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Prognostic factors in patients with diabetes hospitalized for COVID-19: Findings from the CORONADO study and other recent reports.

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Mini

Review

Prognostic

factors

in

patients

with

diabetes

hospitalized

for

COVID-19:

Findings

from

the

CORONADO

study

and

other

recent

reports

A.J.

Scheen

a,

*

,

M.

Marre

b,c

,

C.

Thivolet

d

aDivisionofDiabetes,NutritionandMetabolicDisorders,DepartmentofMedicine,CHULie`ge,UniversityofLie`ge,Lie`ge,Belgium bUMR_S1138,MetabolicInflammationinDiabetesanditsComplications,CordeliersResearchCentre,75006PARIS,France c

PresidentoftheFFRDandtheCliniqueAmbroisePare´,92200Neuilly-sur-Seine,France

d

PresidentoftheSFDandDIAB-eCARE,CentreforDiabetes,HospicesCivilsdeLyon,UniversityofLyon,Lyon,France

Introduction

The prevalence of diabetes in patients with COVID-19 (CoronavirusDisease 2019), caused bysevereacute respiratory syndromecoronavirus2(SARS-CoV-2)infection,hasvariedacross countries,rangingfrom5–20%inChina,17%inLombardyinItaly and 33% in the US [1–4]. Diabetes can modulate host–viral interactionsandhost–immuneresponsesviaseveralmechanisms thatcouldalsoleadtopooreroutcomes(seeMuniyappaandGubbi forareview[5]).Ofmajorclinicalimportance,allstudieshaveso farreportedatwo-tothreefoldhigherprevalenceofdiabetesin patientswithsevereinfectionsrequiringadmissiontointensive careunits(ICU)andinvasiveventilationcomparedwiththosewith

less severeinfection, as well as an increasedmortality rate in patientswithdiabetes(Table1)[6–14].

However,diabetespatientsconstituteahighlyheterogeneous populationintermsoftypeofdiabetes,durationofdisease,quality ofglucosecontrol,presenceofdiabeticcomplications,interference of comorbiditiessuchas obesityand hypertension,and type of glucose-loweringtherapy,amongothers.Whichofthesedifferent factorscouldbeplayingasignificantroleinthefinalprognosisof diabetes patients hospitalized becauseof COVID-19 is virtually unknownintheabsenceoflargeprospectivestudiestoaddressthis crucialquestion.

Infact,theavailabledataintheliteratureareratherscarce,and somereports haveonly considered prognosticfactorsbasedon theoretical grounds [15]. One small retrospective single-centre observationalstudyinChinaanalyzedtheclinicalcharacteristics andoutcomesof48severeCOVID-19patientswithdiabetes[16], andfoundthatsurvivorsofCOVID-19withdiabetesdidnotdiffer

* Correspondingauthor.

E-mailaddress:andre.scheen@chuliege.be(A.J.Scheen). ARTICLE INFO Articlehistory: Received15May2020 Accepted15May2020 Availableonlinexxx Keywords: Diabeticcomplications Glucosecontrol Mechanicalventilation Mortality Obesity SARS-CoV-2 ABSTRACT

DiabetesmellitusischallenginginthecontextoftheCOVID-19pandemic.Theprevalenceofdiabetes

patientshospitalizedinintensivecareunitsforCOVID-19istwo-tothreefoldhigher,andthemortality

rate atleastdouble,thanthatofnon-diabetespatients. As thepopulationwithdiabetes ishighly

heterogeneous,itisofmajorinteresttodeterminetheriskfactorsofprogressiontoamoreserious

life-threatening COVID-19 infection. This brief review discusses the main findings of CORONADO, a

prospectiveobservational studyin France thatspecifically addressed this issueaswell as related

observationsfromothercountries,mainlyChinaandtheUS.Someprognosticfactorsbeyondoldage

havebeenidentified:forexample,anincreasedbodymassindexisamajorriskfactorforrequiring

respiratoryassistance.Indeed,obesitycombinesseveralriskfactors, includingimpairedrespiratory

mechanics,thepresenceofothercomorbiditiesandinappropriateinflammatoryresponses,partlydueto

ectopicfatdeposits.Whilepreviousdiabeticmicrovascular(renal)andmacrovascularcomplications

also increase risk of death,the quality of past glucosecontrol had no independent influence on

hospitalizeddiabetespatientoutcomes,butwhetherthequalityofglucosecontrolmightmodulaterisk

ofCOVID-19 innon-hospitalized diabetespatientsis still unknown.Inaddition,nonegative signs

regardingtheuseofRAASblockersandDPP-4inhibitorsandoutcomesofCOVID-19couldbeidentified.

