Evidence of central nervous system infection and neuroinvasive routes, as well as neurological involvement, in the lethality of SARS‐CoV‐2 infection

The outbreak of coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), has become a significant and urgent threat to global health. This review provided strong support for central nervous system (CNS) infection with SARS‐CoV‐2 and shed light on the neurological mechanism underlying the lethality of SARS‐CoV‐2 infection. Among the published data, only 1.28% COVID‐19 patients who underwent cerebrospinal fluid (CSF) tests were positive for SARS‐CoV‐2 in CSF. However, this does not mean the absence of CNS infection in most COVID‐19 patients because postmortem studies revealed that some patients with CNS infection showed negative results in CSF tests for SARS‐CoV‐2. Among 20 neuropathological studies reported so far, SARS‐CoV‐2 was detected in the brain of 58 cases in nine studies, and three studies have provided sufficient details on the CNS infection in COVID‐19 patients. Almost all in vitro and in vivo experiments support the neuroinvasive potential of SARS‐CoV‐2. In infected animals, SARS‐CoV‐2 was found within neurons in different brain areas with a wide spectrum of neuropathology, consistent with the reported clinical symptoms in COVID‐19 patients. Several lines of evidence indicate that SARS‐CoV‐2 used the hematopoietic route to enter the CNS. But more evidence supports the trans‐neuronal hypothesis. SARS‐CoV‐2 has been found to invade the brain via the olfactory, gustatory, and trigeminal pathways, especially at the early stage of infection. Severe COVID‐19 patients with neurological deficits are at a higher risk of mortality, and only the infected animals showing neurological symptoms became dead, suggesting that neurological involvement may be one cause of death.