Thread by @__ice9

@aliostad Reading.

@aliostad Multiple review papers find equivocal to negative effects from use of corticosteroids in ARDS, particularly pulsed steroid therapy.

@aliostad Hmm. Yes PAI-1 is likely elevated in serious cases. Associated with severe inflammation and fibrosis. Could lead to inflammatory damage to pulmonary microvasculature.

Further, more direct evidence from SARS--

So this part looks right.

@aliostad If PAI-1 expression is elevated then logically tPA must be inhibited. Hence fibrinolysis is inhibited. uPA must also be inhibited, so ECM degradation/remodeling will be reduced. Presumably contributes to fibrotic restructuring of lung tissue in critical cases.

@aliostad Risk factors for e.g. disseminated intravascular coagulopathy include severe inflammation, massive tissue damage and particularly burns. Viral epithelial tissue damage is in many respects similar to burns.

And I do see plenty of case reports on DIC in fatal SARS and COVID-19.

@aliostad tPA probably reasonable suggestion.

Difibrotide carries a large risk of spontaneous bleeding in the lungs even in patients without underlying serious lung damage, though. Predict hemorrhage.

Heparin might work. Still kind of dicey.
ncbi.nlm.nih.gov/pmc/articles/P…

@aliostad Nebulized heparin could be a better option if coagulopathy is expected to be primarily limited to the lungs.

ncbi.nlm.nih.gov/pmc/articles/P…

@aliostad Suggestion of Defibrotide use in a patient unresponsive to heparin or warfarin.

ncbi.nlm.nih.gov/pubmed/12233899

May be better viewed as an escalation option. No idea. Unable to locate trial data.

@aliostad DIC often results in multiple organ failure and death. DIC has been reported in a small number of fatal SARS and COVID-19 case reports. In more limited instances, the microvasculature of the lung would most likely be the first region affected.

@aliostad Elevated D-dimer noted as a risk factor for fatal cases in a Wuhan cohort, which is also suggestive.

the-hospitalist.org/hospitalist/ar…

@aliostad NAC and ascorbate probably reasonable as part of supportive care. NAC caspase-1 inhibition may be useful.

No idea about statins here. Literature is equivocal. Could be pro-fibrotic:
pubmed.ncbi.nlm.nih.gov/22278047/
But likely anticoagulant effects:
ahajournals.org/doi/10.1161/01…

@aliostad ARBs and ACE inhibitors likely reasonable.

May even reduce fibrosis risk.

https://twitter.com/__ice9/status/1246226098167386114?s=19

@aliostad Not sure at all about early or prophylactic use of anticoagulants like Lovenox.

This seems like a fundamentally very late stage and uncommon outcome....

@aliostad Idk. Overall much of this looks plausible from available literature, but it seems predominantly relevant to a minority of very severe cases after treatment measures to that point have largely failed.

@aliostad Summoning a few individuals more knowledgeable on applicable physiological details, implications.

From what I can tell, this framework may indeed be relevant in at least a subset of critical cases--
farid.jalali.one/covid19emailpd…

Thoughts?
@BioBreakout @aknappjr @lewistlc