Hyperglycaemiaatthetimeofhospitaladmissionisassociatedwithpooroutcomes,butitmaysimplybe

considered a marker of severity of the infection. Thus, the impact of glucose control during

hospitalization onoutcomes related to COVID-19,which was not investigated in theCORONADO

study,iscertainlydeservingofspecificinvestigation.

C 2020ElsevierMassonSAS.Allrightsreserved.

Available

online

at

ScienceDirect

www.sciencedirect.com

https://doi.org/10.1016/j.diabet.2020.05.008

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significantlyfrom non-survivorswith diabetesin prevalence of associatedcomorbidities,includinghypertension,cardiovascular disease(CVD)andchronicpulmonarydisease.Indeed,survivalwas independentofoverallglycaemiccontrol,asassessedbyglycated haemoglobin(HbA1c)onhospitalization.However,giventhevery

smallnumberofpatients,thisanalysishastobeinterpretedwith caution.Inthelargestseriesof5700patients hospitalizedwith COVID-19inNewYorkCityintheUS,itwasonlymentionedin passingthat,ofthepatientswhodied,thosewithdiabeteswere morelikelytohave receivedinvasivemechanical ventilationor careintheICU comparedwiththose withoutdiabetes,withno furtherinformationprovidedregardingthecharacteristicsofthose diabetespatients[17].

Onekeyquestioniswhetherdiabetesisariskfactorfor COVID-19infectionandpooreroutcomesbecauseofthedeleteriousroleof hyperglycaemia on immune responses and defence against infections [18], the multiple complications associated with diabetes,especiallyCVDand/orrenaldisorders,andthe comorbi-ditiesfrequentlyencountered,suchasobesity,hypertensionand obstructivesleep apnoea, in the type 2 diabetes (T2D) patient population[19].Furthermore,thepotentialinterferenceofcertain medicationsfrequentlyprescribed fordiabetespatientsarealso worthyofattention[19,20]:renin–angiotensin–aldosterone sys-tem(RAAS)blockershavebeensuspectedtofacilitateintracellular penetrationofSARS-CoV-2[21];anddipeptidylpeptidase(DPP)-4 inhibitorscaninterferewiththeimmuneresponse[22].

Thus,identifyingtheriskfactorsofprogressiontoserious life-threateningCOVID-19 infectionis a key step that would allow preventative strategies in the diabetes population to limit the incidenceoftraumatic outcomes, suchastheneedfor tracheal intubationformechanicalventilationordeath.

FindingsfromCORONADO

TheCORONADO (CoronavirusSARS-CoV-2andDiabetes Out-comes)studywas alarge-scale nationwide(68 Frenchcentres) observational study of patients with diabetes hospitalized for COVID-19carriedoutinMarch2020[23].Itsmainobjectivewasto identifytheclinicalandbiologicalcharacteristicsassociatedwith diseaseseverityandmortalityinpatientswithdiabetesinhospital becauseof COVID-19.The primary outcomecombined tracheal intubationformechanicalventilationand/ordeathwithin7days of hospital admission. Individual components of the primary outcomewereconsideredapre-specifiedsecondaryoutcome,as wasalsohospitaldischargebyday7.

AnintermediateanalysisrecentlypublishedinDiabetologia[23] focused on 1317 participants (admitted during 10–31 March 2020at53centres)whowerepredominantlyT2Dpatients(88.5%), withagenderdistributionof35%femalevs.65%male.Theirmean age was 69.8 years and median body mass index (BMI) was 28.4kg/m2.Microvascular(includingchronickidneydisease)and

macrovascular complicationswerefoundin46.8% and 40.8% of patients,respectively,andamedicalhistoryofhypertensionwas identifiedin77.2%(57.1%wereusingRAASinhibitors).Theirmean glycatedhaemoglobin(HbA1c)levelwas8.11.9%(6521mmol/

mol), and their routine glucose-lowering medications mostly comprised metformin (56.6%), insulin therapy(38.3%) and DPP-4 inhibitors(21.6%).

