Calcineurin inhibitors revisited: A new paradigm for COVID-19?

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brazjinfectdis2020;24(4):365–367

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Brief

communication

Calcineurin

inhibitors

revisited:

A

new

paradigm

for

COVID-19?

René

Hage

a,b,∗

_,

_Carolin

_Steinack

a,b

_,

_Macé

_M.

_Schuurmans

a,b

a_University_Hospital_Zurich,_Division_of_Pulmonology,_Zurich,_Switzerland b_University_of_Zurich,_Faculty_of_Medicine,_Zurich,_Switzerland

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Articlehistory:

Received6June2020 Accepted17June2020 Availableonline27June2020

Keywords: Cytokinestorm Hyperinﬂammation Transplantation ARDS

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TheSevereAcuteRespiratorySyndromeCoronavirus2(SARS-CoV-2)cancausemild, mod-erateorseveredisease(COVID-19).Inseveredisease,thereishyperinﬂammationcausing severesymptoms.SevereCOVID-19isanimmunologicalphenomenon,ratherthanadirect viraldamagedisease.TherapiesforCOVID-19areallinvestigationaltherapies.Incaseof severedisease,treatmentwithacalcineurininhibitorcouldbepromising.Inthisarticle we explainthemechanisms ofcalcineurininhibitortreatment forCOVID-19,based on experiencesseeninsolidorgantransplantrecipientswhosufferedfromCOVID-19.

For the infection with the novel coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) whichcausestheCoronavirusDisease2019(COVID-19)there iscurrentlynoeffectiveevidence-basedtherapy.Recently,a preliminaryCanadianguidelineforthetreatmentof immuno-competentpatientswasproposed.1_At_the_moment_various

investigationaltherapiesarebeingstudiedatdifferentlevels mainlycompoundsthathavebeenpreviouslydevelopedfor otherconditions(Table1).Pathogenicityofthecoronaviruses can be either low (such as in the coronavirus subspecies named229E,OC43,NL63andHKU1)orhigh(suchasinthe Middle East Respiratory Syndrome Coronavirus,MERS-CoV, theSevereAcuteRespiratorySyndromeCoronavirus, SARS-CoV,andthenovelcoronavirusSARS-CoV-2).Intheﬁrstgroup, treatmentgenerallyisnotnecessarybecausetheviruscauses mildrespiratoryorgastrointestinalsymptoms. Inthe latter

∗ _{Corresponding}_author.

E-mailaddress:rene.hage@usz.ch(R.Hage).

group, thevirus infection potentiallycauses severe disease associatedwitharelatively highmortality.In thealarming increaseincasesofCOVID-19worldwide,thefastest therapeu-ticoptionistouseexistingmedicationsagainstSARS-CoV-2 infection that have been eithereffective in vitro or in vivo

against other highly pathogenic coronaviruses, such as in SARSandMERS,orevenSARS-CoV-2.

InCOVID-19,threestagesofseverityhavebeenproposed.2

StageI(earlyinfection)includespatientswithmild constitu-tionalsymptoms,andaregenerallytreatedintheambulatory settingincludinghomequarantine.StageII(pulmonaryphase) patientshavepneumoniawithcoughand/orfever.Thiscan be subdivided in Stage IIa (no hypoxia) and IIb (hypoxia, deﬁnedasPaO2/FiO2<300mmHg).Thesepatientsgenerally

willbehospitalized.InStageIII(systemichyperinﬂammation) there is severe COVID-pneumonia with ARDS, SIRS/shock, and/orcardiacfailure.Thesepatientsareoftentreatedwith mechanicalventilationorextracorporealmembrane oxygena-tion(ECMO).

https://doi.org/10.1016/j.bjid.2020.06.005

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braz j infect dis.2020;24(4):365–367

Table1–Investigationaltherapiesconsideredfor treatmentofCOVID-19.

Therapy Mechanismofaction/Rationale

(Hydroxo)chloroquine* Blocksviralentryinendosome *negativestudyresultssofar,further resultspending

Remdesivir BlocksRNAdependentpolymerase

Lopinavir/ritonavir ProteaseInhibitor,ﬁrststudywith disappointingresults.

Tocilizumab Anti-IL-6(anti-inﬂammatory)

Corticosteroids T-cellinhibition(anti-inﬂammatory)

Tacrolimus T-cellinhibition/suppresses

cytokines(i.e.IL-2,IL-4,TNF-␣and IFN-␥)

Umifenovir Preventsviralhostcellentryby

inhibitionofmembranefusionofviral envelopeandhostcellcytoplasmic membraneviainhibitionof clathrin-mediatedendocytosis

Favipiravir Selectivelyinhibitsviral

RNA-dependentRNApolymerase (RdRp)

Ribavirin Guanosineanalogthatinterfereswith

theviralreplication Anticoagulation

(Heparine)

Hypercoagulability,thromboembolic events

Vaccination Half-lifeofantibodiesappearstobe

short

Plasmapheresis Bindskeycomponentsofviral

replicationorthevirusitself

RNA=ribosomicnucleicacid;IL=interleukin;TNF=tumornecrosis factor;IFN=interferon.

