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COVID-19 Literature Review_ Some Recent Studies of Note

The document summarizes recent studies on COVID-19, focusing on various clinical features, treatments, immune responses, and the D614G mutation. Key findings include the clinical characteristics of MIS-C in children, the lack of evidence for viral encephalitis in brain autopsies, and the potential implications of high-dose corticosteroids on viral shedding. Additionally, the document discusses the increased prevalence of the D614G mutation and its potential impact on transmissibility and immune response.

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Nuttaki Sidhu
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2 views31 pages

COVID-19 Literature Review_ Some Recent Studies of Note

The document summarizes recent studies on COVID-19, focusing on various clinical features, treatments, immune responses, and the D614G mutation. Key findings include the clinical characteristics of MIS-C in children, the lack of evidence for viral encephalitis in brain autopsies, and the potential implications of high-dose corticosteroids on viral shedding. Additionally, the document discusses the increased prevalence of the D614G mutation and its potential impact on transmissibility and immune response.

Uploaded by

Nuttaki Sidhu
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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COVID-19: Some Recent

Studies of Note
MIS-C
Important study describing clinical features of 95
cases of MIS-C in NY state: note features by age &
lag behind COVID surge

Dufort NEJM DOI: 10.1056/NEJMoa2021756


NYS Department of Health website is updated
regularly and is one of the best resources I’m aware
of for this important condition

https://coronavirus.health.ny.gov/childhood-inflammatory-disease-related-covid-19?gclid=Cj0KCQjwoub3BRC6ARIsABGhnyavoFUZtE
UsLooLSjxW5Y1hoV_6pYO98T4ez_ZapygyRL2q_lN9MKgaAojEEALw_wcB
Pathophysiology
COVID-toes positive for SARS-CoV-2 spike protein
in endothelial cells. Detailed review of path of 7
patients with lymphocytic vascular damage seen

Colmenero BJD
These 7 children had mild COVID-19 symptoms.
Does this suggest higher rates of viremia than we
currently realize?

Colmenero BJD
The Question of Neuroinvasion
Brain autopsy analysis of 18 cases from Boston
showed only hypoxemic injury without cytoplasmic
staining for SARS-CoV-2

Authors conclude:
no evidence for
viral encephalitis

Solomon NEJM DOI: 10.1056/NEJMc2019373


Systematic review of neurologic & neuropsychiatric
manifestations of COVID-19 in the UK

Varatharaj Lancet Psych https://doi.org/10.1016/S2215-0366(20)30287-X


● They report 7 cases of “encephalitis” defined as:
“encephalopathy with evidence of inflammation in
the CNS [CSF white cell count >5 cells per µL,
protein >0·45 g/dL, or MRI consistent with
inflammation” (no report of whether SARS-CoV-2
RNA was sent from CSF)
● Altered mental status: included new psychosis,
new dementia, and catatonia in 1 patient

Varatharaj Lancet Psych https://doi.org/10.1016/S2215-0366(20)30287-X


In a very interesting preprint from researchers at Yale, researchers
showed SARS-CoV-2 could infect human brain organoids and replicate in
neurons. TUNEL staining, which detects dying cells, showed increased
cell death was associated with higher density of SARS-CoV-2 but that cell
death occurred in many uninfected cells. This may suggest that infected
cells promote cell death of nearby cells. ACE2 was necessary for infection

Song bioRxiv https://doi.org/10.1101/2020.06.25.169946


Hypothesis generating: To reconcile the paper from
NEJM by Solomon et al with the Yale preprint, authors
note: “It is possible that viral infection induces locally
hypoxic regions which aids in lowering the threshold for
tissue damage in the context of an already oxygen
deprived state.... Given the evidence of acute hypoxic
ischemic damage without microthrombi in post-mortem
brain of COVID-19 patients, our observations suggest a
possible avenue to SARS-CoV-2 induced
neuropathology.”
Solomon NEJM DOI: 10.1056/NEJMc2019373
Song bioRxiv https://doi.org/10.1101/2020.06.25.169946
Treatments
Lopinavir/ritonavir Usual Care

n 1596 3376

28-day mortality 22.1% 21.3% RR 1.04, p = 0.58

Press release notes results “consistent in different subgroups.”