The composite primary outcome was noted in 29.0% of participants, while10.6%diedand 18%weredischarged byday 7. Whereas, on univariate analyses, several characteristics at admissionweresignificantlyassociatedwiththeprimaryoutcome (higher BMI, male gender and previous treatment with RAAS blockers, the latter two of only borderline significance), on multivariableanalyses, onlyBMIremainedpositivelyassociated withtheprimaryoutcome[oddsratio(OR):1.28;95%confidence interval (CI):1.10–1.47].Ofnote, however,thisassociationwas largelydrivenbytrachealintubationratherthandeath.Moreover, theincreasedriskoftheprimaryoutcomeappearedtobelessin patientswithgrade-3obesity(BMI40kg/m2)thaninthosewho

wereoverweight(25–29.9kg/m2)orwithgrade1–2obesity(BMI

30–39.9kg/m2).

Itwasalsonoteworthythatage,historyofmicrovascularand macrovascular complications, decreased estimated glomerular filtrationrate(eGFR)andcomorbiditiessuchastreatedobstructive sleepapnoeawereallindependentlyassociatedwithriskofdeath byday7(OR:2.14–2.80).Ageplayedamajorrole(OR:14)when diabetespatients>75yearsofagewerecomparedwithdiabetes patients<55yearsofage.Previouslong-termglucosecontrol,as assessedbyHbA1cmeasurement,wasnotsignificantlyassociated

withtheprimaryoutcome,unlikeearlyclinical(dyspnoea)and biological [elevated C-reactive protein (CRP)] markers of more severe disease. In fact, in age-and gender-adjusted non-linear models, plasma glucose concentrations at admission were significantly and positively associated with both the primary outcome anddeath by day7. However, thenegativeimpact of admissionambientglucoseconcentrationswasnolonger signifi-cantonmultivariateanalysis.Itisalsoworthnotingthat diabetes-related disorderswithseverehyperglycaemia, includingketosis andketoacidosis,andalsohypoglycaemiceventswerereportedat thetimeofadmission.

Table1

RiskofpoorclinicaloutcomesanddeathindiabetespatientswithCOVID-19infection.

References Studies(n)(nofpatients) PoorcompositeoutcomesHR/OR(95%CI) DeathHR/OR(95%CI)%CI) Observationalstudies

Zhouetal.,2020[6] One,Wuhan,China(191) NA 2.85(1.35–6.05)

Guanetal.,2020[7] One,nationwide,China(1500) 1.59(1.03–2.45)a

NA Meta-analyses

Lietal.,2020[8] Three(1278) 2.21(0.88–5.57)b

NA Ronconetal.,2020[9] Four(1380/354) 2.79(1.85–4.22)b

3.21(1.82–5.64) Fadinietal.,2020[10] Six,China(1687) 2.26(1.47–3.49)c

NA

Yangetal.,2020[11] Seven(1576) 2.09(0.89–4.82)c NA

Zhengetal.,2020[12] 11(2570) 3.68(2.68–5.03)d NA

Huangetal.,2020[13] 30(6452) 2.38(1.88–3.03)e

2.12(1.44–3.11)

Wangetal.,2020[14] 31(6104) 2.61(2.05–3.33)c

NA HR:hazardratio;OR:oddsratio;CI:confidenceinterval;NA:notavailable

a

Intensivecareunit(ICU),ventilationordeath.

b

ICUadmission.

c

severeCOVID-19infection.

dmortality/criticalevents. e

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Inconclusion,theCORONADOstudyconfirmedtheseverityof theprognosisforCOVID-19infectioninpeoplewithdiabetes,as 20.3% of the study population required tracheal intubation for mechanicalventilation,andthemortalityratewas10.6%asearly as7daysafteradmission.Onmultivariateanalysis,anincreased BMI (already starting in the overweight range) was the only independentprognosticfactorofCOVID-19severity,asassessedby thecomposite primaryoutcomeinthis largecohortofdiabetes patients. Of major importance, however, having a history of vascular diabetes complications and treated obstructive sleep apnoea significantly increased the risk of death. In contrast, parametersofpreviousoradmissionglucosecontrolandroutine pharmacological therapies, including RAAS blockers and DPP-4 inhibitors, were not independently associated with such a prognosis.

