In the last few weeks, Italy first and then several other countries across the world have been swept up by a deadly wave of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which causes the illness named COVID‐19, from the acronym CO (corona) VI (virus) D (disease) and 19 (year of the virus identification). The medical community is working day and night to assist affected people and experts in communicable diseases are striving in multiple ways to understand the progression of events leading to the lethal respiratory syndrome.

Lombardy is the most heavily affected area in the Italian coronavirus epidemic and the one with the highest number of reported fatalities. Doctors assisting patients in the front line of the Policlinico San Matteo of Pavia, one of the Italian hospitals with the highest number of SARS‐CoV‐2 cases, report that several patients in the latest stages of disease, when their lung parenchyma is devastated by the infection, may not manifest dyspnoea (personal observations). Data from the Wuhan area show that more than 90% of patients in need of intensive care cannot breathe spontaneously [1]. On the other hand, patients with severely affected lungs may be paucisymptomatic and recover fully from the infection.

Thus, at least in some cases, there seems to be a discrepancy between the severity of the lung involvement and the respiratory function. Severe COVID‐19 leads to death via multiple mechanisms, including myocardial injury, kidney failure, shock and disseminated intravasal coagulopathy [1, 2]. However, an additional explanation worth exploring in this phase of uncertainties, also in the light of the initial evidence of neuronal localization of COVID‐19, is that the respiratory failure may be driven by a dysfunction of the cardiorespiratory centres in the brainstem.

Coronaviruses (CoVs) are neurotropic [3] and SARS‐CoV particles have been detected in neurons of the human brain [4, 5]. Given the high level of genetic homology of CoVs, which also share many other characteristics, it is also likely that SARS‐CoV‐2 may gain access to the central nervous system, where it can induce neuronal injury. The peripheral invasion of nerves by SARS‐CoV‐2 is further suggested by the occurrence of anosmia and ageusia in more than 5% of a population of 214 COVID‐19 people [6]. From the peripheral nerves the virus may have access to the central nervous system via trans‐synaptic transfer, a possibility documented for other coronaviruses in vitro and in vivo [7]. Recent experimental evidence demonstrates that a human CoV strain, HCoV OC43, can travel from the nasal cavity to the olfactory bulb, then spreading to the piriform cortex and ultimately to the brainstem, via both passive diffusion and axonal transport [8, 9]. Alternatively or in addition – which would increase central nervous system vulnerability to SARS‐CoV‐2 diffusion – the virus may travel retrogradely along the vagus nerve, which innervates many of the visceral organs that can be invaded by the virus beyond the lungs, such as the heart and the gastrointestinal tract. Once in the vagal nerve endings, retrograde axonal transport may grant access to the brainstem.

Whatever the entry point, the final destination of SARS‐CoV‐2 could be the neurons of the nucleus of the solitary tract in the medulla oblongata, which form the dorsal respiratory group that generates the basic rhythm of respiration and emits repetitive bursts of inspiratory neuronal action potentials. The nucleus of the solitary tract is connected with the nucleus ambiguus, the main components of the ventral respiratory group that controls forceful inspiration and expiration. Interestingly a similar efferent pathway can also be traced for the cardiac control centre.

A recent retrospective analysis of COVID‐19 manifestations in 214 subjects in the Wuhan area reported the presence of neurological symptoms in 36% of them, a percentage that rises to 46% when the most severely affected subjects are considered [10]. Thus, it is possible that the invasion of the nervous system by SARS‐CoV‐2 is one of the pathogenetic mechanisms leading to death. This is a call to action for using the available sophisticated neuroimaging, neurophysiological and biochemical techniques to detect and document SARS‐CoV‐2 invasion of the peripheral and central nervous system. These investigations will of course greatly benefit also from systematic histopathological analyses of autoptic tissues to enhance our understanding of the preferential routes of invasion and sites of possible neuronal damage. This may clarify additional modalities through which COVID‐19 is killing people all over the world, possibly provide markers for the identification of the subjects who are at higher risk to evolve into the more serious manifestations of COVID‐19 and, even more importantly, foster the identification of additional therapeutic strategies.

