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COX2 inhibition in the treatment of COVID-19: Review of literature to propose repositioning of celecoxib for randomized controlled studies

Open AccessPublished:September 29, 2020DOI:https://doi.org/10.1016/j.ijid.2020.09.1466

      Highlights

      • Coronavirus-triggered pulmonary and systemic disease has an unpredictable clinical course in different subsets of patients.
      • COX2, p38 MAPK, IL-1b, IL-6 and TGF-β play pivotal roles in coronavirus-related cell death, cytokine storm and pulmonary interstitial fibrosis.
      • Discussion is ongoing on refining immunomodulation in COVID-19 without COX2 inhibition.
      • We searched the literature to show a potential target (COX2) and a weapon (celecoxib).

      Abstract

      Coronavirus-triggered pulmonary and systemic disease, i.e. systemic inflammatory response to virally triggered lung injury, named COVID-19, and ongoing discussions on refining immunomodulation in COVID-19 without COX2 inhibition prompted us to search the related literature to show a potential target (COX2) and a weapon (celecoxib). The concept of selectively targeting COX2 and closely related cascades might be worth trying in the treatment of COVID-19 given the substantial amount of data showing that COX2, p38 MAPK, IL-1b, IL-6 and TGF-β play pivotal roles in coronavirus-related cell death, cytokine storm and pulmonary interstitial fibrosis. Considering the 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 properties that should be evaluated in randomized controlled studies and is also available for off-label use.

      Keywords

      Introduction

      Coronovirus disease 2019 (COVID-19) rapidly became a pandemic and at the time this review was written there were increasing numbers of deaths and new cases. 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 became empirical treatments and clinical studies are ongoing in attempts to find the best alternatives until a definitive treatment is found (i.e. vaccine- and/or drug-based). Until definitive treatments are determined, readily available medications might have a role in preventing progression of the disease from Stage 1 to 2 and might decrease the hospitalization rate.
      From the beginning of the outbreak, ongoing searches and discussions have included immunomodulation strategies to limit immune-system-related tissue damage, which is now very well accepted as a leading factor in mortality. Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, Interleukin-6 (IL-6) antagonists, and Janus kinase (JAK) inhibitors are the main actors discussed and used in the treatment of COVID-19. Despite worldwide extensive efforts and ever-increasing numbers of publications, there has been no direct mention of cyclooxygenase-2 (COX2) inhibition and this prompted us to search the related literature to show the availability of a possible target and a weapon to be tested in clinical trials.

