covid 19 neuropathology at columbia university irving medical center new york presbyterian CORD-Papers-2021-10-25 (Version 1)

Title: 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.
Published: 3/20/2021
DOI: 10.1101/2021.03.16.21253167
DOI_URL: http://doi.org/10.1101/2021.03.16.21253167
Author Name: Thakur, K
Author link: https://covid19-data.nist.gov/pid/rest/local/author/thakur_k
Author Name: Miller, E H
Author link: https://covid19-data.nist.gov/pid/rest/local/author/miller_e_h
Author Name: Glendinning, M D
Author link: https://covid19-data.nist.gov/pid/rest/local/author/glendinning_m_d
Author Name: Al Dalahmah, O
Author link: https://covid19-data.nist.gov/pid/rest/local/author/al_dalahmah_o
Author Name: Banu, M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/banu_m
Author Name: Boehme, A K
Author link: https://covid19-data.nist.gov/pid/rest/local/author/boehme_a_k
Author Name: Boubour, A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/boubour_a
Author Name: Bruce, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/bruce_s
Author Name: Chong, A M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/chong_a_m
Author Name: Claassen, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/claassen_j
Author Name: Faust, P
Author link: https://covid19-data.nist.gov/pid/rest/local/author/faust_p
Author Name: Hargus, G
Author link: https://covid19-data.nist.gov/pid/rest/local/author/hargus_g
Author Name: Hickman, R
Author link: https://covid19-data.nist.gov/pid/rest/local/author/hickman_r
Author Name: Jambawalikar, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/jambawalikar_s
Author Name: Khandji, A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/khandji_a
Author Name: Kim, C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/kim_c
Author Name: Klein, R S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/klein_r_s
Author Name: Lignelli Dipple, A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lignelli_dipple_a
Author Name: Lin, C C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lin_c_c
Author Name: Liu, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/liu_y
Author Name: Miller, M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/miller_m
Author Name: Moonis, G
Author link: https://covid19-data.nist.gov/pid/rest/local/author/moonis_g
Author Name: Nordvig, A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/nordvig_a
Author Name: Overdevest, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/overdevest_j
Author Name: Prust, M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/prust_m
Author Name: Przedborski, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/przedborski_s
Author Name: Roth, W
Author link: https://covid19-data.nist.gov/pid/rest/local/author/roth_w
Author Name: Soung, A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/soung_a
Author Name: Tanji, K
Author link: https://covid19-data.nist.gov/pid/rest/local/author/tanji_k
Author Name: Teich, A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/teich_a
Author Name: Agalliu, D
Author link: https://covid19-data.nist.gov/pid/rest/local/author/agalliu_d
Author Name: Uhlemann, A C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/uhlemann_a_c
Author Name: Goldman, J E
Author link: https://covid19-data.nist.gov/pid/rest/local/author/goldman_j_e
Author Name: Canoll, P
Author link: https://covid19-data.nist.gov/pid/rest/local/author/canoll_p
sha: 9464518d287350b32f247bf4ab003d0e8fb58d17
license: medrxiv
source_x: MedRxiv; WHO
source_x_url: https://www.who.int/
url: http://medrxiv.org/cgi/content/short/2021.03.16.21253167v1?rss=1 https://doi.org/10.1101/2021.03.16.21253167
has_full_text: TRUE
Keywords Extracted from Text Content: microglial SARS-CoV-2 medRxiv preprint COVID-19 RNAscope brain brains microglial nodules vein nasal epithelia kidney T lymphocyte brainstem nucleocapsid COVID-19 brains Hispanic/Latinx perivascular tissues blood cultures embolism brain parenchyma patients tissue samples Iba1 parenchyma GFAP Cat# R1200 WarpRed neuronal cranial nerve cingulate cortex nasal pharyngeal F,I CNS vascular wall anterior hippocampus lungs leptomeningeal vessels isocortex thalamus cerebral edema Irvine CA frontal gyrus medRxiv Zika virus RNAscope ® brainstem lateral geniculate olfactory bulbs tissues Hispanic/Latinx Parenchymal hemorrhages/hemorrhagic globus pallidus SARS-CoV-2 nucleocapsid brain sections coronal plane olfactory bulb cerebral hemispheres individuals vascular lesions inferior olivary nucleus caudal midbrain B,D brain samples perivascular cells COVID-19 brain