重型COVID-19患者体内检测出的高数值的中间普氏菌、梭杆菌等都是坏死性牙周病的致病菌,怀疑这是COVID-19和细菌合并感染（特别是中间普氏菌）所导致的。
COVID-19和牙周病之间有密切联系。一方面,COVID-19的存在引发或加重牙周病的发生发展,Fernandes等[26]发现7例COVID-19死亡病例中有5例牙周组织中呈现2019-nCoV阳性,这提示牙周组织似乎是2019-nCoV的靶标。另一方面,对本身存在牙周病的患者来说,罹患COVID-19的风险增加。牙周病原菌的内毒素会引起细胞衰老,而衰老细胞会促进2019-nCoV与宿主细胞内特定受体的结合。牙周病原菌在入侵早期抑制白细胞介素-8（interleukin-8,IL-8）的表达来延缓中性粒细胞的招募,这样的免疫逃逸机制不仅促进其生长,还可以促进2019-nCoV在细胞内的复制。另外牙周病原菌可能通过促进核因子-κB（nuclear factor kappa-B,NF-κB）的激活而导致S蛋白与ACE-2受体的结合,加重炎症反应[27]。
对于COVID-19患者伴发牙周病时,为避免治疗中形成的气溶胶传播病毒,一般采取保守治疗,如口服抗菌药物（如青霉素类、四环素类等）,含漱液（氯己定、聚维碘酮等）[27]。
6 口腔黏膜症状
6.1 口腔溃疡
口腔溃疡是黏膜上皮的完整性发生持续性缺损或破坏,因其表层坏死脱落而形成凹陷。Brandão等[10]报道了8位不同年龄段的COVID-19患者出现溃疡的情况,8位患者中有6位均在舌部（舌背,舌侧,舌尖等）出现溃疡,其次好发部位是上下唇。Riad等[28]总结了26例确诊COVID-19患者出现舌部溃疡的特征,发现大部分溃疡分布在舌背或舌侧。COVID-19引起的系统长时间的免疫失调进一步引发了口腔损害。另外,COVID-19患者的肿瘤坏死因子-α（tumor necrosis factor,TNF-α）水平升高可引起中性粒细胞对口腔黏膜的趋化,导致溃疡形成[29]。舌和唾液腺上皮细胞的ACE-2受体和2019-nCoV之间的相互作用可能会破坏口腔角质形成细胞的功能和唾液腺导管的上皮层,引发口腔溃疡[10]。伴发溃疡时,遵循消炎止痛、防止继发感染、促进愈合的基本原则。临床上除了局部使用曲安奈德和含漱0.12%葡萄糖酸氯己定漱口液外,光生物调节疗法也被用于治疗溃疡[28]。
6.2 念珠菌病
口腔念珠菌病是COVID-19患者最常见的真菌感染,通常与免疫功能受损的宿主有关。一项研究报道了53例感染口腔念珠菌病的重症COVID-19患者,平均年龄为63.1岁[8]。这提示患者年龄,用药情况（53/53抗病毒药物,49/53抗菌药物,52/53抗真菌药物）及COVID-19的严重程度与感染念珠菌病有着密切的联系。广谱抗生素的使用是COVID-19患者发生口腔念珠菌病的最相关危险因素。使用广谱抗生素导致的细菌枯竭引起的微生物失调可以改变局部口腔菌群,为念珠菌的繁殖提供有利条件[8]。并且COVID-19患者的淋巴细胞减少,感染口腔念珠菌病的患者年龄偏高,均会导致患者的免疫功能低下[8]。伴发念珠菌病时,常会选择唑类（氟康唑、伊曲康唑等）抗真菌药,局部选择2%~4%的碳酸氢钠溶液或氯己定含漱从而抑制念珠菌生长繁殖[8]。
6.3 多形性红斑
6.4 其他口腔黏膜病变
除了常见的几种黏膜表现外,COVID-19患者还可能表现出其他的口腔黏膜病变,如疱疹样病变、地图舌等[30],年龄偏高而存在的基础疾病（如糖尿病,高血压等）,机会性感染,创伤（治疗期间的气管插管）,机体免疫系统引起的细胞因子风暴等都是黏膜病出现的原因。
7 小结
随着对COVID-19研究的深入,国外（特别是欧洲国家）对于COVID-19的口腔表现的病例报道日益增加,值得注意的是,味觉障碍已被证实与COVID-19之间存在强关联,成为各卫生组织及医院进行筛查的重要标准。然而目前对COVID-19的口腔表现方面的研究仍存在一些不足。首先,国内研究者未能对COVID-19患者的口腔表现给予足够的重视;其次,除味觉障碍外,其余的口腔表现与COVID-19之间的关系并没有进行彻底的研究,无法判断是由2019-nCoV直接引起还是合并感染后出现。因此,在未来的研究中,针对COVID-19患者可进行更全面的临床检查和记录,完善国内患者的口腔健康状况;进一步探讨不同新冠病毒变异毒株所引起的临床表现上的差异,为有效筛查提供更有利的依据。
【Author contributions】 Yu JL, Yang LQ, Yao JJ, Huang HD, Tao L, Gao Y, Zhang HL, Ren JW, Liu ZH collected the references and wrote the article. Liu ZH revised the article. All authors read and approved the final manuscript as submitted.
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