      Pathophysiology of COVID-19

      Severe acute respiratory syndrome (SARS)-associated coronavirus has been demonstrated to induce COX2 in mammalian cells via both its S and N proteins of its nucleocapsid (
      • Liu M.
      • Gu C.
      • Wu J.
      • Zhu Y.
      Amino acids 1 to 422 of the spike protein of SARS associated coronavirus are required for induction of cyclooxygenase-2.
      ,
      • Yan X.
      • Hao Q.
      • Mu Y.
      • Timani K.A.
      • Ye L.
      • Zhu Y.
      • et al.
      Nucleocapsid protein of SARS-CoV activates the expression of cyclooxygenase-2 by binding directly to regulatory elements for nuclear factor-kappa B and CCAAT/enhancer binding protein.
      ). This represents a pivot point to induce subsequent intracellular and then intercellular cascades. It has been shown that coronavirus-induced endoplasmic reticulum (ER) stress leads to unfolded protein response including Mitogen-activated protein kinase (MAPK) activation, autophagy and apoptosis of eukaryotic cells infected with this virus (
      • Fung T.S.
      • Huang M.
      • Liu D.X.
      Coronavirus-induced ER stress response and its involvement in regulation of coronavirus–host interactions.
      ). It was also shown that coronavirus-induced autophagy is mediated by activation of ER stress sensors, and prolonged ER stress leads to unfolded protein response to restore ER stability which involves MAPK activation (
      • Fung T.S.
      • Liu D.X.
      The ER stress sensor IRE1 and MAP kinase ERK modulate autophagy induction in cells infected with coronavirus infectious bronchitis virus.
      ). Induction of COX2 and p38MAPK plays a role in virally induced pulmonary alveolar, interstitial and then systemic inflammation. Whether virally induced or not, a state of cytokine storm also damages the pulmonary capillary network through activation of the p38MAPK pathway with eventual pulmonary arterial hypertension (
      • Tielemans B.
      • Stoian L.
      • Gijsbers R.
      • Michiels A.
      • Wagenaar A.
      • Farre Marti R.
      • et al.
      Cytokines trigger disruption of endothelium barrier function and p38 MAP kinase activation in BMPR2-silenced human lung microvascular endothelial cells.
      ). Interferon (IFN) -γ-related cytokine storm has been shown after SARS coronavirus infection with lymphopenia and neutrophilia, together with increased levels of IFN-γ (
      • Huang K.J.
      • Su I.J.
      • Theron M.
      • Wu Y.C.
      • Lai S.K.
      • Liu C.C.
      • et al.
      An interferon‐γ‐related cytokine storm in SARS patients.
      ). At pathological levels, IFN-γ is known to induce pulmonary injury via the COX2 and p38MAPK pathways (
      • Choo-Wing R.
      • Syed M.A.
      • Harijith A.
      • Bowen B.
      • Pryhuber G.
      • Janér C.
      • et al.
      Hyperoxia and interferon-γ–induced injury in developing lungs occur via cyclooxygenase-2 and the endoplasmic reticulum stress–dependent pathway.
      ).
      Hydroxychloroquine is no surprise for possible use in treating COVID-19 since it has been shown that chloroquine inhibits p38MAPK and inhibits coronavirus replication (
      • Kono M.
      • Tatsumi K.
      • Imai A.M.
      • Saito K.
      • Kuriyama T.
      • Shirasawa H.
      Inhibition of human coronavirus 229E infection in human epithelial lung cells (L132) by chloroquine: involvement of p38 MAPK and ERK.
      ). Hydroxychloroquine also has been shown to inhibit TNF-α induced endothelial inflammation via inhibition of p38 expression (
      • Li R.
      • Lin H.
      • Ye Y.
      • Xiao Y.
      • Xu S.
      • Wang J.
      • et al.
      Attenuation of antimalarial agent hydroxychloroquine on TNF-α-induced endothelial inflammation.
      ). Inhibiting p38MAPK is also important to prevent IL-1b-mediated acute lung injury.
      • Zheng D.-Y.
      • Zhou M.
      • Jin J.
      • He M.
      • Wang Y.
      • Du J.
      • et al.
      Inhibition of P38 MAPK downregulates the expression of IL-1β to protect lung from acute injury in intestinal ischemia reperfusion rats.
      showed that inhibition of p38 downregulates expression of IL-1b receptors in pulmonary alveoli and prevents acute lung injury due to ischemia-reperfusion injury. Another hallmark of coronavirus-induced pulmonary disease is interstitial fibrosis in which epithelial–mesenchymal transition plays a role – again p38 MAPK is pivotal in this complex phenomenon (
      • Jolly M.K.
      • Ward C.
      • Eapen M.S.
      • Myers S.
      • Hallgren O.
      • Levine H.
      • et al.
      Epithelial–mesenchymal transition, a spectrum of states: role in lung development, homeostasis, and disease.
      ,
      • Yan W.
      • Xiaoli L.
      • Guoliang A.
      • Zhonghui Z.
      • Di L.
      • Ximeng L.
      • et al.
      SB203580 inhibits epithelial–mesenchymal transition and pulmonary fibrosis in a rat silicosis model.
      ). Debates commenced, however, on the use of hydroxychloroquine soon after initial experiences with the medication, questioning the evidence provided for its use (
      • Ferner R.E.
      • Aronson J.K.
      Chloroquine and hydroxychloroquine in covid-19.
      ). Recent literature concerning previous studies of hydroxychloroquine demonstrated that no significant benefit has so far been observed in the use of hydroxychloroquine against COVID-19 (
      • Pathak D.S.K.
      • Salunke D.A.A.
      • Thivari D.P.
      • Pandey A.
      • Nandy D.K.
      • Ratna Harish V.K.
      • et al.
      No benefit of hydroxychloroquine in COVID-19: results of systematic review and meta-analysis of randomized controlled trials.
      ).