Unansweredquestions

Atthistime,CORONADOisthelargestpublishedobservational study specifically focused on the characteristics of diabetes patientshospitalizedforCOVID-19infection.Itwasdesignedto addressthreemainobjectives:

 to characterize the phenotype of patients with diabetes hospitalizedforCOVID-19;

 todeterminetheprevalenceofpoorprognosesusingaprimary outcomecombiningdeathandtrachealintubationfor mechani-calventilationwithinthefirst7daysofhospitaladmission;and  toidentifyanyprognosticfactorsassociatedwithearlyseverity ofCOVID-19inthisspecificin-patientdiabetespopulation,akey step towardsimplementing preventativestrategies to reduce theriskoflife-threateningoutcomes.

However,numerousfactorsmayinterferewiththerelationship betweenCOVID-19infectionandpooroutcomesinpatientswith

diabetes(Fig.1).Thepresentdiscussionfocusesonlyonthethree thatmeritparticularinterestandwhichmostlyconcernpatients with T2D, who represented 88.5% of patients included in the CORONADO study [23]. The number of patients with type 1diabetes(T1D)wasdeemedtoosmallfromwhichtodrawany definiteconclusionsinthispatientsubgroup.

Roleofdiabeticcomplicationsandglucosecontrol

Althoughvasculardiabeticcomplicationsdidnotsignificantly influencethecompositeprimaryoutcome,theyweresignificantly associatedwithdeathintheCORONADOcohort[23].Thisisnot surprising, as it is well established that both CVD and renal impairmentareassociatedwithhigherdeathratesinthediabetes populationinbothlong-termandacuteconditions,suchasthose encountered with severe COVID-19 infection [14]. In addition, besidescausingseverepneumonia,itiswellknownthatthe SARS-CoV-2coronaviruscaninducecardiovascularcomplications[8,24] andacuterenalinjury[25,26],makingithighlyplausiblethatthese detrimental complications are likely to be more frequent and severeinsuchpredisposedpatients.

Onequestionofinterestisthepotentialroleofglucosecontrol onoutcomesrelatedtoCOVID-19inpatientswithdiabetes.This crucial point should be analyzed according to three separate periods:

 priortoadmission(assessedbyHbA1cmeasurement);

 at thetime of hospital admission (indicated by concomitant plasmaglucoseconcentrations);and

 duringthehospitalstay(Fig.1).

AnimportantmessageofthepresentresultsofCORONADOis thatpreviousglucosecontrolhasnosignificantimpactonseverity ofCOVID-19inpeoplewithdiabeteswhorequirehospitalization. Indeed,HbA1clevelswereassociatedwithneitherthecomposite

Fig.1.FactorsthatmayhaveanimpactonoutcomesofCOVID-19(CoronavirusDisease2019)infectioninpatientswithdiabetesaspertheCoronavirusSARS-CoV-2and DiabetesOutcomes(CORONADO)studyandothers.RAAS:renin–angiotensin–aldosteronesystem;DPP-4is:dipeptidylpeptidase-4inhibitors;OSA:obstructivesleep apnoea;NAFLD:non-alcoholicfattyliverdisease.

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primaryoutcomenorthedeathrate[23].Suchresultsmayseem surprising as chronic hyperglycaemia has long been known to damp down the immunological defences of diabetes patients [18,27].However,cautionisstillrequired,asHbA1cmeasurements

weremissinginaboutone-thirdofthestudiedpopulation.Thus,it wouldappeartobemostprudenttowaitforthefinalanalysisof CORONADOinanevenlargercohortbeforedrawinganydefinite conclusionsastotheroleofpatients’pastglucosecontrolonfinal outcomes.Moreover,asCORONADOwasfocusedonhospitalized patientswithdiabetes,itisstillnotknownwhetherpoorglucose control might favour the occurrence of less severe COVID-19 infectionindiabetespatientsnotrequiringhospitalization.

