COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital

Abstract

Many patients with SARS-CoV-2 infection develop neurological signs and symptoms, though, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological, and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical center. The mean age was 74 years (38–97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit (ICU). Hospital-associated complications were common, including 8 (20%) with deep vein thrombosis/pulmonary embolism (DVT/PE), 7 (17%) patients with acute kidney injury requiring dialysis, and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 hours of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20–30 areas from each brain revealed hypoxic/ischemic changes in all brains, both global and focal; large and small infarcts, many of which appeared hemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, though none had evidence of vasculitis. Eighteen (44%) contained pathologies of neurodegenerative diseases, not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR (qRT-PCR), RNAscope, and immunocytochemistry with primers, probes, and antibodies directed against the spike and nucleocapsid regions. qRT-PCR revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in nasal epithelia. RNAscope and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in COVID-19 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but rather likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischemia. Further studies are needed to define whether these pathologies, if present in patients who survive COVID-19, might contribute to chronic neurological problems.

SARS-CoV-2 spike protein induces brain pericyte immunoreactivity in absence of productive viral infection

“…It has been shown that the virus could possibly reach the olfactory bulb and the brainstem [40]. In this regard, recent reports have outlined the presence of SARS-CoV-2 viral proteins in the brainstem, which was not necessarily associated with the severity of neuropathological changes [14, 15, 40]. Moreover, multifocal microvasculature injuries were recently reported in the brain of patients who were infected with SARS-CoV-2 presenting mild to severe symptoms and who died later after viral infection resolution [14, 15].…”

“…In this regard, recent reports have outlined the presence of SARS-CoV-2 viral proteins in the brainstem, which was not necessarily associated with the severity of neuropathological changes [14, 15, 40]. Moreover, multifocal microvasculature injuries were recently reported in the brain of patients who were infected with SARS-CoV-2 presenting mild to severe symptoms and who died later after viral infection resolution [14, 15]. The injury was associated to punctate hypointensities, corresponding to congested blood vessels with surrounding areas of fibrinogen leakage, and areas of linear hypointensities, corresponding to microhemorrhages [14].…”

“…Furthermore, it has been shown that multifocal microvasculature injuries associated to lesions that comprise either bleeding or inflammation are present in the brain of COVID-19 patients who died at later stages after infection [14]. In a recent study, neuropathological investigations have revealed the presence of global and focal hypoxic/ischemic associated to large and small infarcts changes in the brains of COVID-19 patients who died at later stages after hospitalization [15]. These changes were associated to microglial cell activation most prominently in the brainstem [15].…”

“…In a recent study, neuropathological investigations have revealed the presence of global and focal hypoxic/ischemic associated to large and small infarcts changes in the brains of COVID-19 patients who died at later stages after hospitalization [15]. These changes were associated to microglial cell activation most prominently in the brainstem [15]. Interestingly, in both reports, SARS-CoV-2 could not be detected in the post-mortem brain samples [14, 15], outlining the presence of mechanisms that are not directly caused by productive viral infection in the brain parenchyma.…”

“…These changes were associated to microglial cell activation most prominently in the brainstem [15]. Interestingly, in both reports, SARS-CoV-2 could not be detected in the post-mortem brain samples [14, 15], outlining the presence of mechanisms that are not directly caused by productive viral infection in the brain parenchyma. As such, it is becoming critically important to better characterize the response of pericytes to SARS-CoV-2, which may account for microvasculature injury in COVID-19.…”