sections endothelial cell upper cervical spinal cord COVID-19 lung sections brain parenchyma SARS-CoV-2 N mesial temporal lobe lung tissues cells medRxiv preprint HybEZ TM Supplementary Figure 2A Gaps dentate nucleus pons https://wwwn.cdc.gov/nndss/conditions/coronavirus-disease-2019-covid-19/casedefinition/2020/ olfactory bulb/gyrus rectus gyrus rectus hippocampal corpus callosum 3/41 Microglial nodules CD20 postmortem brain samples SARS-CoV-2 S Figure 6K tegmental nuclei body fibrinoid vessel walls rostral midbrain pituitary gland phosphate buffer saline CLAUDIN-5 transverse plane Coronavirus B lymphocyte NE was 43,840 COVID-19 brains 9/41 perivenular neurons survivors subarachnoid space microglia CNS samples vessels CD68 cerebellum (N=1) brain tissues vascular basement membrane olfactory bulb/tracts CNS blood vessels meninges sagittal plane blood vessel nasal epithelium 17/41 patients Parkinson's disease pineal gland hippocampus COVID-19 Lung sections F,G olfactory sections striatum macrophages microglial nodules lung specimens ethmoid bones blood vessel cells AMP5 cord Supplementary Table 4 medulla line COVID-19 patients medullary sections splenium medial anterior cranial fossa renal lymphocytic genu COVID-19 patient SARS-CoV-2 RNA encoding the spike protein 31 woman cardiac thrombi amyloid plaques lateral ventricle vasculature blood ACD anterior thalamus AAAS9987 blood vessels postmortem nasal epithelial tissue adventitia Sino Biological choroid plexus microglial medulla oblongata caudal pons T cell SARS-CoV-2 HSV-1 ethanol brain tissue cerebral calcarine cortex Neurons RNAscope brain T cells brains multiorgan N=24 Protease IV b-coronaviruses arteriolar cervical spinal cord bone glial fibrillary acidic protein F Guillain-Barré neurofibrillary tangles rostral pons Lewy bodies Neuronal lobe HSV1 nucleus accumbens cell soma uppermost spinal cord K') tissue B,E cerebellum patient Cell CNS sections St Louis focal microglial nuclei amygdala tau tangles CD3 Cat #40143-R001 medullas MA Pathology & Cell lung samples Hanina Hibshoosh patients
Extracted Text Content in Record: First 5000 Characters: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 All rights reserved. No reuse allowed without permission. : medRxiv preprint 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. Neurological manifestations of SARS-CoV-2 infection are increasingly recognized 1 and include seizures 2,3 , cerebrovascular accidents 4, 5, 6, 7, 8 , encephalopathy 7 , isolated cases of acute necrotizing hemorrhagic encephalopathy 9 , and Guillain-Barré Syndrome 10 . Many of the neurological conditions seen in the context of SARS-CoV-2 infection are associated with systemic effects, including multiorgan damage, hypercoagulability and a proinflammatory state 11, 12, 13, 14 . Whether SARS-CoV-2 directly infects the brain remains controversial. Related b-coronaviruses such as SARS and MERS show neuroinvasive potential 15, 16, 1, 17 and clinicians have reported cases of meningoencephalitis in COVID-19 patients, without neuropathological confirmation 18, 19, 20, 21, 3, 22, 23, 16 . Further characterization of the neuropathological and molecular findings in COVID-19 brains is needed to understand the pathophysiological mechanisms underlying the neurological conditions seen in the context of COVID-19. A few autopsy studies have reported the neuropathological findings of patients with SARS-CoV-2 infections (Supplementary Table 1) , including hypoxic changes, vascular lesions, demyelinating pathology resembling acute disseminated encephalomyelitis (ADEM) 24 , reactive astrocytosis and microgliosis 25 and cerebral hemorrhage or hemorrhagic suffusion 26 . Viral RNA by quantitative reverse transcriptase-PCR (qRT-PCR) has been detected at low levels in some cases 27, 28, 29 , but evidence directly linking virus to the COVID-associated neuropathology is controversial. We present the neuropathological findings of 41 consecutive patients with histories of confirmed SARS-CoV-2 infection, investigating the clinical and pathological characteristics. Board and is in line with the Declaration of Helsinki. The requirement for written informed consent for chart review was waived as the study design was deemed to be no more than minimal risk. The Institutional Review Board approved this study (AAAS9987) on May 4, 2020. Consent for autopsy was obtained from patient surrogates through standardized consenting procedures via telephone, given that no visitors were allowed in hospital during t
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