Thyrotoxicosis in Patients with COVID-19: the THYRCOV Study

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A Lania and others Thyrotoxicosis and COVID-19 183:4 381–387 Clinical Study

Thyrotoxicosis in patients with COVID-19: the THYRCOV study

Andrea Lania1,2, Maria Teresa Sandri3, Miriam Cellini1, Marco Mirani1, Elisabetta Lavezzi1 and Gherardo Mazziotti1,2 on behalf of Humanitas COVID-19 Correspondence Task Force should be addressed 1Endocrinology, Diabetology and Medical Andrology Unit, Humanitas Clinical and Research Center, IRCCS, Milan, to G Mazziotti Italy, 2Department of Biomedical Sciences, Humanitas University, Milan, Italy, and 3Laboratory Medicine, Humanitas Email Clinical and Research Center, IRCCS, Milan, Italy gherardo.mazziotti@ hunimed.eu

Abstract

Objective: This study assessed thyroid function in patients affected by the coronavirus disease-19 (COVID-19), based on the hypothesis that the cytokine storm associated with COVID-19 may influence thyroid function and/or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may directly act on thyroid cells, such as previously demonstrated for SARS-CoV-1 infection. Design and methods: This single-center study was retrospective and consisted in evaluating thyroid function tests and serum interleukin-6 (IL-6) values in 287 consecutive patients (193 males, median age: 66 years, range: 27–92) hospitalized for COVID-19 in non-intensive care units. Results: Fifty-eight patients (20.2%) were found with thyrotoxicosis (overt in 31 cases), 15 (5.2%) with hypothyroidism (overt in only 2 cases), and 214 (74.6%) with normal thyroid function. Serum thyrotropin (TSH) values were inversely correlated with age of patients (rho −0.27; P < 0.001) and IL-6 (rho −0.41; P < 0.001). In the multivariate analysis, thyrotoxicosis resulted to be significantly associated with higher IL-6 (odds ratio: 3.25, 95% confidence interval: 1.97–5.36; P < 0.001), whereas the association with age of patients was lost (P = 0.09). Conclusions: This study provides first evidence that COVID-19 may be associated with high risk of thyrotoxicosis in European Journal of Endocrinology relationship with systemic immune activation induced by the SARS-CoV-2 infection.

European Journal of Endocrinology (2020) 183, 381–387

Introduction

The severe acute respiratory syndrome coronavirus 2 Th1/Th17 immune response with increased production of (SARS-CoV-2) is a novel enveloped RNA beta-coronavirus several proinflammatory cytokines, including interleukin responsible for the coronavirus disease-19 (COVID-19) 6 (IL-6) and tumor necrosis factor-alfa (2, 3). The cytokine ranging from asymptomatic cases to severe respiratory pattern observed in patients with COVID-19 is similar to involvement (1). The first clinical case of COVID-19 that occurring in some rheumatological diseases or during in Italy was diagnosed on February 20, 2020; then the immunotherapies for cancer (4). Moreover, the cytokine infection has rapidly spread involving at this time more response described in COVID-19 seems to resemble, at than 100 000 subjects and configuring our Country as one least in part, the immune activation that accompanies of the largest and most serious clusters of COVID-19 in inflammatory thyroid diseases. Specifically, a hyper- the world. activation of Th1 response in peripheral lymphocytes was A subgroup of patients with severe COVID-19 might described in patients with autoimmune and drug-induced have a cytokine storm characterized by hyperactivity of thyroiditis (5, 6, 7) and an increase in IL-6 was reported in

