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THREAD 1/15: The 26Mar2020 #MGH grand rounds was an excellent summary of #COVID19 pathogenesis, respiratory management, exploratory therapies, and developing science. Worth listening to in entirety, but summarizing some key points here. https://www.massgeneral.org/news/coronavirus/grand-rounds
2/15: Speakers listed here: ARDS case ( @jehanalladina); Mech of #ARDS ARDS (RB); Critical Care management ( @almoskow); Aberrant immune response (JG); #COVID19 #Therapies (RH) and Biology (JR; @harvardstemcell).
3/15 Mechanism underlying ARDS. Lung tissue is injured as result of both DIRECT damage from #COVID19 virus as well as INDIRECT damage caused by aberrant immune system, that also leads to vascular leakage ("drowning": air sacs fill with fluid in #ARDS).
4/15 To treat serious #covid19 infections targeting the virus makes sense, but can you target the aberrant immune system? There are studies suggesting there are patients with certain phenotypes (ie elevated #cytokines) predisposing them to sepsis and ARDS https://pubmed.ncbi.nlm.nih.gov/24853585/
5/X15 So efforts have been made to treat hyperactive immune system unfortunately without success. In pandemic influenza (2009) steroids had no benefit and possibly caused HARM particularly if used EARLY (Brun-Buisson, 2011; Zhang Y 2015)
6/15 A more recent study summarized the lack of benefit of corticosteroids when used to treat #SARS (original) and #MERS, two highly pathogenic relatives of #SARSCoV2
(Russell CD, Lancet 2020 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30317-2/fulltext )
(Russell CD, Lancet 2020 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30317-2/fulltext )
7/15 A key reason it is challenging to target the immune system, is because it is critical for survival, and it can be hyperactive early on or hypoactive later. You simply don't know where a patient is on the curve when they present.
8/15 A hyper-inflammatory early INNATE immune response (non-specific) is critical for gaining control of virus. Preclinical studies show that inhibiting the early innate response leads to bad outcomes, and also likely reason early steroid use may be harmful in patients
9/15 Overtime however, the innate immune response triggers the generation of the adaptive (virus specific) immunity, but this takes days. Eventually killer T cells are formed that help gain control of infection, as well as regulatory T cells that keep immune system in check
10/15 However, in certain individuals the early INNATE response goes haywire. Cytokine release results in larger influx of immune cells, with more cytokine release, etc. Lung tissue (in case of #COVID19) is damaged as result of this viscous feed-forward loop
11/15 Steroids are likely too blunt of an instrument (smashes the entire immune system). Some promise has been seen with more targeted anti-inflammatory such as #tocilizumab which targets a single cytokine #IL6
12/15 Some early data out of china has shown success in treating patients with #tocilizumab (Xu X
chinaXiv:202003.00026v1 ), and larger pivotal studies are in progress https://www.biospace.com/article/sanofi-and-regeneron-launch-second-kevzara-trial-against-covid-19/
chinaXiv:202003.00026v1 ), and larger pivotal studies are in progress https://www.biospace.com/article/sanofi-and-regeneron-launch-second-kevzara-trial-against-covid-19/
13/15 Few additional random tidbits to wrap up: Lui demonstrated that #choloroquine and #hydroxychloroquine block the
process of viral entry into cell by preventing the formation of #endolysosomes providing a plausible MoA. https://www.nature.com/articles/s41421-020-0156-0
process of viral entry into cell by preventing the formation of #endolysosomes providing a plausible MoA. https://www.nature.com/articles/s41421-020-0156-0
14/15 The possible #antinflammatory benefit of #statins was discussed, particularly in patients with hyper-inflammatory phenotype https://www.sciencedirect.com/science/article/abs/pii/S2213260018301772 . MoA thought to be due decrease LDL-R that are pro-inflammatory https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00103/full
15/15 Finally @harvardstemcell is characterizing host tissue of #SARSCoV2 . Of interest is the variable expression of #ACE2 on various tissue types and how it can be affected by age, gender and other factors. This must be accounted for when developing therapies and vaccines
