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

  1. Kiran T Thakur
  2. Emily Happy Miller
  3. Michael D Glendinning
  4. Osama Al-Dalahmah
  5. Matei A Banu
  6. Amelia K Boehme
  7. Alexandra L Boubour
  8. Samuel S Bruce
  9. Alexander M Chong
  10. Jan Claassen
  11. Phyllis L Faust
  12. Gunnar Hargus
  13. Richard A Hickman
  14. Sachin Jambawalikar
  15. Alexander G Khandji
  16. Carla Y Kim
  17. Robyn S Klein
  18. Angela Lignelli-Dipple
  19. Chun-Chieh Lin
  20. Yang Liu
  21. Michael L Miller
  22. Gul Moonis
  23. Anna S Nordvig
  24. Jonathan B Overdevest
  25. Morgan L Prust
  26. Serge Przedborski
  27. William H Roth
  28. Allison Soung
  29. Kurenai Tanji
  30. Andrew F Teich
  31. Dritan Agalliu
  32. Anne-Catrin Uhlemann
  33. James E Goldman
  34. Peter Canoll

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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.

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  1. Version published to 10.1093/brain/awab148
  2. ScreenIT

    SciScore for 10.1101/2021.03.16.21253167: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: This study was approved by the Columbia University Irving Medical Center (CUIMC) Institutional Review Board and is in line with the Declaration of Helsinki.
    Consent: The requirement for written informed consent for chart review was waived as the study design was deemed to be no more than minimal risk.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    All antibodies used are available for clinical diagnostics, including HSV1 (Cell Marque #361A-ASR) In a subset of cases, additional immunoperoxidase staining was performed on paraffin sections of the pons and choroid plexus from the lateral ventricle in a subset of patients as described30.
    HSV1
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Limitations: This study has several limitations. Our patients, a multi-ethnic group, drawn from a single center in New York City, may not represent the general COVID-19 population. Autopsy studies over-represent severe cases, and our findings may not be generalizable to less severe cases. There are currently limited data on the sensitivity and specificity of SARS-CoV-2 qRT-PCR in various tissues including brain, and positive qRT-PCR in the brain may be due to virions in the blood rather than brain tissue. Additionally, clinical data for this study were obtained through retrospective chart review and thus fully reliant on EMR. Most patients had significant pre-existing comorbidities, which confound our ability to attribute our findings to COVID-19 infection. Future studies with appropriate controls are needed to delineate which neuropathological findings result from COVID-19 infection and treatment and are not caused by other processes.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2021.03.16.21253167v1 on medRxiv