Similarly,whileplasmaglucoseconcentrationatadmissionwas not significantly correlated with the primary outcome on multivariate analysis, in age- and gender-adjusted non-linear models,admission plasma glucoseconcentrations were signifi-cantlyandpositivelyassociatedwithboththeprimaryoutcome anddeathbyday7.Nevertheless,thisobservationreliedupononly one glucose measurement, which was not performed under standardized conditions acrossall study patients (forexample, venousvs.capillaryglucose,fastingvs.postprandial,variabletime delayfrom last administration of glucose-lowering medication, especiallyinsulin...).Thus,hereagain,cautionisrequiredinthe interpretationofthesedata.Itmaybespeculatedthat,atleastin somepatients,acutehyperglycaemiaatadmissioncouldbelinked todiseaseseverityandstressfulconditions,especiallyifhypoxia and respiratory distress (dyspnoea at hospital admission was associatedwiththeprimaryoutcome)werealreadypresent.Thus, plasmaglucoseatadmissioncouldbeconsideredanearlymarker ofdiseaseseverity.

Also ofpotentialinterest,itwaspreviouslyreported thatthe SARScoronavirusmaybeabletoenterpancreaticisletsthroughits ACE2receptor,therebycausingdamagetobetacellsandleadingto acutediabetes[28].However,whether ornotthereisareverse causality relationship between COVID-19 infection and acute hyperglycaemiaremainsspeculative,asthis questioncannotbe answeredbyanyobservationalstudy(suchasCORONADO).

OneimportantaspectnotconsideredatallintheCORONADO studywas the management of diabetes and quality of glucose controlduringhospitalization(fromadmissiontoday7).Attention to good glucose control was recently recommended [29] and demonstratedinalargestudyof7337casesofCOVID-19(ofwhich 952hadpreexistingT2D)[30].Inthatretrospectiveobservational study from China, patients with well-controlled blood glucose (range: 3.9–10.0mmol/L) during hospitalization experienced markedly lower mortality compared with those with poorly controlled blood glucose [upper limit of glycaemic variabili-ty:>10.0mmol/L;adjustedhazardratio(HR):0.14,95%CI:0.03– 0.60; P=0.008]. Previous studies done before the COVID-19 pandemichadshown thatthequalityofglucosecontrolduring hospitalizationinICUsforanacuteevent(cardiovascularsurgery, myocardial infarction ...) could influence the final outcome, althoughcontroversialresultswerereportedconcerningoptimal target levels of glycaemia [31,32]. Nevertheless, there is some consensus for maintaining blood glucose concentrations at 4– 10mmol/LindiabetespatientshospitalizedinICUsaswellasin thosenowwithCOVID-19[33].

However, even if the impact of glucose control during the hospitalizationofdiabetespatientswithCOVID-19hasyettobe prospectivelyinvestigated,theneedfordiabetescarecustomized forICUshasbeenstronglysuggestedtohelphealthcareproviders whoarealreadyoverwhelmedbythedramaticpandemicsituation andtheneedtosupportothervitalfunctions,therebypotentially exposingpatients withdiabetestopoorermanagementof their specificdisease [34]. Likewise,it hasalso been suggested that individualizedcarestrategies,noveltherapeuticregimensandthe

use of modern diabetes technology might help to reduce the clinicalinertiahamperingproperdiabetesmanagementinICUs,a situationthatcouldleadtopoorglucosecontrolandpotentially worseoutcomesforpatientswithdiabetesandCOVID-19infection [35].

Infact,diabetespatientswithCOVID-19havetocontroltheir glucose levels in a situation with more variable, and often decreased,foodintakes,whilealsobeingconfrontedwithasevere infectiongenerallyaccompaniedbyfeverandacytokine-mediated insulin-resistantstate.Inaddition,asalreadymentioned,itisalso possiblethattheSARScoronaviruscanpenetrateintopancreatic isletsand damagebeta cells,thereby aggravating thecourseof diabetesandtriggeringacutehyperglycaemia[28].Thus, COVID-19 represents a double threat to patients with diabetes. The difficulty of controlling diabetes in such a setting has been confirmed by, on the one hand, the rather large number of ketoacidosisepisodesalreadyreported[36]and,ontheotherhand, theepisodesofhypoglycaemiamostprobablyduetoan unantici-pated lack of food, two metabolic adverse events reported at hospitaladmissionintheCORONADOcohort[23].

