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

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COX2

inhibition

in

the

treatment

of

COVID-19:

Review

of

literature

to

propose

repositioning

of

celecoxib

for

randomized

controlled

studies

Semih

Baghaki

a,

*

,

Can

Ege

Yalcin

a

,

Hayriye

Sema

Baghaki

b

,

Servet

Yekta

Aydin

a

,

Basak

Daghan

a

,

Ersin

Yavuz

a

a

IstanbulUniversityCerrahpasa–CerrahpasaMedicalFaculty,DepartmentofPlastic,ReconstructiveandAestheticSurgery,Istanbul,Turkey

b

BakirkoySadiKonukResearchandTrainingHospital,DepartmentofObstetricsandGynecology,Istanbul,Turkey

ARTICLE INFO Articlehistory: Received18June2020

Receivedinrevisedform23September2020 Accepted24September2020 Keywords: COX2 COVID-19 Immunomodulation Coronavirus Celecoxib ABSTRACT

Coronavirus-triggeredpulmonaryandsystemicdisease,i.e.systemicinflammatoryresponsetovirally triggeredlunginjury,namedCOVID-19,andongoingdiscussionsonrefiningimmunomodulationin COVID-19withoutCOX2inhibitionpromptedustosearchtherelatedliteraturetoshowapotentialtarget (COX2)andaweapon(celecoxib).TheconceptofselectivelytargetingCOX2andcloselyrelatedcascades mightbeworthtryinginthetreatmentofCOVID-19giventhesubstantialamountofdatashowingthat COX2,p38MAPK,IL-1b,IL-6andTGF-βplaypivotalrolesincoronavirus-relatedcelldeath,cytokine stormandpulmonaryinterstitialfibrosis.Consideringthelackofdefinitivetreatmentandimportanceof immunomodulationinCOVID-19,COX2inhibitionmightbeavaluableadjuncttostill-evolvingtreatment strategies.Celecoxibhaspropertiesthatshouldbeevaluatedinrandomizedcontrolledstudiesandisalso availableforoff-labeluse.

©2020TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(

http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Coronovirus disease 2019 (COVID-19) rapidly became a pandemic and at thetime this review was writtenthere were increasingnumbersofdeathsandnewcases.Lackoftimetorecruit evidence-based treatmentsled physicians worldwideto imple-mentempiricdrugcombinations.Inseveralweeks,anumberof agents proposed with variable or arguable efficacy became empiricaltreatmentsandclinicalstudiesareongoinginattempts tofindthebestalternativesuntiladefinitivetreatmentisfound (i.e.vaccine-and/ordrug-based). Untildefinitivetreatmentsare determined, readily available medications might havea role in preventingprogressionofthediseasefromStage1to2andmight decreasethehospitalizationrate.

From the beginning of the outbreak, ongoing searches and discussionshaveincludedimmunomodulationstrategiestolimit immune-system-related tissuedamage, whichis nowverywell accepted as a leading factor in mortality. Nonsteroidal anti-inflammatorydrugs(NSAIDs),corticosteroids,Interleukin-6(IL-6)

antagonists,andJanuskinase(JAK)inhibitorsarethemainactors discussed and used in the treatment of COVID-19. Despite worldwide extensive efforts and ever-increasing numbers of publications, therehasbeennodirect mentionof cyclooxygen-ase-2(COX2)inhibitionandthispromptedustosearchtherelated literaturetoshowtheavailabilityofapossibletargetandaweapon tobetestedinclinicaltrials.

PathophysiologyofCOVID-19

Severeacuterespiratorysyndrome(SARS)-associated corona-virushasbeendemonstratedtoinduceCOX2inmammaliancells viabothitsSandNproteinsofitsnucleocapsid(Liuetal.,2006; Yanetal.,2006).Thisrepresentsapivotpointtoinducesubsequent intracellularand thenintercellularcascades.It hasbeenshown thatcoronavirus-inducedendoplasmicreticulum(ER)stressleads tounfoldedproteinresponseincludingMitogen-activatedprotein kinase(MAPK)activation,autophagyandapoptosisofeukaryotic cellsinfectedwiththisvirus(Fungetal.,2014).Itwasalsoshown thatcoronavirus-inducedautophagyismediatedbyactivationof ER stress sensors, and prolonged ER stress leads to unfolded protein response to restore ER stability which involves MAPK activation(FungandLiu,2019).InductionofCOX2andp38MAPK

*Correspondingauthor.

E-mailaddress:semihbaghaki@gmail.com(S.Baghaki).

https://doi.org/10.1016/j.ijid.2020.09.1466

1201-9712/©2020TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

InternationalJournalofInfectiousDiseases101(2020)29–32

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

(2)

playsaroleinvirallyinducedpulmonaryalveolar,interstitialand then systemic inflammation. Whethervirally 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 et al., 2019).Interferon(IFN)-g-relatedcytokinestormhasbeenshown afterSARScoronavirus infectionwithlymphopeniaand neutro-philia,togetherwithincreasedlevelsofIFN-g(Huangetal.,2005). Atpathologicallevels,IFN-gisknowntoinducepulmonaryinjury viatheCOX2andp38MAPKpathways(Choo-Wingetal.,2013).