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-20-0335 European Journal of Endocrinology https://eje.bioscientifica.com Continuous datawerepresentedas medianandrange. Prior venousthromboembolism Prior stroke Prior coronaryarterydisease Chronic obstructivepulmonary disease Active cancer Dyslipidemia ontreatment Diabetes mellitusontreatment Arterial hypertensionontreatment Duration ofCOVID-19(days)before Sex (F/M) Age (years) n patients atthestudyentry. Table 1 end-pointsweexplored:(i)the COVID-19. Assecondary inhospitalizedpatientswith range inourlaboratory) of lowserumTSHvalues(i.e.belowthereference supportatthetimeofTSHevaluation. respiratory values; and(iv)requirementofintubationmechanical immunotherapies startedbeforemeasurementofTSH of TSH evaluation; (ii) treatment with amiodarone; (iii) L-thyroxine oranti-thyroiddrugsbeforeandatthetime 19 diagnosis.Exclusioncriteriawere(i)treatmentwith serum thyrotropin(TSH)measurementafterCOVID- radiological signsofpneumonia( broncoalveolar lavagefluidassociatedwithclinicaland swabspecimensandor assay ofnasalandpharyngeal time reversetranscriptase–polymerasechainreaction (i) hospitalizationforCOVID-19diagnosedbyreal- and April1,2020( Rozzano-Milan, Italy, intheperiodbetweenMarch 1 at theHumanitasClinicalandResearch CenterIRCCS, 287 consecutivepatientshospitalizedforCOVID-19 This is a retrospective single-center study performed on Subjects andmethods in patientshospitalizedforCOVID-19. prevalence anddeterminantsofalteredthyroidfunction of SARS-CoV-2 onthethyroidgland. COVID-19, asaconsequenceofdirectorindirecteffects whether asimilarinvolvementmayoccuralsoduring the mechanisms were not clarified and it is stillunknown reported inpatientsaffectedbySARS-CoV-1 ( of fact, alterations ofthyroid function and structure were the courseofdestructivethyroiditis( Clinical Study hospitalization The firstend-pointofthestudywasprevalence In thisretrospectivestudy, weaimed to investigate the Demographical andclinicaldataofCOVID-19 Table 1 ). Theinclusioncriteriawere A Laniaandothers 1 ) and(ii)atleastone 8 , 9 , 10 ). Asamatter 11 142 (49.5%) 11 (3.8%) 20 (7.0%) 41 (14.3%) 35 (12.2%) 63 (22.0%) 70 (24.4%) 66 (27–92) , 9 (3.1%) 5 (1–15) 94/193 12 287 ), but function. Insomepatientswithovertthyrotoxicosis, measured foracomprehensiveevaluationofthyroid thyroxine (FT4)andfree-triiodothyronine(FT3)were values eitherbeloworabovethereferencerange,free- patients withCOVID-19.InserumTSH in theroutinebiochemicalevaluationofhospitalized evaluation ofclinicalcharts. who werestillhospitalizedatthetimeofretrospective calculated excludingfromtheanalysisthosepatients anddurationofhospitalizationwere patients’ survival findings andclinical charts ofthepatients. The laboratory end-points were addressed by a retrospective review of presentation andoutcomeofovertthyrotoxicosis.These and(v)theclinical hospitalization andpatients’survival; (iv) theassociationbetweenTSHvaluesanddurationof association between TSH values and sex and age of patients; (ii) theassociationbetweenTSHandIL-6values;(iii) prevalence ofovertandsubclinicalthyroiddysfunction; was analyzer andreferencerangeinourlaboratory the Kryptor TRACE (Time-Resolved Emission)on AmplifiedCryptate < 4.80 mU/L,7.82–17.29pmol/L, 3.38–6.45pmol/Land the referencerangesofTSH,FT4,FT3andIL-6were0.34– DxI 800Access®immunoassaysystem.Inourlaboratory, using chemiluminescent methods on the Beckman Coulter Serum TSH, FT4, FT3 and IL-6 were measured at 08:00 h Biochemical assays clinical andbiochemicaldataforresearch purposes. IRCCS andthepatientsgavetheirconsenttouse Committee ofHumanitasClinicalandResearch Center, analyzed within8hfromthebloodsamples. last administrationofheparinandthespecimenswere of thyroidfunctionwasperformed9–14hafterthe with low-molecular-weightheparin.Themeasurement evaluation, 127patientshadreceivedthromboprophylaxis events wereclinicallysuspected.Beforethyroidfunction was usedinonlysevencaseswhomthromboembolic (CT) fordiagnosisofpneumonia,butiodinecontrast patients hadperformedthoraciccomputedtomograpghy condition. Overthehoursbeforehospitalization,all hospitalization withbloodsamplesdrawninthefasting Thyroid functionwasevaluatedonthefirstdayof thyroperoxidase antibodies(TPOAb)wereperformed. antibodies (TRAb),thyroglobulin(TgAb)and thyroid ultrasoundandmeasurementsofTSHreceptor Thyrotoxicosis andCOVID-19 6.4 pg/mL,respectively. TRAbweredeterminedusingthe In ourhospital,measurementofTSHwasincluded The retrospectivestudywasapprovedbytheEthical < 1.8 IU/L.Overtthyrotoxicosis wasdefinedbylow Downloaded fromBioscientifica.com at09/29/202103:24:04AM 183 :4 382 via freeaccess European Journal of Endocrinology pmol/L, range:9.68–16.90; thyrotoxicosis (22.31pmol/L, range:17.38–36.33vs15.10 serum FT4valuesascompared tothosewithsubclinical patients withoutthyrotoxicosis). performed thoracicCTwithiodinecontrast( without thyrotoxicosis) and 3patients (5.2%) had with low-molecular-weightheparin( thyrotoxicosis (51.7%) received thromboprophylaxis Before assessment of thyroid function, 30 patients with with thyrotoxicosisand13hypothyroidism). thyroid dysfunctionwaspresentin40patients(27 and 2 with hypothyroidism), whereas a subclinical was diagnosedin33patients(31withthyrotoxicosis with abnormal TSH values. Overt thyroiddysfunction and 1.0mU/L. the referencerange,99(46.3%)hadvaluesbetween0.34 patients, respectively. In214patientswithTSHvaluesin and highintheremaining214(74.6%) and 15(5.2%) 0.10 and0.33mU/Lin42cases),whereasTSHwasnormal the referencerange( Fifty-eight patients(20.2%)werefoundwithTSHbelow Results considered significant. and IL-6valuesstratifiedintertiles.A the association between thyrotoxicosis, age of patients (CI)werecalculatedtoevaluate 95% confidenceinterval analysis wasperformedandtheoddsratio(OR)with by calculating Spearman’s coefficient. A logistic regression Correlations betweencontinuousvariablesweresought Chi-square’s test,withFishercorrection when appropriate. Kruskal–Wallis’ tests.Frequencieswerecomparedbythe The comparisonswereperformedbyMann–Whitney’s and groups ( stated. BasedonTSHvalues,patientswerestratifiedinfour Data werepresentedasmedianandrange,unlessotherwise Statistical analysis in thereferenceranges. TSH was either low or high accompanied by FT4 and FT3 ranges. Subclinicalthyroiddysfunctionwasdefinedwhen values andserumFT4and/orFT3belowthereference ranges. Overt hypothyroidism was defined by high TSH TSH valuesandserumFT3and/orFT4abovethereference Clinical Study Thyroid hormones were measured in 73 patients Patients withovertthyrotoxicosis showedhigher < 0.10, 0.10–0.33,0.34–4.80,and < 0.10 mU/Lin16cases,between P