      Selective COX2 inhibition

      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 L.
      • Li R.
      • Pan Y.
      • Chen J.
      • Li Y.
      • Wu J.
      • et al.
      High-throughput screen of protein expression levels induced by cyclooxygenase-2 during influenza a virus infection.
      ). This enzyme has a great effect on proinflammatory cytokines, and its inhibition or deficiency alone does not blunt immune response against viral disease. Pharmacologic inhibition of COX2 by celecoxib decreases TNF-α, G-CSF and IL-6 levels without significant increase in viral titers in bronchoalveolar lavage fluid in mice with Influenza A infection (
      • Carey M.A.
      • Bradbury J.A.
      • Rebolloso Y.D.
      • Graves J.P.
      • Zeldin D.C.
      • Germolec D.R.
      Pharmacologic inhibition of COX-1 and COX-2 in influenza A viral infection in mice.
      ). Hyperinduction of COX2 has been shown in patients who have died of H5N1 infection, along with increased levels of TNF-α and other major proinflammatory cytokines (
      • Lee S.M.
      • Cheung C.-Y.
      • Nicholls J.M.
      • Hui K.P.
      • Leung C.Y.
      • Uiprasertkul M.
      • et al.
      Hyperinduction of cyclooxygenase-2-mediated proinflammatory cascade: a mechanism for the pathogenesis of avian influenza H5N1 infection.
      ). Many of these critical effects might be targeted by the clinically available COX2 inhibitor, celecoxib. These pathophysiologic steps might be especially important in disease progression from Stage 1 to 2, at which many patients can be treated on an outpatient basis. In addition to inhibiting COX2, celecoxib inhibits p38MAPK, although it is not a pure or potent p38MAPK inhibitor (
      • da Silva G.M.S.
      • Lima L.M.
      • Fraga C.A.
      • Sant’Anna C.M.
      • Barreiro E.J.
      The molecular basis for coxib inhibition of p38α MAP kinase.
      ). However, it is important that inhibition of COX2 might result in delayed specific immunoglobulin production by blunting Lipoxin B4 mediated memory B cell activation (
      • Kim N.
      • Lannan K.L.
      • Thatcher T.H.
      • Pollock S.J.
      • Woeller C.F.
      • Phipps R.P.
      Lipoxin B4 enhances human memory B cell antibody production via upregulating cyclooxygenase-2 expression.
      ). Notwithstanding, the benefits of alleviating a rapid and immense cytokine storm seem to outweigh the delay in production of specific antibodies (
      • Carey M.A.
      • Bradbury J.A.
      • Seubert J.M.
      • Langenbach R.
      • Zeldin D.C.
      • Germolec D.R.
      Contrasting effects of cyclooxygenase-1 (COX-1) and COX-2 deficiency on the host response to influenza A viral infection.
      ).
      Among the proven and putative effects of COX2 inhibition, a number have not been clarified. For instance, celecoxib has been shown to ameliorate hepatic cirrhosis through inhibition of epithelial–mesenchymal transition of hepatocytes (
      • Wen S.L.
      • Gao J.H.
      • Yang W.J.
      • Lu Y.Y.
      • Tong H.
      • Huang Z.Y.
      • et al.
      Celecoxib attenuates hepatic cirrhosis through inhibition of epithelial‐to‐mesenchymal transition of hepatocytes.
      ) but other studies have shown that it does not (
      • Harris T.R.
      • Kodani S.
      • Rand A.A.
      • Yang J.
      • Imai D.M.
      • Hwang S.H.
      • et al.
      Celecoxib does not protect against fibrosis and inflammation in a carbon tetrachloride-induced model of liver injury.
      ). 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 M.K.
      • Ward C.
      • Eapen M.S.
      • Myers S.
      • Hallgren O.
      • Levine H.
      • et al.
      Epithelial–mesenchymal transition, a spectrum of states: role in lung development, homeostasis, and disease.
      ,
      • Rout-Pitt N.
      • Farrow N.
      • Parsons D.
      • Donnelley M.
      Epithelial mesenchymal transition (EMT): a universal process in lung diseases with implications for cystic fibrosis pathophysiology.
      ) – possible antifibrotic effects of COX2 inhibition might benefit COVID-19 patients. Celecoxib has been shown to inhibit TGF-β-induced epithelial–mesenchymal transition in numerous studies. It has also been shown to inhibit FoxO1-mediated phosphorylation and eventual collagen production in human cardiac fibroblasts (
      • Tseng H.-C.
      • Lin C.-C.
      • Hsiao L.-D.
      • Yang C.-M.
      Lysophosphatidylcholine-induced mitochondrial fission contributes to collagen production in human cardiac fibroblasts.
      ). Additionally, celecoxib reduced peritoneal fibrosis in an animal model (
      • Fabbrini P.
      • Schilte M.N.
      • Zareie M.
      • ter Wee P.M.
      • Keuning E.D.
      • Beelen R.H.
      • et al.
      Celecoxib treatment reduces peritoneal fibrosis and angiogenesis and prevents ultrafiltration failure in experimental peritoneal dialysis.
      ). Since interstitial pulmonary fibrosis is one of the hallmarks of COVID-19, the effects of celecoxib in fibrotic processes might be worth clinically trialing, preferably with a randomized controlled trial (RCT) or at least off-label under current conditions.

