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研究称「新冠感染后的嗅觉丧失或与免疫反应强度有关」,哪些信息值得关注?

Frank的回答

找了一大圈,基本上媒体都没提到原文链接,最后去找英文媒体找到了原文,原文是PLOS ONE的文献。

Chemosensory deficits are best predictor of serologic response among individuals infected with SARS-CoV-2[1]

简单说结论,作者认为在新冠感染后,出现血清学上的变化和嗅觉失灵或味觉失灵有一定的关系。

本文包括306人的研究,其中64.1%的人在感染的两周内出现嗅觉失灵,63.7%出现味觉失灵。利用未校正的线性回归,作者发现和正常的患者比起来,出现味觉失灵的患者其超阈值的抗体滴度高出了1.98倍(1.14-3.42);出现嗅觉失灵的患者超阈值抗体滴度高出了2.02倍(1.17-3.48)。在多重线性回归的模型校正后,IgG抗体反应和嗅觉的OR为1.90(1.05-3.44),味觉OR为2.01(1.12-3.61)。

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这里可以看到抗体阳性里嗅觉失灵的人占比71.6%,阴性中嗅觉失灵占比56.7%,这个比值差异很大,但是Chi-square的结果显示p值为0.047,虽然是有显著差异但是这个P值很接近0.05。味觉也类似,抗体阳性里味觉失灵占比71%,阴性里占比56.7%,p值在0.033。综合看下来,只能说抗体强度和味觉嗅觉失灵有联系,但是这个结果的置信力只能说勉强接受。

后面作者用了线性回归来计算味觉失灵和嗅觉失灵的OR

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左边的p值出自单线性回归,右边p值来自多显现回归。如果只看多重回归的结果,嗅觉失灵OR为1.90(1.05-3.44),p为0.033;味觉失灵OR为2.01(1.12-3.61),p为0.019。这个结果都是有显著差异的,只是这嗅觉失灵的95%CI太接近了1了。

最后说一下这篇文章,用了Cross-Section的方法,且样本容量不算很大,个人觉得为了验证抗体强度和味觉/嗅觉失灵的关系,还需要进一步大规模的Case-Control甚至Cohort来进行研究。

综上,

嗅觉和味觉的失灵确实可能和免疫强度有一定的关系,免疫强度越大,味觉或嗅觉失灵的可能性越大,但是这个结果仍需要更多研究来进一步证明。


我身边就有4例在感染新冠之后出现嗅觉失灵的朋友,甚至有一个人到现在都没有完全恢复。这里为了搞清楚新冠是如何对嗅觉造成影响的,我也去翻阅了一下文献。

COVID-19 related olfactory dysfunction

Page not available

本文中作者提到了目前对于嗅觉失灵的一些发现和设想

Localised obstruction caused by oedema within the olfactory cleft may contribute to early OD restricting the delivery of odorants to the OE, although nasal congestion is less frequently reported in COVID-19 compared to other endemic coronaviruses [19,20]. Although one study [21▪] found a high prevalence of complete obstruction of the olfactory cleft in MRI scans performed within 15 days of onset of COVID-19 related OD), other radiological studies of patients with more persistent loss [22▪] have found this to be an uncommon finding.

大义就是,鼻腔堵塞是一个可能的物理性原因。有一篇研究就发现出现症状的15天内,出现鼻腔完全堵塞的概率相当高。

Olfactory epithelial injury has previously been demonstrated in cases of postviral olfactory loss [23]. Postmortem studies of COVID-19 patients reporting anosmia showed focal atrophy of the OE, leukocytic infiltration of the lamina propria and evidence of axonal damage in the olfactory nerve fibres [24]. Animal models of SARS-CoV-2 [25▪] demonstrated massive destruction of olfactory epithelium after nasal inoculation and loss of cilia; evidence of recovery was observed as early as day 4 although incomplete by day 14 [26▪].

