NSAIDs in COVID-19
NSAIDs are used worldwide to alleviate symptoms of viral infections and
inflammation, such as fever, cough and pain. Since NSAIDs inhibit COX-1
and COX-2 and thus decrease the release of many downstream lipid
mediators, such as various PGs, prostacyclin and TXs, they have very
broad effects on inflammation and immune responses, ranging from
anti-inflammatory, immunosuppressive, anti-thrombotic to pro-resolving(Fig. 2) .1,21 Therefore, at the beginning of
the COVID-19 pandemic, there were several concerns and uncertainties
about the effects of NSAIDs on SARS-CoV-2 infection and the course of
COVID-19.22 They were suspected to alter the
expression of angiotensin-converting enzyme 2 (ACE2), the main entry
receptor for SARS-CoV-2 and/or modify viral
replication.23-26 In addition, they could be either
harmful by impairing anti-viral response and delaying resolution of
inflammation15,18,27,28 or be beneficial by dampening
of hyperinflammation and cytokine storm29,30 and
preventing thrombosis31,32 (Fig. 3) . Some of
these concerns have now been addressed experimentally and
epidemiologically and several clinical trials have been initiated.
Indeed, SARS-CoV-2 increases PTGS2 (COX-2) gene expression in
variety of cell lines, in mouse lungs and in primary human bronchial
epithelial cells as well many eicosanoids and docosanoids are increased
in the lungs of severe COVID-19 patients.33-35 However
inhibition of the COX pathway by either ibuprofen (non-selective
COX1/COX2 inhibitor) or meloxicam (more selective COX-2 inhibitor) did
not change the expression of ACE2 in human cell lines (Calu-3 or Huh7.5)in vitro or in lungs, kidney, heart or ileum of mice in
vivo. 33 Similarly, both NSAIDs did not affect
SARS-CoV-2 entry or its replication in the same human cell
lines.33 Aspirin also did not affect ACE2 or
transmembrane serine protease 2 (TMPRSS2) expression in human nasal
epithelium.36 Meloxicam also did not prevent
SARS-CoV-2-infection-induced weight loss in mice and did not change
frequencies or activations status of alveolar macrophages, neutrophils,
NK cells, Ly6C+ Mo/Mθ, CD4+ T cells,
CD8+ T cells, γδ T cells. However, meloxicam treatment
decreased the amount of spike-specific IgM and IgG antibodies and their
neutralizing capacities as well as decreased infection-induced levels of
IL-6, CCL2, GM-CSF, CXCL10, IL-2, and TNF-α, suggesting that while
meloxicam can impair humoral immune response against SARS-CoV-2 to some
extent, it might also limit levels of proinflammatory
cytokines.33 In contrast, naproxen, which is a
non-selective COX-1/COX-2 inhibitor, has been shown to bind to the
nucleocapsid protein N of SARS-CoV-2, which led to inhibition of
SARS-CoV-2 replication in VeroE6 cells and primary human bronchial
epithelial cells and protected epithelium against SARS-CoV-2-induced
barrier damage.37 There were no analogous effects in
similar experiments with paracetamol (acetaminophen, which may affect PG
production in the brain or may act via its metabolite on the cannabinoid
receptors),38,39 or celecoxib (selective COX-2
inhibitor).37 Naproxen is currently examined in the
clinical trial in COVID-19 (eudract_number:2020-001301-23; accessed
11.06.2021). So far, in various patient groups, it has been shown that
usage of NSAIDs does not lead to the worse COVID-19 outcomes, however
others still claim such associations.40 In a
retrospective study of 403 confirmed cases of COVID-19 there were no
differences in terms of mortality rate or need for respiratory support
between patients who were taking ibuprofen or those who did not take any
NSAIDs.41 It was also confirmed in the large
prospective cohorts that either acute or chronic use of NSAIDs was not
associated with worse COVID-19 outcomes.42-44 It was
even shown that in patients, who were treated with aspirin or other
NSAIDs due to the cardiovascular diseases, positive aspects of such
therapies have been noted, including reduction of COVID-19
mortality.31 This clinical observation is further
supported by a study on COX-2 induction and PGE2overproduction in the human lung infected by
SARS-CoV-2.45 However, further basic in vitro, in vivo
and large clinical studies assessing the influence of NSAIDs on the
pathogenesis and treatment of COVID-19 are still greatly needed.