0.001), withoutsignificant A Laniaandothers P P .9 s patients vs =0.39 value > 4.80 mU/L). P < .7 vs =0.17 0.05 was whereas theremaining27patientsdidnotreceive treated withthiamazole(5mgperdayinallcases), recorded bythephysicians. local signsorsymptomsofsubacutethyroiditiswere two cases,venousthromboembolisminthreecases).No developed thromboembolicevents(ischemicstrokein (32.3%). Moreover, five patients with overt thyrotoxicosis by atrialfibrillationwithhighheartrateintenpatients thyroid structure.Overtthyrotoxicosiswasaccompanied three patientsdidnotshowanysignificantalterationof nodules inotherthreepatients,whereastheremaining inflammation were reported in two cases, small thyroid whom thyroidultrasoundwasperformed,signsof Among theeightpatientswithovertthyrotoxicosisin patients andinallofthem,theyresultednegative. Serum TRAb, TgAb and TPOAb were measured in nine 3.49–5.28 vs4.11pmol/L,range: 3.00–5.20; difference inserumFT3values(4.42pmol/L,range: among closedcases( corresponding toanin-hospital mortalityrateof21.4% P not withtheageofpatients (OR: 1.03,95%CI:0.99–1.06; higher IL-6(OR:3.25,95%CI:1.97–5.36; thyrotoxicosis resultedtobesignificantlyassociatedwith thyrotoxicosis. IL-6 ( ( significant differencebetween as comparedtothose with higher TSH values, without significantly higherinpatientswithTSH of patients(rho0.39; correlated withTSHvalues( measured in 210patients and resulted to be significantly < with higherTSH,withoutsignificantdifferencebetween 0.34 mU/L weresignificantly older ascompared topatients of patients( 17.54 vs1.15IU/L,range:0.01–75.40; found between males and females (0.83 IU/L, range: 0.01– treatment ofthyrotoxicosis( showing areductioninserumFT4valuesregardlessofthe (two treatedwiththiamazoleandfivewithouttreatment) A short-termfollow-upwasavailableinsevenpatients thiamazole after3daysduetoincreaseinliverenzyme. thyroid-targeting drugs.Onepatientwaswithdrawnfrom Thyrotoxicosis andCOVID-19 Fig. 3 =0.09). 0.10 and0.10–0.33mU/L( Of thepatientswithovertthyrotoxicosis,4were We recorded a total of 60 in-hospital deaths, In themultivariatelogisticregressionanalysis, Serum TSHvalueswereinverselycorrelatedwithage No significantdifferenceinserumTSHvalueswas P ). Nosignificantdifferencesinage(