对新冠死者的遗体研究后发现,患者的嗅觉上皮组织出现局灶性萎缩,黏膜固有层出现白细胞浸润,嗅觉神经纤维也出现轴突损伤,这些都可能引起了患者的嗅觉失灵。老鼠实验得到类似的结果,在被新冠感染后,老鼠的嗅觉上皮组织出现大规模损伤。

ACE2 receptors, important for viral entry of SARS-CoV-2, are expressed by the sustentacular supporting and basal cells of the OE [27▪,28▪]. Damage to these cells may induce reduced sensitivity and loss of cilia from the ORNs, resulting in OD even though the ORNs do not themselves express ACE2 or become directly infected. This hypothesis is consistent with the pattern of early recovery as direct ORN injury would require a significantly longer period to achieve resolution of OD. More recent in vivo studies using mucosa brush sampling demonstrate both infected mature sensory neurones as well as sustentacular cells, confirming entry into the ORNs themselves, with evidence of apoptosis of both cell groups [26▪].

新冠病毒一般作用于ACE2受体然后进入细胞进行破坏,而这个受体在嗅觉上皮组织中的很多细胞都表达。这些细胞受损都可能导致嗅觉受体神经元敏感度降低,从而引起嗅觉失灵。最新的研究发现,虽然嗅觉受体神经元不表达ACE2,但是也会和支持细胞一起被新冠病毒感染。

Some of the most recent studies propose an inflammatory-mediated loss of odorant receptor expression on otherwise intact ORNs; this is supported by animal models, and in olfactory epithelial biopsies harvested from COVID-19 patients postmortem. A study of SARS-CoV-2 in golden Syrian hamsters has demonstrated that the local immune response increases macrophage expression in the OE and lamina propria, which may prevent recovery of the OE and restoration of the ORNs [25▪]. In an in vivo study of patients with persistent loss, viral persistence has been demonstrated in the olfactory epithelium with associated on going inflammation, elevated IL6 and apoptosis.[26▪]. The regenerative capacity of basal stem cells has been shown to be significantly impaired by inflammation and this mechanism may therefore account for prolonged olfactory dysfunction [29]. Anecdotal reports of enhanced recovery after vaccination perhaps reflect more effective viral clearance [30▪].

一些最新的动物实验或者病人样本研究认为嗅觉失灵可能是因为炎症导致的嗅觉受体减少。老鼠实验发现感染新冠后嗅觉上皮组织和黏膜固有层的巨噬细胞增多,这就导致嗅觉上皮组织和嗅觉受体神经元的恢复减缓。新冠患者身体里也发现嗅觉上皮的炎症,IL6上调和细胞凋亡现象。另外炎症反应还会对嗅觉上皮修复造成不利影响,从而引起更长的嗅觉失灵。

Propagation of viruses by retrograde axonal transport to the OB and to the CNS is well described [31,32]. Animal models of OC43 coronavirus infection have demonstrated viral particles within the OB 3 days after inoculation and the cortex by day 7 [33]. ACE2 transgenic mice inoculated with SARS-CoV-1 similarly supported a route of viral entry through the OB with rapid invasion of the CNS [34]; similarly high viral RNA loads were found along the entire routine form the olfactory endothelium to the bulb [26▪]. Several case reports documented hyperintensity in the olfactory bulb which resolved on repeat imaging one month later with subsequent loss of volume of the OB [35,36,37], whereas one neuroimaging cohort reported signal abnormalities of the OB in 19% of cases [38]. One patient with persistent COVID-19 induced OD had MRI imaging prior to COVID-19 infection which provided baseline volumes and confirmed significant atrophy of their OB in images performed 2 months after onset [39]. PET imaging found hypometabolism in the gyrus rectus in 2 patients with persistent COVID-19 OD [40]. Although these studies have reported evidence of neurotropism, atrophy and hypometabolism, this may be an indirect consequence of loss of function at the level of the OE and they do not provide direct proof of retrograde transport of SARS-CoV-2 into the OB.

甚至有论文认为新冠病毒可以从嗅觉球体通过轴突进入中央神经系统。老鼠实验证明在新冠感染后的第3天病毒就进去了嗅觉球体,第7天就到了大脑皮层。在ACE2转基因老鼠实验里,病毒甚至很快到了中央神经系统。但是目前人体上还没有发现病毒从嗅觉上皮反向入侵嗅觉球体甚至中央神经的情况。

Progress in our understanding of the mechanism of olfactory loss will help to drive therapeutic options and therefore further research in this area is essential.

还需要更多研究嗅觉失灵的原理的工作,这样有助于治疗因新冠引起的嗅觉失灵。

综上,

新冠引起的嗅觉失灵可能原因

1.鼻腔堵塞

2.嗅觉上皮组织因病毒入侵受损

3.感染后的炎症

4.病毒从鼻部反向感染到神经系统

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