Hydroxychloroquineisnosurpriseforpossibleuseintreating COVID-19 since it has been shown that chloroquine inhibits p38MAPKandinhibitscoronavirusreplication(Konoetal.,2008). HydroxychloroquinealsohasbeenshowntoinhibitTNF-αinduced endothelialinflammationviainhibitionofp38expression(Lietal., 2018). Inhibiting p38MAPK is also important toprevent IL-1b-mediated acute lung injury. Zheng et al. (2016) showed that inhibitionofp38downregulatesexpressionofIL-1breceptorsin pulmonaryalveoliandpreventsacutelunginjurydueto ischemia-reperfusion injury. Another hallmark of coronavirus-induced pulmonary disease is interstitial fibrosis in which epithelial– mesenchymaltransitionplaysarole–againp38MAPKispivotalin this complexphenomenon (Jolly et al., 2018;Yan et al., 2016). Debatescommenced,however,ontheuseofhydroxychloroquine soonafterinitialexperienceswiththemedication,questioningthe evidenceprovidedforitsuse(FernerandAronson,2020).Recent literature concerning previous studies of hydroxychloroquine demonstratedthatnosignificantbenefithassofarbeenobserved intheuseofhydroxychloroquineagainstCOVID-19(Pathaketal., 2020).

SelectiveCOX2inhibition

COX2isacriticalevolutionaryenzymeinmanyphysiologic andpathologicprocesses.Ithasacentralroleinviralinfections and regulates expression levels of many serum proteins (Liu etal.,2011).Thisenzymehasagreateffectonproinflammatory cytokines,anditsinhibitionordeficiencyalonedoesnotblunt immuneresponseagainstviraldisease. Pharmacologic inhibi-tionofCOX2bycelecoxibdecreasesTNF-α,G-CSFandIL-6levels without significant increase in viraltiters in bronchoalveolar lavage fluid in mice with Influenza A infection (Carey et al., 2010).HyperinductionofCOX2hasbeenshowninpatientswho havediedofH5N1infection,alongwithincreasedlevelsof TNF-αandothermajorproinflammatorycytokines(Leeetal.,2008). Manyofthesecriticaleffectsmightbetargetedbytheclinically available COX2 inhibitor, celecoxib. These pathophysiologic steps might be especially important in disease progression fromStage1to2,atwhichmanypatientscanbetreatedonan outpatient basis. In addition to inhibiting COX2, celecoxib inhibitsp38MAPK,althoughitisnotapureorpotentp38MAPK inhibitor (daSilvaet al.,2005).However, itis importantthat inhibition of COX2 might result indelayed specific immuno-globulinproductionbybluntingLipoxinB4mediatedmemoryB cellactivation(Kimetal.,2018).Notwithstanding,thebenefits of alleviating a rapid and immense cytokine storm seem to outweighthedelayinproductionofspecificantibodies(Carey etal.,2005).

Amongtheprovenandputative effectsofCOX2inhibition, a numberhavenotbeenclarified.Forinstance,celecoxibhasbeen shown to ameliorate hepatic cirrhosis through inhibition of epithelial–mesenchymal transition of hepatocytes (Wen et al., 2014)butotherstudieshaveshownthatitdoesnot(Harrisetal., 2018). Since epithelial–mesenchymal transition is a pivotal evolutionaryphenomenonin numerousphysiologicanddisease states of lung – e.g. lung development, COPD,lung cancerand

pulmonary fibrosis (Jolly et al., 2018; Rout-Pitt et al., 2018) – possible antifibrotic effects of COX2 inhibition might benefit COVID-19patients. Celecoxibhasbeenshown toinhibitTGF- β-inducedepithelial–mesenchymaltransitioninnumerousstudies. IthasalsobeenshowntoinhibitFoxO1-mediatedphosphorylation and eventual collagenproduction in humancardiac fibroblasts (Tseng et al., 2019). Additionally, celecoxib reduced peritoneal fibrosisinananimalmodel(Fabbrinietal.,2009).Sinceinterstitial pulmonaryfibrosisisoneofthehallmarksofCOVID-19,theeffects ofcelecoxibinfibroticprocessesmightbeworthclinicallytrialing, preferablywitharandomizedcontrolledtrial(RCT)oratleast off-labelundercurrentconditions.