= 0.45) werefoundbetweensubclinicalandovert rho : -0.27; n P P = <

< Downloaded fromBioscientifica.com at09/29/202103:24:04AM

0.001). PatientswithTSHbelow

280). Thein-hospitalmortality 0.001). SerumIL-6valueswere rho Fig. 1 < : Fig. 2 https://eje.bioscientifica.com − 0.10 and0.1–0.33mU/L 0.41; ). 183 ). SerumIL-6was P P =0.08). :4

0.001) andage P P <

< .2 and =0.22) 0.34 mU/L .0) but 0.001) P =0.195). 383 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com Kruskal–Wallis’ andMann–Whitney’s tests. values ineachgroup.Comparisons wereperformedby thyrotropin (TSH)values.Thesolid linesidentifiedthemedian Scatter plotofageinCOVID-19 patientsstratifiedforserum Figure 2 not treatedwiththyroid-targetingdrugs. thiamazole, whereastheotherfivepatients(solidline)were function. Twopatients(dashedline)weretreatedwith COVID-19 whoweresequentiallyevaluatedforthyroid seven patientswithovertthyrotoxicosisinthecourseof Individual outcomesofserum-freethyroxine(FT4)valuesin Figure 1 Clinical Study A Laniaandothers and Mann–Whitney’stests. each group.ComparisonswereperformedbyKruskal–Wallis’ (TSH) values.Thesolidlinesidentifiedthemedianvaluesin log-scale inCOVID-19patientsstratifiedforserumthyrotropin Scatter plotofseruminterleukin-6(IL-6)valuesexpressedin Figure 3 critical illness,configuring theso-callednon-thyroidal axistakesplaceduring of hypothalamic–pituitary–thyroid ( TSH measurementinhospitalized patientsarecontroversial of thecasesbeingmild. hypothyroidism waslowinthisclinicalsettingwithmost circulating levels of IL-6. Noteworthy, the prevalence of patients withCOVID-19,incloserelationshiphigh prevalence ofovertandsubclinicalthyrotoxicosis in This retrospective study reported, for the first time, high Discussion hypothyroidism ( as comparedtothosewitheithernormalTSHor be significantlylongerincaseswiththyrotoxicosis patients, thedurationofhospitalizationresultedto thyrotoxicosis orhypothyroidism( in thereferencerangeascomparedtothosewitheither rate wassignificantlylowerinpatientswithTSHvalues Thyrotoxicosis andCOVID-19 13 , The cost-effectivenessanddiagnostic valueofserum 14 , 15 ). Asamatteroffact,animportant derangement Fig. 5 ). Downloaded fromBioscientifica.com at09/29/202103:24:04AM Fig. 4 183 :4 ). Indischarged 384 via freeaccess European Journal of Endocrinology during follow-up . A further finding supporting the during follow-up.Afurther findingsupportingthe thyrotoxicosis wasoftenmild andimprovedspontaneously This hypothesiswassupported bythefindingsthat that thyrotoxicosiswascaused bydestructivethyroiditis. patients withCOVID-19,it isreasonabletohypothesize the mechanismsresponsibleforthyroiddysfunction in ( incidence thanthatexpectedinthegeneralpopulation may favorthedevelopmentofthyrotoxicosisatahigher the referencerange.ThesefindingssuggestthatCOVID-19 and severalothersshowed serum TSHin the lowerpart of normal levelsofFT3inourthyrotoxicoticpatients( to decreaseT3secretionpossiblycontributingthe IL-6 maybehypothesized.Incellcultures,wasshown in non-hospitalizedpatients.Inthiscontext,theroleof were performed)wasapparentlyfasterthanthatobserved in whomlongitudinalmeasurementsofthyroidhormones ofthyrotoxicosis(i.e.inthefewpatients and therecovery found betweenovert and subclinicalthyroid dysfunction less thanFT4,nosignificantdifferenceinFT3valueswas presentation ofthyrotoxicosis,sinceserumFT3increased coexistent NTImayhaveinfluencedthebiochemical range. Nevertheless,wecannotexcludethatapossible one-half ofthem,FT4valueswereabovethereference of thesepatientshadlowFT3valuesandinmorethan expression ofthyrotoxicosisratherthanNTI.Infact,none likely suppressed TSHvaluesandthisfindingwasvery A remarkable number of our hospitalized patients had total andFT4,sometimeslowTSH,canbeobserved. in reverse-T3( FT3 valuesconsequenttoincreaseddeiodinationofT4 illness’ (NTI) which is consistently characterized by low serum thyrotropin(TSH)values.* In-hospital mortalityrateinCOVID-19patientsstratifiedfor Figure 4 17 Clinical Study ). Although our study was not designed to clarify ). Althoughourstudywasnotdesignedtoclarify Thyrotoxicosis was found in about 20% of our patients Thyrotoxicosis wasfoundinabout20%ofourpatients 16 ). With increasing severity of illness, low P

