We have previously suggested numerous immunomodulatory and
anti-inflammatory benefits when NSAIDs are administered to manage
COVID-19 and in this commentary, we add other potential benefits related
to SARS CoV-2 ORF proteins dependent activation of caspases with
subsequent mitochondrial dysfunction, endoplasmic reticulum stress and
necroptosis that were described with complicated COVID-19 as NSAIDs are
known to be caspase inhibitors. Moreover, NSAIDs might independently
inhibit other COVID-19 associated downstream pathological signaling
mechanisms. We also postulate that CARD-14, a caspase recruitment
domain-containing protein, polymorphisms might play a role in
development of severe and critical COVID-19. We believe that it is very
unfortunate that for more than one year of relentless struggle, our
recommendation to adopt NSAIDs as first choice COVID-19 therapy has not
adopted while lives are lost are succumbed every day.