Roleofantihypertensiveandantidiabeticmedications

ManypatientswithdiabetesaretreatedwithRAASblockersas either antihypertensive agents or for nephroprotection. In the CORONADO study, 57.1% of the diabetes cohort received such pharmacotherapy.Yet,there hasbeen somecontroversyin the literature over the possible negative, neutral or even positive impactofRAASblockersonriskassociatedwiththesemedications when administered to COVID-19 patients [20,37,38]. However, CORONADO has provided reassuring results, as RAAS blockers were not associated with the primary outcome according to multivariableanalysis[23];theseobservationsareinagreement with the results of other studies [21,39,40] and support the recommendationnottostopRAASblockersindiabetespatients possiblyexposedtoSARS-CoV-2infection[41].Also,asdiscussed bytheauthors,thenegativeimpactofdiureticsreported inthe studycouldbeattributedtothemoreseverebaselineconditionof patientssufferingfromheartfailureormoreseverehypertension. The final question is whether or not glucose-lowering medications could differentially affect the risk of COVID-19 infectionandmoresevereoutcomes[42,43],althoughthereare stillmanyuncertaintiesinseekinganswers[19].Asimilarconcern asthatdiscussedwithRAASblockershasbeenraisedovertheuse ofDPP-4inhibitors[20,22],althoughnoworsesignswerereported among the 21.6% of patients treated with such agents in the CORONADOcohort.Theincreasedriskassociatedwithinsulinwas probably due tothefact that the useof this pharmacotherapy reflectsmoreadvanceddiabetesdiseaseinpatientswhoareoften olderandmorefrail[44].Thepossibleprotectiveroleofmetformin has been proposed based on theoretical grounds, and the pleiotropiceffects ofthecompoundhaveyettobeinvestigated inclinicalpractice[45].OfnoteinCORONADO,however,fewerof the people who died were using metformin. It has also been hypothesizedthatdapagliflozin(notavailableinFranceuntilonly recently)canpreventtheseverecourseofCOVID-19infectionby preventingtheloweringofcytosolicpHandreducingtheviralload [46].Alargeinternationalrandomizedcontrolledtrialiscurrently underwaytoinvestigatethepotentialroleofdapagliflozininboth diabetesandnon-diabetespatientswithCOVID-19(Dapagliflozin inRespiratoryFailureinPatientswithCOVID-19;ClinicalTrials.gov identifier: NCT04350593). In ICUs, the proper use of insulin therapyis,withoutquestion,themainstaytherapy[33]. Neverthe-less, in view of the major interest raised by COVID-19 in the diabetespopulation,itisanticipatedthatdedicatedobservational studies,andpossiblyrandomizedcontrolledtrials,willbedesigned

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in the near future to investigate the various positive and/or negativeinfluences of theavailable glucose-lowering agents in patientswithT2DwhenexposedtoSARS-CoV-2coronavirus[47]. Roleofobesity

Thefrequent concurrence of both diabetesand obesity may confound,oratleastcomplicate,identificationoftheindependent roleofeitherconditiononitsown.Thenegativeeffectsofobesity on the severity of COVID-19 [48] and the need for invasive mechanical ventilation [49,50] have already been reported independently of the presence of diabetes. In addition, the CORONADOstudyhasconfirmedthedeleteriousroleofobesity, and even overweight, in life-threatening outcomes in a large diabetic (mainly T2D) population with COVID-19 [23]. On multivariateanalyses, BMI remainedtheonly prognosticfactor forthecompositeprimaryoutcome.Thenegativeimpactofobesity onoutcomewaslargelydrivenbyitseffectontrachealintubation for mechanical ventilation whereas its effect on mortality was considerably lower. While death is an unequivocal outcome, mechanicalventilationdependsonboththephysician’sdecision andpatient’sacceptance.

