4  Non-steroidal anti-inflammatory drugs
The safety of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with COVID-19 has been debated since the discovery that ACE-2 is an entry receptor for SARS-CoV-2 [39]. Fang et al. hypothesized that ibuprofen increases the risk of developing severe and fatal COVID-19 as it is known that it can increase the expression of ACE-2 receptors [40]. However, this has not been supported by any clinical study, and cannot be confirmed post hoc given the common practice of not making raw patient data available. Nevertheless, taking into account the above-mentioned relationship between endosomal trafficking and viral replication, NSAIDs could provide additional benefits in the treatment of COVID-19 as a result of their inhibitory effect on autophagic flux [41]. Indomethacin is particularly interesting in this context. Several studies have shown that indomethacin can increase the pH of lysosomes [41,42]. Moreover, some results have suggested that indomethacin can block viral RNA synthesis independently of its effect on cyclo-oxygenase inhibition, and this effect was confirmed both in vitro and in vivo on dogs infected with canine coronavirus [43,44]. Furthermore, it has been shown that indomethacin enhances the inhibitory effect of CQ on autophagy, suggesting that NSAIDs and CQ could have a synergistic effect on viral replication [42]. In conclusion, at this point, there are not enough studies to demystify the potential role of NSAIDs in COVID-19; however, in addition to standard anti-inflammatory and antipyretic properties, other factors should be taken into account, such as the possible effect of NSAIDs on the expression of ACE-2, interference with autophagic flux and possible direct antiviral activity. The authors believe that more attention should be directed towards these potential effects, and structured clinical data should be collected in order to examine if some NSAIDs should be considered better than others for this indication.