In COVID-19 Stage III, it is not only the viral damage (cytopathiceffect)causingdisease,butalsomainlythe hyper-inﬂammation (cytokine storm). In this stage, there is an overshootingreactionofbothinnateandadaptive immune system, leading to further systemic multiorgan damage.3

Thevirus enters the endothelial cells inthe lungs via the angiotensinogen converting enzyme receptor-2 (ACE2) and canprovokeacytokinestorm.

Interestingly,SARS-CoV-2is avirus probablyoriginating frombats.Inbatstherecouldbeanaturalprotectionagainst thisvirusastheyhavehighlevelsofmelatonininactivating theACE2,andthereforeblockingSARS-CoV-2fromentering the immunecells ofthebats. By this mechanismthe bats are probably not strongly affected by the presence of the virus.

Inhumans,the ACE2normally inactivatesthe ligandof the bradykinin receptor. However,when SARS-CoV-2 occu-piesACE2,bradykinincannotbeinhibited,andthebradykinin concentrationincreases.4_Bradykinin_leads_to_increased_vessel

permeability,vasodilatationwithangioedema,andincreased natriuresis,thus leading tohypotension. Thelocal plasma leakagetriggersextensiveﬁbrinproductionandclotting lead-ingtoextensivethrombosisofthesmallvessels,whichthen alsoprogressestothelargerbloodvessels.5

Moreover, in this phase there is also an overreacting innate and adaptive immune system. The innate immu-nitycomprises environmentalbarriers(skin,mucosa),cells (macrophages,monocytes,neutrophils),andmediatorsofthe

immuneresponse(cytokines,chemokines,complement).The adaptiveimmunitycomprisestheantiviralB-cell (antibody-mediated)andT-cellimmuneresponse.

TheB-cellresponseisinvolvedinantibody-mediatedviral binding,butintheacutesettingtheT-cellresponsehasa dom-inant role inrecognizing and destroyingthe infectedcells. Normally,thesecretionofcytokinessuchasinterleukin (IL)-1␤,IL-6,TNF-␣,and IFN-␥isatransient event.However,in hyperinﬂammation,aggravatedbythehighbradykinin con-centration,thisresponseisexaggeratedandcausesamassive destructionofhosttissuebyacytokinestorm.Thiscytokine stormcan worsenthebradykinin-related vascularcollapse, associatedwithdisseminatedintravascularcoagulationand septic shock, as can be observed in patients with severe COVID-19.

The thrombo-angiopathy results in extensive and pro-longed plasma leakage and (further) clotting, ultimately developingapulmonaryﬁbrosis.6_In_the_near_future,

COVID-19 related ﬁbrosis could be an important newentity and, inseverecases,thispopulationmayevenbeconsideredfor lungtransplantation.7_Attenuating_this_severe_{inﬂammatory}

responsecouldthereforebeanimportanttreatmentstrategy. Onestrategymayincludetheuseofcorticosteroids.However, asisknownforotherviraldiseases,highdosesof corticos-teroidsmaybeassociatedwithprolongedviralsheddingof thevirus,ashasbeenobservedwithSARS,andadditionally worsenedARDSmayoccur.InanimalexperimentswithSARS, dexamethasone promoted viral replication after prolonged administration.

Analternativeanti-inﬂammatorytreatmentcouldbethe immunosuppressanttacrolimus,knownfrompatients need-ing immunosuppressionafterasolidorgan transplantation (SOT).Surprisingly,despiteover4.000.000patientsworldwide infectedwithSARS-CoV-2,onlyafewcasereportsdescribing COVID-19inSOTpatientshavebeenpublished.3_These_SOT

patientsgenerallyareunderchronicdualortriple immuno-suppressive therapy, whichingeneralincreases theriskof severe infections.However,aspartofthe immunosuppres-sivetherapy,tacrolimushasshownapotentialbeneﬁtinother highlypathogenic coronaviruses,andmightbean interest-ingcompoundinthetreatmentofsevereCOVID-19(Ref4,5). Tacrolimusisimmunosuppressivebyinhibitingcalcineurin, andsuppressingtheearlyphaseofT-cellactivation,andthe expression ofmany cytokines(IL-2, IL-4, TNF-␣ and IFN-␥) that are needed in the activation of the cellular immune response,possiblypreventingacytokinestormasobserved insevereCOVID-19.Ithasbeensuggestedtobeeffectivein MERS-CoV,basedoncasereportsintheliterature.8_In_animal

experiments,itshowedeffectiveinhibitionofviralreplication of SARS-CoV.9 _This _could _explain _the _relatively _low

num-berofSOTpatientswith(symptomatic)COVID-19.Also,the severeCOVID-19stageIIIhashardlybeenreportedinpatients withCOVID-19undertacrolimustherapysofar.Althoughﬁrm conclusionsarenotpossibleyet,tacrolimusmaybean inter-estingcompoundforCOVID-19toreduce,preventoreventreat thehyperinﬂammationcausedbytheSARS-CoV-2infection. Tacrolimusshouldbeconsideredasacomponentinthe treat-ment aspart ofthe proactivemanagement inhospitalized immunocompetentpatientswithmoderatelysevereoreven severeCOVID-19.

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brazj infect dis.2020;24(4):365–367

367 Conﬂicts

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interest

Theauthorsdeclarenoconﬂictsofinterest.

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