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.