在过去的几周中，意大利首先在世界上其他几个国家被致命的严重急性呼吸系统综合症冠状病毒2（SARS-CoV-2）席卷而来，这导致了名为COVID-19的疾病。首字母缩写词CO（电晕）VI（病毒）D（疾病）和19（病毒鉴定年份）。医学界正在昼夜不停地协助受影响的人们，传染病专家正在以多种方式努力了解导致致命性呼吸综合征的事件的进展。

伦巴第地区是意大利冠状病毒流行病中受灾最严重的地区，也是报告死亡人数最多的地区。协助Pavia Policlinico San Matteo（意大利SARS-CoV-2病例数最高的医院之一）一线的患者的医生报告说，几名处于疾病最新阶段的患者在肺实质被严重破坏时感染后，可能不会表现出呼吸困难（个人观察）。武汉地区的数据表明，需要重症监护的患者中有90％以上无法自发呼吸[ 1 ]。另一方面，肺部严重受累的患者可能会出现症状，并从感染中完全康复。

因此，至少在某些情况下，肺部受累程度与呼吸功能之间似乎存在差异。严重的COVID-19会通过多种机制导致死亡，包括心肌损伤，肾脏衰竭，休克和弥散性血管内凝血病[ 1、2 ]。然而，根据COVID-19神经元定位的初步证据，在这一不确定性阶段中值得探讨的另一种解释是，呼吸衰竭可能是由脑干的心肺中心功能障碍引起的。

冠状病毒（CoV）具有神经营养作用[ 3 ]，并且已在人脑神经元中检测到SARS-CoV颗粒[ 4、5 ]。鉴于CoV的遗传同源性很高，它也具有许多其他特征，SARS-CoV-2也可能进入中枢神经系统，从而诱发神经元损伤。在214名COVID-19人中，超过5％的人发生了失眠和早衰，进一步表明了SARS-CoV-2对神经的周围侵袭[ 6 ]。病毒可通过突触转移从周围神经进入中枢神经系统，这在体外和体内都被其他冠状病毒记录[ 7]。]。最新的实验证据表明，人类CoV株HCoV OC43可以通过被动扩散和轴突运输从鼻腔传播到嗅球，然后扩散到梨状皮质，最后扩散到脑干[ 8，9 ]。替代地或另外地-这将增加中枢神经系统对SARS-CoV-2扩散的脆弱性-该病毒可能沿着迷走神经逆行，这迷惑了许多内脏器官，这些内脏器官可能被病毒侵袭到肺部以外，心脏和胃肠道。一旦进入迷走神经末梢，逆行轴突运输就可以进入脑干。

无论进入哪个入口，SARS-CoV-2的最终目的地都可能是长延髓中孤立道核的神经元，它形成了背侧呼吸群，产生了基本的呼吸节奏并发出重复的吸气神经元爆发动作电位。孤立道核与歧义核相连，歧义核是腹侧呼吸群的主要组成部分，控制着有力的吸气和呼气。有趣的是，也可以为心脏控制中心追踪类似的传出途径。

最近对武汉地区的214名受试者进行的COVID-19表现的回顾性分析报告说，其中36％的人存在神经系统症状，当考虑到受影响最严重的受试者时，这一比例上升到46％[ 10]。因此，SARS-CoV-2对神经系统的入侵可能是导致死亡的致病机制之一。这是使用可用的先进神经影像，神经生理学和生化技术来检测和记录SARS‐CoV‐2对周围和中枢神经系统入侵的号召。当然，这些研究也将极大地受益于对尸体组织的系统组织病理学分析，以增进我们对优先侵入途径和可能的神经元损伤部位的了解。这可能阐明了COVID-19杀死全世界其他人的其他方式，可能为识别高风险个体演变成更严重的COVID-19表现的对象提供了标记，更重要的是，