COVID-19andCOX2inhibition

Inapandemicwithongoingandunforeseeneffects,thereare many obstacles to forming treatment strategies. Absence of definitivedrugsand/orvaccinesagainstahighlycontagiousviral diseasecreatesclinical,scientificandethicalproblems.Proposalof manydifferentagentsandtreatmentswithvariableandarguable efficacy without RCTs is the center of these abovementioned problems.Astimepassesthereareincreasingnumbersofpatients anddeaths,togetherwithstretchedhealthcaresystemsinmany parts of the world. There are examples of old friends like hydroxychloroquineandneweroneslikemonoclonalantibodies against certain cytokines of the exaggerated inflammatory responsetriggeredbyCOVID-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 clinicaltrialshaveevaluatedtheuseofNSAIDs,steroidsandnewer immunomodulatory agents suchas tocilizumab and sarilumab. Similardiscussionstookplacethroughouta previouspandemic, theH5N1avianflu,inwhichitwasarguedthatadjunctiveuseof COXinhibitorswithantiviraltherapymayhaveabeneficialrolein alleviating the robust immune response causing the severe respiratorydisease;however, thesewerenever triedor studied usingRCTs(SimmonsandFarrar,2008;Zhengetal.,2008).During theearlyperiodsofthecurrentpandemic,theuseofNSAIDswas 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 NSAIDwithoutanti-inflammatoryactivity(Little,2020;Willsher, 2020).Paracetamolhasbeenpromotedbysomestudiesbecauseof a saferside-effect profileand becauseother NSAIDshave been demonstratedasacauseofdelayeddiagnosisandincreasedrateof complicationsinrespiratory tractinfections (deGirolamoet al., 2020;Little,2020;SestiliandStocchi,2020).Thiscreatesaparadox betweentreatmentmodalitiesandpathophysiologyofCOVID-19, since the over-the-counter medications used toameliorate the symptomsthat can beused in theearly stages 1 and 2 of the disease(e.g.paracetamol)havenobeneficialroleinhalting the progressionoftheconditionbecausetheyhavenoanti-in flamma-toryaction, whichiscrucial forkeeping theinflammatorystate under control. Although it may cause symptomatic relief for patients,inthecaseofCOVID-19,paracetamolhasnoinfluenceon disease progression,and withoutanti-inflammatory action this risksmaskingthesymptoms.Thenumberofstudiesopposingthis approachis growing,includinga recentcohort suggestingtheir concomitantusemaybepotentiallyharmless(FitzGerald,2020; Lundetal.,2020).Webelievetheuseofibuprofeninthecaseof COVID-19hasbeenobjectedtoforlogicalandscientificreasons. Althoughfurtherresearchisrequired,ibuprofenisassociatedwith anupregulationofACE2enzyme,whichmayincrease susceptibil-itytothevirus.Inaddition,aswesummarizedabove,inhibitionof COX1maynotbeagoodideasinceitbluntsantiviralimmunityand

S.Baghaki,C.E.Yalcin,H.S.Baghakietal. InternationalJournalofInfectiousDiseases101(2020)29–32

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alsoshowsnoselectivealleviationofcytokinestorm.Inaddition, therapeutic potential of celecoxib was demonstrated in studies employingsearchingofmolecularlibraries(Gimenoetal.,2020;Ke etal.,2020).

Celecoxib,asmentionedabove,isacandidatefortreatmentof COVID-19.Itiswidelyavailable,relativelycheapandhasa well-recordedsafetyprofileinadultsandchildrenwithalonghistoryof clinicaluseforvariablediseasestates,e.g.osteoarthritis, rheuma-toidarthritis,juvenilerheumatoidarthritis,colorectalcancerand lungcancer.Likewise,anotherNSAID,celecoxib,hasbeenstudied foritscardiovascularside-effectsincomparativestudies.Although some studiesindicate that celecoxib increasestheincidence of majorcardiovascularevents–i.e.myocardialinfarction,worsening ofheartfailureandthromboticcerebralstrokes–thereareothers showingnosignificantdifferencecomparedtonon-selectiveCOX inhibitorsthataremorewidelyused.Twoofthemainparameters seeminglyimportantinthesestudiesarethedurationofuseand thedoseofthisagent(Mascleeetal.,2018).Inalltheselong-term studies,patient groupsusedcelecoxib formany(approximately 20–30)monthsandsuggestedthatcardiovasculartoxicityistime dependent.However,celecoxibhasbeenfoundtobenoninferiorto ibuprofenandnaproxen,whichareusedonlargerscales(Nissen et al., 2016). For treating COVID, this might not be a major drawbacksincetheexpecteddurationoftreatmentwillnotexceed a few days to weeks. However, patients with significant cardiovascularcomorbidities(e.g.obesity,uncontrolleddiabetes, coronary arterydisease or ischemicstroke) might not beideal candidates for using this agent. To determine such issues will requireRCTs(Catella-LawsonandCrofford,2001).

Conclusions

Considering its highcontagiousness, lack of definitive treat-mentandvariablecourseofdiseasereflectingbiologicalbehavior of immunesystemsofpatientswithCOVID-19,COX2 inhibition mightbeavaluableadjuncttostill-evolvingtreatmentstrategies. CelecoxibhaspropertiesthatshouldbeevaluatedinRCTs,aswell asbeingavailableforoff-labeluse.WebelievethatselectiveCOX2 inhibitionmighthavegreatimplicationsintreatingviraldiseases becauseshortdurationoftreatmentwillnotbeanissueintermsof majorcardiovascularside-effects.

Conflictofinterest

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

Fundingsource

Thisperspectivepaperwasnotfunded. Ethicalapprovalandconsenttoparticipate

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

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