Abstract
Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, 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 centre. 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. Hospital-associated complications were common, including eight patients (20%) with deep vein thrombosis/pulmonary embolism, seven (17%) with acute kidney injury requiring dialysis and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 h 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/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; 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, although none showed evidence of vasculitis. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases, which was 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, RNAscope® and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleocapsid regions. The PCR analysis revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in the nasal epithelia. RNAscope® and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in coronavirus disease 2019 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 more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischaemia. Further studies are needed to define whether these pathologies, if present in patients who survive coronavirus disease 2019, might contribute to chronic neurological problems.
Keywords: COVID-19; SARS-CoV-2; microglia activation; microglial nodules; neuropathology.
【저자키워드】 COVID-19, SARS-CoV-2, neuropathology., microglia activation, microglial nodules, 【초록키워드】 coronavirus disease, pathology, Coronavirus disease 2019, Diseases, intensive care, hypoxia, antibody, SARS-COV-2 infection, Infection, intensive care unit, nasal, Acute kidney injury, virus, Autopsy, Brain, dialysis, Protein, lymphocyte, Neuropathology, Region, Viral, Culture, nucleocapsid, Pulmonary embolism, Signs and symptoms, Atherosclerosis, male, Patient, Complication, Vasculitis, age, Hospital admission, Viral RNA, Brainstem, systemic inflammation, molecular, microglia, Pathologies, Quantitative, Admission, SARS-CoV-2 infections, patients, Blood, Deep vein thrombosis, Primary infection, Evidence, Artery, evidence of, during admission, Deep vein, Activation, tissue, T lymphocyte, probes, positive, nodule, PCR analysis, Primers, neurological signs, brains, direct viral infection, reverse-transcriptase PCR, immunocytochemistry, probe, epithelia, neurological problems, Neuronophagia, regions, synergistic, arteriolosclerosis, Seven, detect, develop, examined, died, detectable, eight, exhibited, majority, changes in, contribute, to define, histopathological, fixed, neurodegenerative, microglial, accompanied, perivascular, alterations, consecutive patient, neurological sign, patients died, patients with SARS-CoV-2, 【제목키워드】 York, Columbia University,