key: cord-0853420-m7u9a3x5
authors: Baghaki, Semih; Yalcin, Can Ege; Baghaki, Hayriye Sema; Aydin, Servet Yekta; Daghan, Basak; Yavuz, Ersin
title: COX2 Inhibition in the Treatment of COVID-19: Review of Literature to Propose Celecoxib Repositioning for Randomized Controlled Studies
date: 2020-09-30
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.09.1466
sha: 915628296fa12575dc803e68dbaecef258df3d97
doc_id: 853420
cord_uid: m7u9a3x5

Coronavirus triggered pulmonary and systemic disease, i.e. systemic inflammatory response to virally triggered lung injury, named as COVID-19 and still ongoing discussions on refining immunomodulation in COVID-19 without COX2 inhibition directed us to search the related literature to point out a potential target (COX2) and a weapon (celecoxib). The impression of selectively targeting COX2 and closely related cascades might be worth to try in the treatment of COVID-19 given the substantial amount of data regarding COX2, p38 MAPK, IL-1b, IL-6 and TGF-b are playing pivotal roles in coronavirus related cell death, cytokine storm and pulmonary interstitial fibrosis. Considering lack of definitive treatment and importance of immunomodulation in COVID-19; COX2 inhibition might be a valuable adjunct to still evolving treatment strategies. Celecoxib has credentials to be proposed and evaluated in randomized controlled studies besides being available to be used off label.

COVID-19 rapidly became a pandemic with increasing numbers of deaths and new cases at the time this review was being written. Lack of time to recruit evidence based treatments led physicians worldwide to implement empiric drug combinations. In several weeks, a number of agents proposed with variable or arguable efficacy have become empirical treatments and ongoing clinical studies try to find the best alternatives until a definitive treatment (i.e. vaccine based and / or drug based) is found. Until definitive treatments can be defined, readily available medications might have a role in preventing the progression of the disease from Stage 1 to Stage 2 and might decrease the rate of hospitalizations.

From the beginning of outbreak, ongoing searches and discussions include immunomodulation strategies to limit immune system related tissue damage which is now very well accepted as leading factor in mortality. Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, Interleukin-6 (IL-6) antagonists, Janus kinase (JAK) inhibitors are the main actors to be discussed and used in the treatment of COVID-19. Despite worldwide extensive efforts and ever increasing numbers of publications, there has not been any direct mentioning of J o u r n a l P r e -p r o o f cyclooxygenase-2 (COX2) inhibition and this directed us to search the related literature to point out availability of a possible target and a weapon to be tested in clinical trials.

SARS-associated coronavirus has been demonstrated to induce COX2 in mammalian cells via both its S and N proteins of its nucleocapsid (Liu et al., 2006 , Yan et al., 2006 . This stands as a pivot point to induce subsequent intracellular and then intercellular cascades. It has been shown that coronavirus-induced endoplasmic reticulum stress leads to unfolded protein response including Mitogen-activated protein kinase (MAPK) activation, autophagy and apoptosis of eukaryotic cells infected with this virus (Fung et al., 2014) . It was also showed that coronavirus-induced autophagy is mediated by activation of endoplasmic reticulum (ER) stress sensors and prolonged ER stress leads to unfolded protein response to restore ER stability which involves MAPK activation (Fung and Liu, 2019) . Induction of COX2 and p38MAPK plays role in virally induced pulmonary alveolar, interstitial and then systemic inflammation. Whether virally induced or not, a state of cytokine storm also damages pulmonary capillary network through activation of p38MAPK pathway with eventual pulmonary arterial hypertension (Tielemans et al., 2019) . Interferon-gamma-related cytokine storm has been shown after SARS coronavirus infection with lymphopenia and neutrophilia together with increased levels of IFNgamma (Huang et al., 2005) . In pathological levels, IFN-gamma is known to induce pulmonary injury via COX2 and p38MAPK pathways (Choo-Wing et al., 2013) .