It remains unclear as to why obesity aggravates COVID-19 severityandmarkedlyincreasestheneedfortrachealintubation for mechanical ventilation [49], although several underlying mechanismsmay be considered. Obesepatients have impaired respiratory mechanics resulting from a combination of poor respiratory muscle strength, reduced lung volume, increased airwayresistanceandimpairedgasexchange.In addition,more subtleyetcomplexinteractionsmayarisebetweenadiposetissue andtheimmunesystem[48,51].Forinstance,anoverexpressionof inflammatoryadipokinesfromvisceralfatdepots canaffectthe immune response, impair chemotaxis and alter macrophage differentiation [52]. In addition, the inflammatory response of visceral,butalsothoracic(epicardialandmediastinal),fatdeposits canleadtoanupregulationandgreaterreleaseofinflammatory cytokinessuchasinterleukin(IL)-6[5].Ithasbeensuggestedthat adiposetissueinpeoplewithobesitymayactasareservoirfor more extensive viral spread and increased shedding, immune activationandcytokineamplification[53].Indeed,ithasevenbeen hypothesizedthatexcessfatmightleadtothepossiblepresenceof ectopicfatdepositsinthealveolarinterstitialspacethatisexposed toviralinfection.This,inturn,couldaggravatetheinflammatory infiltrate,aphenomenonthatcouldthencontributetothemassive oedemaobservedinCOVID-19patientswhorequiremechanical ventilation[50].

Moreover, obesity is associated with an increased risk of comorbidities,suchashypertension,renal impairment, obstruc-tive sleep apnoea [54] and non-alcoholic fatty liver disease (NAFLD) [55], all conditions that can aggravate the prognosis [14].Ofparticularinterest,intheCORONADOcohort,obstructive sleepapnoeawasfoundtobeanindependentriskfactorofearly death,aswerealsoelevatedlevelsofaspartatetransaminase(AST). Whilea previoushistoryofNAFLDwasnotassociatedwiththe primaryoutcome,theelevatedASTlevelsnotedatadmissionmay havebeenareflectionoflivercytolysisdirectlyduetoSARS-CoV-2 infection[56]orrelatedtomultiple-organdamagesecondaryto hypoxia,asystemiccytokinestormand/orhaemodynamicshock [14,57].Infact,ASTelevationhasmorefrequentlybeenobservedin severeformsofCOVID-19infection,especiallyduring hospitaliza-tion [56]. In a longitudinal retrospective cohort study of 5771patientswithCOVID-19inChina,abnormalASTlevelswere associatedwiththehighest mortalityrisk comparedwithother indicatorsofliverdamage,withanHRof4.81withASTlevelsof 40–120U/LandanHRof14.87whenASTwas>120U/L[58].Ina meta-analysisof13studiesinvolvingatotalof3027patientswith

SARS-CoV-2infection,AST>40U/LwasassociatedwithanORof 4forcritical/fatalCOVID-19[12].ThefindingsofCORONADOarein linewithsuchobservations.

Taking BMIintoaccount evenin apopulation withdiabetes might improve risk stratification, thereby allowing for more effectiveselectionofthediabetespatientswhoaremostlikelyto requireearlyhospitaladmissionand strictersafetymeasuresto minimizetheirincreasedriskofdevelopingmoresevere compli-cations.However,notallstudiesreportedthesameBMIcut-offin associationwithgreater risk ofsevere complicationsrelated to COVID-19.InCORONADO,ahigherriskhadalreadybeenobserved inoverweightpatientswithdiabetes.However,anincreasedrisk for the primary outcome appeared to be less pronounced in diabetes patients with grade-3 obesity (BMI40kg/m2). The

authorsconsideredthisobservationtobeinagreementwiththe so-called‘‘obesityparadox’’previouslyreportedinICUsinpatients exposed tosevererespiratory distresssyndromes.Nevertheless, researchersin a French studyreported higher risksif BMIwas 35kg/m2 [49], whereas one US study [59]reported an even

higherriskifBMIwas40kg/m2asdidanotherlargeUSstudy

[60] incohortsofCOVID-19patientsnotspecificallyfocusedon diabetes.Infact,ithasbeensuggestedthatCOVID-19maybea challengetothe‘‘obesityparadox’’[61],althoughmoredatafrom patientswithmorbidobesity(BMI40kg/m2)areasyetrequired

tosupportthisconclusion[48].