< A Laniaandothers 0.05 vstheothergroups. 10 ). performed byKruskal–Wallis’andMann–Whitney’stests. identified themedianvaluesineachgroup.Comparisonswere stratified forserumthyrotropin(TSH)values.Thesolidlines Scatter plotofhospitalizationlengthinCOVID-19patients Figure 5 being morethantwotimes higherthanthatrecently thyrotoxicosis developedthromboembolic events,arate of COVID-19.Sixteenpercent ofpatientswith overt relevance andmanagement ofthyrotoxicosisinpatients highlights some specific clinical concerning the clinical human cells( which is the protein used by SARS-CoV-2 for invading expresses theangiotensin-convertingenzyme2( ( may bedirectlydamagedbythevirusduringCOVID-19 ( the possibledirectactionofSARS-CoV-2 onthyroidgland immunotherapies ( thyroid disordersdevelopingduringthecourse of the cytokine storm associated with COVID-19, mimicking gland inflammationmightbetriggeredandsustainedby and higherserumIL-6inourpatientssuggeststhatthyroid cases ( cannot excludeGraves-likemildhyperthyroidisminall were evaluated, although the absence of circulating TRAb for TRAbinthefewpatientswhomtheseantibodies diagnosis ofdestructivethyroiditiswasthenegativity Thyrotoxicosis andCOVID-19 21 12 ). Indeed, there is evidence that thyroid tissue highly ). Indeed,thereisevidencethatthyroidtissuehighly ), basedontheevidencethatseveraltissuesandorgans Besides thepathophysiologicalaspects,thisstudy 18 ). The close relationship between thyrotoxicosis ). Thecloserelationshipbetweenthyrotoxicosis 23 ). 19 , 20 Downloaded fromBioscientifica.com at09/29/202103:24:04AM ). An alternative hypothesis is ). Analternativehypothesisis https://eje.bioscientifica.com 183 :4 385 22 via freeaccess ), ), European Journal of Endocrinology https://eje.bioscientifica.com suppressed TSHvaluesassociated withhighFT4were hormone fromthebinding proteins( in ourpatientsasaneffectof displacementofthethyroid the useofheparinmayhave favoredtheelevationofFT4 complications ofCOVID-19 ( for preventionofvenousandarterialthromboembolic course oftreatmentwithlow-molecular-weightheparin several patients,thyroidfunctionwasassessedinthe and theriskofthyrotoxicosisinthisclinicalsetting.In define thetrueimpactofCOVID-19onthyroidfunction cohort ofpatientswithpneumoniadidnotallow to rhythm ( caution inpatientswithpre-existingalterationsofheart heart (e.g.beta-blockers)shouldbeadministeredwith counteract the negative effects of thyroid hormones on in thesettingofCOVID-19,sincesomedrugsusedto thyrotoxicosis-related heartdisordersmaybechallenging 28 19, asaneffectoftherapiesand/orelectrolytedisorders( ( prolonged QTinterval the developmentoffatalarrhythmiasinpresence infection ( arrhythmias describedinpatientswithSARS-CoV-2 ( even aftershortexposuretothyroidhormoneexcess thyrotoxicosis mightincreasethecardiovascularrisk be notcompletelysafeinthesettingofCOVID-19,since spontaneously. One could argue that this approach may treatment of thyrotoxicosis and thyroid function improved most ofourpatientswerefollowed-upwithoutspecific infection duringcorticosteroidtherapy( about potentialimpairmentofunderlyingSARS-CoV-2 ( order to accelerate the resolution of thyroid dysfunction There waslikelyarationaleforusingglucocorticoidsin required beyondsymptomatictreatmentwhenindicated. by destructivethyroiditisinwhichnospecifictherapyis based on the hypothesis that thyrotoxicosis was caused fewpatients rather limited.Thiamazolewasusedinvery approach inourCOVID-19patientswasempiricand performed onlyinfewcases.Therefore,thetherapeutic allowed and ultrasound evaluation of thyroid gland was clinically relevantinCOVID-19patients. longer hospitalizationsuggestthatthyrotoxicosismaybe between suppressedTSHandhighmortalityrate prevalence ofatrialfibrillationandthecloserelationship intensive careunits( reported in COVID-19 patients hospitalized in non- 20 26 Clinical Study ). Ontheotherhand,preventionandtreatmentof ) favoring the cardiovascular complications and ). However, thesedrugswerenotusedduetoconcerns This studyhaslimitations.Thelackofanindependent As patientswereisolated,thyroidscintigraphywasnot 28 1 , ). 27 , 28 ). Noteworthy, thyrotoxicosismayfavor 24 ). Thisfindingalongwiththehigh 29 ), acommoneventinCOVID- 24 ). Onecouldarguethat A Laniaandothers 30 ). However, the 25 ). Therefore, 1 ,