      COVID-19 and COX2 inhibition

      In a pandemic with ongoing and unforeseen effects, there are many obstacles to forming treatment strategies. Absence of definitive drugs and/or vaccines against a highly contagious viral disease creates clinical, scientific and ethical problems. Proposal of many different agents and treatments with variable and arguable efficacy without RCTs is the center of these abovementioned problems. As time passes there are increasing numbers of patients and deaths, together with stretched healthcare systems in many parts of the world. There are examples of old friends like hydroxychloroquine and newer ones like monoclonal antibodies against certain cytokines of the exaggerated inflammatory response triggered by COVID-19.
      Despite ongoing studies and scientific discussions showing immunomodulation is one of the main issues in treatment of COVID-19, inhibition of COX2 has seemingly been missed. All clinical trials have evaluated the use of NSAIDs, steroids and newer immunomodulatory agents such as tocilizumab and sarilumab. Similar discussions took place throughout a previous pandemic, the H5N1 avian flu, in which it was argued that adjunctive use of COX inhibitors with antiviral therapy may have a beneficial role in alleviating the robust immune response causing the severe respiratory disease; however, these were never tried or studied using RCTs (
      • Simmons C.
      • Farrar J.
      Insights into inflammation and influenza.
      ,
      • Zheng B.-J.
      • Chan K.-W.
      • Lin Y.-P.
      • Zhao G.-Y.
      • Chan K.-W.
      • Zhang H.-J.
      • et al.
      Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus.
      ). During the early periods of the current pandemic, the use of NSAIDs was strongly objected to by some authors and even governments, arguing that the disease may be aggravated by use of these medications and advocating the use of paracetamol, another NSAID without anti-inflammatory activity (
      • Little P.
      Non-steroidal anti-inflammatory drugs and COVID-19.
      ,
      • Willsher K.
      Anti-inflammatories may aggravate Covid-19.
      ). Paracetamol has been promoted by some studies because of a safer side-effect profile and because other NSAIDs have been demonstrated as a cause of delayed diagnosis and increased rate of complications in respiratory tract infections (
      • de Girolamo L.
      • Peretti G.M.
      • Maffulli N.
      • Brini A.T.
      Covid-19—The real role of NSAIDs in Italy.
      ,
      • Little P.
      Non-steroidal anti-inflammatory drugs and COVID-19.
      ,
      • Sestili P.
      • Stocchi V.
      Repositioning chromones for early anti-inflammatory treatment of COVID-19.
      ). 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 early stages 1 and 2 of the disease (e.g. paracetamol) have no beneficial role in halting the progression of the condition because they have no anti-inflammatory action, which is crucial for keeping the inflammatory state under control. Although it may cause symptomatic relief for patients, in the case of COVID-19, paracetamol has no influence on disease progression, and without anti-inflammatory action this risks masking the symptoms. The number of studies opposing this approach is growing, including a recent cohort suggesting their concomitant use may be potentially harmless (
      • FitzGerald G.A.
      Misguided drug advice for COVID-19.
      ,
      • Lund L.A.-O.
      • Kristensen K.A.-O.
      • Reilev M.A.-O.
      • Christensen S.
      • Thomsen R.A.-O.
      • Christiansen C.A.-O.X.
      • et al.
      Adverse outcomes and mortality in users of non-steroidal anti-inflammatory drugs who tested positive for SARS-CoV-2: a Danish nationwide cohort study.