Hydroxychloroquine is no surprise for being used in COVID-19 since it has been shown that chloroquine inhibits p38MAPK and inhibits coronavirus replication (Kono et al., 2008) .

hydroxychloroquine also has been shown to inhibit TNF-a induced endothelial inflammation via inhibition of p38 expression (Li et al., 2018) . Inhibiting p38MAPK is also important to prevent IL-1b mediated acute lung injury. De-Yi Xheng et al. showed that inhibition of p38 downregulates expression of IL-1b receptors in pulmonary alveoli and prevent acute lung injury J o u r n a l P r e -p r o o f due to ischemia-reperfusion injury (Zheng et al., 2016) . Another hallmark of coronavirusinduced pulmonary disease is interstitial fibrosis in which epithelial-mesenchymal transition plays role again p38 MAPK is pivotal in this complex phenomenon (Jolly et al., 2018 , Yan et al., 2016 . Debates have been started, however, on the use of hydroxychloroquine soon after the initial experiences with the medication, questioning the evidence provided for the use of it (Ferner and Aronson, 2020) . Recent literature studying the previous studies of hydroxychloroquine demonstrated that so far, no significant benefit has been observed in the use of hydroxychloroquine against COVID-19 (Pathak et al., 2020) .

COX2 is a critical evolutionary enzyme in many physiologic and pathologic processes. It has a central role in viral infections and regulates expression levels of many serum proteins (Liu et al., 2011) . This enzyme is more affecting proinflammatory cytokines and its inhibition or deficiency alone does not blunt immune response against viral disease. Pharmacologic inhibition of COX2 by celecoxib decreases TNF-a, G-CSF and IL-6 levels without significant increase in viral titers in bronchoalveolar lavage fluid in mice with Influenza A infection (Carey et al., 2010) . Hyperinduction of COX2 has been shown in patients died of H5N1 infection with increased levels of TNF-a and other major proinflammatory cytokines (Lee et al., 2008) . Many of these critical effects might be targeted by a clinically available COX2 inhibitor, celecoxib.

These pathophysiologic steps might especially be important in disease progression from Stage 1 to Stage 2 where many patients can be treated in an outpatient basis. Besides inhibiting COX2, celecoxib inhibits p38MAPK, although it's not a pure or potent p38MAPK inhibitor (da Silva et al., 2005) . But there is an important point here that inhibition of COX2 might result in delayed J o u r n a l P r e -p r o o f specific immunoglobulin production by blunting Lipoxin B4 mediated memory B cell activation (Kim et al., 2018) . Still, the benefits of alleviating rapid and immense cytokine storm seems to outweigh the delay in production of specific antibodies (Carey et al., 2005) .

Among proven and putative effects of COX2 inhibition, there are a number of unclarified ones.

For instance, celecoxib has been shown to ameliorate hepatic cirrhosis through inhibition of epithelial-mesenchymal transition of hepatocytes (Wen et al., 2014) besides studies showing it does not (Harris et al., 2018) . Since epithelial-mesenchymal transition is a pivotal evolutionary phenomenon in numerous physiologic and disease states of lung; e.g. lung development, COPD, lung cancer and pulmonary fibrosis (Jolly et al., 2018 , Rout-Pitt et al., 2018 ; possible antifibrotic effects of COX2 inhibition might benefit COVID-19 patients. Celecoxib has been shown to inhibit TGF-beta induced epithelial-mesenchymal transition in numerous studies. It has also been shown that this drug inhibits FoxO1-mediated phosphorylation and eventual collagen production in human cardiac fibroblasts (Tseng et al., 2019) . Celecoxib has also been shown to reduce peritoneal fibrosis in an animal model (Fabbrini et al., 2009 ). Since interstitial pulmonary fibrosis is one of the hallmarks of COVID-19, the effects of celecoxib in fibrotic processes might be worth to try clinically preferably with a RCT, or at least off label in today's conditions.