Thus, there is clearly a need for more evidence to raise awarenessofwhatBMIscoreshouldbeconsideredthecut-offfor anincreasedriskofsevereillnessasaresultofCOVID-19[62].In addition,whethersuchacut-offmightdifferinpatientswithand withoutdiabetesalsorequiresfurtherinvestigation.Inanycase, giventhepotentiallycriticalroleofbodyweightandfatmassin determining the severity of pneumonia requiring respiratory assistance,itisimportanttosystematicallycollectanthropometric informationfrompatientshospitalizedwithCOVID-19[63].One noteworthysuggestionisthatobesitycouldshiftsevereCOVID-19 infectionstowardsyoungeragegroups[64,65].Indeed,itmaybe speculatedthatasimilarshiftoccurredinpatientswithdiabetesin the CORONADO cohort (about one-third of whom were aged<65years),althoughdirectcomparisonwithanon-diabetes populationremainsmandatorytoconfirmsuchanhypothesis.

Ultimately, if obesity plays a crucial role, then therapeutic actionstargetingadiposetissuecouldhelptoreducetheburdenof COVID-19disease,includinginthelargecohortofpatientswith T2D [51]. Likewise,if adipose tissuerelated to obesityplays a deleteriousroleintheexcessiveimmunereactionand inflamma-tion,thendiabetespatientswithobesitymightbenefittoagreater extentfroma pharmacologicaltherapythat modulatescytokine activity,especiallyIL-6, and/orthecomplementsystem[50].As such,tocilizumabhasbeenproposedasatherapeuticoptionfor compassionate use in patients with COVID-19 [66]. A recent observationhasfoundthathyperglycaemia,bothatadmissionand duringthehospitalstay,wasassociatedwithhigherIL-6levelsand areducedefficacyoftocilizumab,leadingtopooreroutcomesin COVID-19 patients regardless of thepresence or notof known diabetes [67]. However, further studies are now necessary to confirmthisfinding.

Conclusion

Diabetesisoneofthemoreimportantcomorbiditieslinkedto theseverityofinfectionbySARS-CoV-2.TheCORONADOstudywas designedtocharacterizethephenotypeofpatientswithdiabetes hospitalizedforCOVID-19,todeterminetheprevalenceoftheneed formechanicalventilationordeathandtoidentifytheprognostic factors associated with poorer outcomes. As the first such

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large-scale observationalstudy, it has undoubtedly provided a majorpieceofthecomplexpuzzlelinkingdiabetesandCOVID-19 infection:someprognosticfactorshavebeenidentified,focusing onBMIinrelationtotheneedforrespiratoryassistanceandthe presenceofpreviousdiabetescomplicationsassociatedwithriskof death. However, otheranswers still requirefurther analysesin evenlargercohorts,especiallyinordertoreassesstheinfluenceof previous glucose control based on larger numbers of HbA1c

measurements, which means that the final results of the CORONADO study areawaited with great interest. In addition, theimpactofglucosecontrolduringhospitalizationonoutcomes relatedtoCOVID-19—whichwasnotinvestigatedinCORONADO— is certainly deserving of specific investigation. Moreover, the results of certain pharmacological therapies currently under investigationtoimprovetheprognosisin high-riskpopulations, suchasdiabetespatients,arealsolikelytobeavailableinthenear future.

Disclosureofinterest

Andre´ J.Scheendeclaresthathehasnocompetinginterest.

MichelMarreworkedasaclinicalinvestigatorintheCORONADOstudy

anddeclaresnoconflictsofinterestdirectlyrelevanttothecontentofthis

manuscript.HeisPresidentoftheFondationFrancophonepourlaRecherche

surleDiabe`te(FFRD),afinancialsponsoroftheCORONADOstudy;theFFRD

issponsoredbytheFe´de´rationFranc¸aisedesDiabe´tiques,NovoNordisk,MSD,

EliLilly,AbbottLaboratoriesandAstraZeneca.

Charles ThivoletworkedasaclinicalinvestigatorintheCORONADO

studyanddeclaresnoconflictsofinterestdirectlyrelevanttothecontentof

thismanuscript.

Acknowledgements

The CORONADO study received funds from the Fondation Francophone pour la Recherche sur le Diabe`te (FFRD), the Fe´de´rationFranc¸aise des Diabe´tiques(FFD),the Socie´te´ Franco-phoneduDiabe`te(SFD)andFondsdedotationduCHUdeNantes. References

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Figure

Fig. 1. Factors that may have an impact on outcomes of COVID-19 (Coronavirus Disease 2019) infection in patients with diabetes as per the Coronavirus SARS-CoV-2 and Diabetes Outcomes (CORONADO) study and others

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