      ). We believe the use of ibuprofen in the case of COVID-19 has been objected to for logical and scientific reasons. Although further research is required, ibuprofen is associated with an upregulation of ACE2 enzyme, which may increase susceptibility to the virus. In addition, as we summarized above, inhibition of COX1 may not be a good idea since it blunts antiviral immunity and also shows no selective alleviation of cytokine storm. In addition, therapeutic potential of celecoxib was demonstrated in studies employing searching of molecular libraries (
      • Gimeno A.
      • Mestres-Truyol J.
      • Ojeda-Montes M.J.
      • Macip G.
      • Saldivar-Espinoza B.
      • Cereto-Massagué A.
      • et al.
      Prediction of novel inhibitors of the main protease (M-pro) of SARS-CoV-2 through consensus docking and drug reposition.
      ,
      • Ke Y.-Y.
      • Peng T.-T.
      • Yeh T.-K.
      • Huang W.-Z.
      • Chang S.-E.
      • Wu S.-H.
      • et al.
      Artificial intelligence approach fighting COVID-19 with repurposing drugs.
      ).
      Celecoxib, as mentioned above, is a candidate for treatment of COVID-19. It is widely available, relatively cheap and 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, another NSAID, celecoxib, has been studied for its cardiovascular side-effects in comparative studies. Although some studies indicate that celecoxib increases the incidence of major cardiovascular events – i.e. myocardial infarction, worsening of heart failure and thrombotic cerebral strokes – there are others showing no significant difference compared to non-selective COX inhibitors that are more widely used. Two of the main parameters seemingly important in these studies are the duration of use and the dose of this agent (
      • Masclee G.A.-O.X.
      • Straatman H.
      • Arfè A.
      • Castellsague J.
      • Garbe E.
      • Herings R.
      • et al.
      Risk of acute myocardial infarction during use of individual NSAIDs: a nested case-control study from the SOS project.
      ). In all these long-term studies, patient groups used celecoxib for many (approximately 20–30) months and suggested that cardiovascular toxicity is time dependent. However, celecoxib has been found to be noninferior to ibuprofen and naproxen, which are used on larger scales (
      • Nissen S.E.
      • Yeomans N.D.
      • Solomon D.H.
      • Lüscher T.F.
      • Libby P.
      • Husni M.E.
      • et al.
      Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis.
      ). For treating COVID, this might not be a major drawback since the expected duration of treatment will not exceed a few days to weeks. However, patients with significant cardiovascular comorbidities (e.g. obesity, uncontrolled diabetes, coronary artery disease or ischemic stroke) might not be ideal candidates for using this agent. To determine such issues will require RCTs (
      • Catella-Lawson F.
      • Crofford L.J.
      Cyclooxygenase inhibition and thrombogenicity.
      ).

      Conclusions

      Considering its high contagiousness, lack of definitive treatment and variable course of disease reflecting biological behavior of immune systems of patients with COVID-19, COX2 inhibition might be a valuable adjunct to still-evolving treatment strategies. Celecoxib has properties that should be evaluated in RCTs, as well as being available for off-label use. We believe that selective COX2 inhibition might have great implications in treating viral diseases because short duration of treatment will not be an issue in terms of major cardiovascular side-effects.

      Conflict of interest

      No potential conflict of interest relevant to this article was reported.

      Funding source

      This perspective paper was not funded.

      Ethical approval and consent to participate

      This paper was a perspective and ethical approval was not required.

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