In a pandemic with ongoing and unforeseen effects, there are many obstacles in formation of treatment strategies. Absence of definitive drugs and/or vaccines against a highly contagious Despite ongoing studies and scientific discussions showing immunomodulation is one of the main issues in treatment of COVID-19, inhibition of COX2 was seemingly missed. All clinical trials evaluate the use of NSAIDs, steroids, and newer immunomodulatory agents such as tocilizumab and sarilumab. Similar discussions took place throughout one of the previous pandemics, H5N1 the Avian Flu, where authors argued adjunctive use of COX-inhibitors with antiviral therapy may have a beneficial role alleviating the robust immune response causing the severe respiratory disease, which were however not tried or studied by any following randomized clinical studies (Simmons and Farrar, 2008, Zheng et al., 2008) . During the early periods of the pandemic, the use of NSAIDs were strongly objected by some authors and even governments, arguing that the disease may be aggravated with the use of these medications and advocating the use of paracetamol, which is another NSAID without anti-inflammatory activity (Little, 2020 , Willsher, 2020 . Paracetamol has been upvoted by some studies because of a safer side effect profile and because NSAIDs have been demonstrated as a cause of delayed diagnosis and increased rate of complications in respiratory tract infections (de Girolamo et al., 2020 , Little, 2020 , Sestili and Stocchi, 2020 .This creates a paradox between treatment modalities and pathophysiology of COVID-19, since the over-the-counter medications used to ameliorate the symptoms that can be used in the earlier stages I and II of the disease such as paracetamol do not really play a beneficial role in halting the progression of the condition because paracetamol has no anti-inflammatory action, which is crucial for keeping the inflammatory state under control. Although it may cause symptomatic relief for patients, in case of COVID-19, it has no influence on the disease progression, and without the anti-inflammatory action, paracetamol has the risk of masking the symptoms. Number of studies against this approach is growing including a recent cohort suggesting their concomitant use may be potentially harmless J o u r n a l P r e -p r o o f (FitzGerald, 2020, Lund et al.) . We believe the use of ibuprofen in the case of COVID-19 has been objected with logical and scientific reasons, although further research is required, ibuprofen was associated with an upregulation of ACE2 enzyme, which may increase the susceptibility to the virus. In addition, as we tried to summarize already documented literature above, inhibition of COX1 may not be a good idea since it blunts antiviral immunity besides with no selective alleviation of cytokine storm. Besides these, therapeutic potential of celecoxib was demonstrated in studies searching molecular library (Gimeno et al., 2020 , Ke et al., 2020 .

Celecoxib with abovementioned review seems to be a candidate in the treatment of COVID-19. It's widely available, relatively cheap, has a well-recorded safety profile in adults and children with a long history of clinical use for variable disease states, e.g. osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, colorectal cancer and lung cancer. Likewise other NSAIDs celecoxib has been studied for its cardiovascular side effects in comparative studies. Although there are studies pointing towards celecoxib increases the incidence of major cardiovascular events, i.e. myocardial infarction, worsening of heart failure, thrombotic cerebral strokes; there are some other ones showing no significant difference compared to non selective COX inhibitors which are more widely used. Two of the main parameters seeming to be important in these studies are the duration of use and the dose of this agent (Masclee et al.) .

In all these long term studies, patient groups were the ones using celecoxib for many months (app. 20-30 months) and suggested cardiovascular toxicity has been shown to be time dependent. Still, celecoxib has been found to be noninferior to ibuprofen and naproxen which are used in larger scales (Nissen et al., 2016) .

In the treatment of COVID, this might not be a major drawback since the expected duration of treatment will not exceed a few days to weeks. Still, patients with significant cardiovascular comorbidities (e.g. obesity, uncontrolled diabetes, coronary artery disease, ischemic stroke, J o u r n a l P r e -p r o o f

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