https://www.recoverytrial.net/files/lopinavir-ritonavir-recovery-statement-29062020_final.pdf
RECOVERY cohort less sick than Wuhan cohort
previously reported in NEJM. Important since a
criticism of that trial was that benefit might have
been seen if LPV/r was given earlier (likely was in
RECOVERY and still no benefit). Implication: no
role for LPV/r moving forward to treat COVID-19
Baseline O2 requirement Cao et al (Wuhan) RECOVERY trial (UK)

No supplemental O2 26% 14%

Supplemental O2 70% 70%

MV/ECMO 4% 16%

Cao NEJM DOI: 10.1056/NEJMoa2001282


One concern about steroids has been worry about
prolonging viral shedding. Interesting analysis in CID
suggests high dose (defined as methylpred 80
mg/day) but not low dose steroids (defined as
methylpred 40 mg/day) may be associated with
prolonged viral shedding.
LASSO analysis with logistic regression model indicated no impact of corticosteroids on
long-term positive SARS-CoV-2. However, LASSO analysis with Cox regression model
and restricted mean survival time analysis demonstrated that high-dose (80mg/d, aHR=
0.67, 95%CI: 0.46 - 0.96, P = 0.031) but not low-dose corticosteroids (40mg/d, aHR=
0.72, 95%CI: 0.48 - 1.08, P = 0.11) potentially delayed viral shedding of patients with
COVID-19.

Li CID https://doi.org/10.1093/cid/ciaa829
Fascinating, creative, detailed large retrospective on
role of statins finds improved outcomes, decrease
mortality/less inflammation. RCT needed

Zhang Cell Metabolism https://doi.org/10.1016/j.cmet.2020.06.015


A retrospective study of 154 patients with COVID-19
from nursing homes in Belgium found that being on a
statin was associated with asymptomatic infection.

20% in this study


were on statins

De Spiegeleer JAMDA https://doi.org/10.1016/j.jamda.2020.06.018


Immune Responses
In a fascinating preprint from France, researchers report
household contacts of people recovering from mild COVID-19
who remain seronegative but have positive T-cell responses:
raises further questions about utility of serology

Gallais medRxiv https://doi.org/10.1101/2020.06.21.20132449


Researchers from San Diego measured virus-reactive T cells
in critically ill patients with COVID-19. They also found
cross-reactive T cells in 2/10 healthy donors, corroborating an
important finding from multiple other studies.

Weiskopf Science Immunology DOI: 10.1126/sciimmunol.abd2071


They show a direct negative correlation between viral load &
IgG as well as viral load & virus reactive CD4+ T cells and a
positive correlation between IgG titers & virus specific T cells

Weiskopf Science Immunology DOI: 10.1126/sciimmunol.abd2071


Yale researchers found 3 distinct clusters of cytokine profiles
of patients with COVID-19 that are associated with outcome
severity. Cluster 1: low inflammation, enriched tissue repair
(moderate outcome). Clusters 2&3 marked pro-inflammatory
state associated with more severe outcomes or death

Lucas medRxiv https://doi.org/10.1101/2020.06.23.20138289


Viral load was slower to decline in critical patients
and was highly correlated with IFN-alpha,
IFN-gamma, and TNF-alpha

Lucas medRxiv https://doi.org/10.1101/2020.06.23.20138289


The D614G mutation
Early work showed increasing prevalence of D614G mutation.
Unclear significance: founder effect (ie mutation present in a
new area more likely to spread there) versus true selective
advantage

Korber bioRxiv https://doi.org/10.1101/2020.04.29.069054


D614G virus more rapidly gets into various ACE-2
expressing cell lines

Daniloski bioRxiv https://doi.org/10.1101/2020.06.14.151357


Researchers found that there is less S1 shedding in the G614
mutant, which leads to more S protein expressed on the virion, a
potential mechanism for increased transmissibility. They found
both wild type and D614G were susceptible to neutralizing sera
Another group showed D614 location is distant from key
antibody binding sites and researchers doubt this mutation
would affect key epitopes: antibodies elicited by wild type
infection likely protective for this virus carrying this mutation

Barnes Cell https://doi.org/10.1016/j.cell.2020.06.025


Key Points D614G
● D614G virus has increased in prevalence globally
● Early on not clear if because of founder effect versus selective
advantage
● D614G virus gets into ACE2 cells more rapidly
● Increased S protein on virions may facilitate more easy binding to
ACE2 which might increase transmissibility
● D614G virus susceptible to neutralizing sera from patients with wild
type infection and modeling predicts preserved key antibody-binding
epitopes

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