infection. Futureprospectivestudieswillclarifythe evidence ofhighriskthyrotoxicosisafterSARS-CoV-2 COVID-19 ( chronic thyroiditis may develop after the resolution of ( be influencedbyimmunotherapiesusedinCOVID-19 allowed toinvestigatewhetherthyroidfunctionmight on theoutcomeofCOVID-19.Moreover, itwasnot to investigate the independentimpact of thyrotoxicosis the relativelysmallsizeofstudygroup,precluded blood samples( the hormoneassayswereperformedinfewhoursafter function andthelastadministrationofheparin elapsed betweenthebiochemicalevaluationofthyroid weight heparinwaslikelymarginal,sinceseveralhours that theassay interference induced by low-molecular- interference. Moreover, itisreasonabletohypothesize highly suggestive for true thyrotoxicosis rather than a drug References the public,commercialornot-for-profitsector. This research did not receive any specific grant from any funding agency in Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisstudy. no is there that declare authors The Declaration ofinterest patients withCOVID-19. clinical and prognostic relevance of thyrotoxicosisin Thyrotoxicosis andCOVID-19 20 5 4 3 2 1 , Mazziotti G, Sorvillo F, Naclerio C,Farzati A, Cioffi M,Perna R, Zhang W, Zhao Y, Zhang F, Wang Q, Li T, Liu Z,Wang J, Qin Y, Prompetchara E, Ketloy C&Palaga T. ImmuneresponsesinCOVID- Wu D &Yang XO. TH17responsesincytokinestormofCOVID- Guan WJ, Ni ZY, Hu Y, Liang WH,Ou CQ,He JX,Liu L,Shan H, (https://doi.org/10.1530/eje.0.1480383) thyroiditis. peripheral CD4+andCD8+Tcellsfrom patientswithHashimoto’s Valentini G, Farzati B,Amato G&Carella C.Type-1 responsein clim.2020.108393) Clinical Immunology 19): theperspectivesofclinicalimmunologistsfromChina. treatment ofpeoplewithseverecoronavirusdisease2019(COVID- Zhang X, Yan X (https://doi.org/10.12932/AP-200220-0772) epidemic. 19 andpotentialvaccines:lessonslearnedfromSARSMERS org/10.1016/j.jmii.2020.03.005) Microbiology, Immunology, andInfection 19: anemergingtargetofJAK2inhibitorFedratinib. (https://doi.org/10.1056/NEJMoa2002032) 2019 inChina. Lei C, Hui DSC In conclusion,thisretrospectivestudyprovidesfirst 31 ). Furthermore,thisstudydidnotclarifywhether Asian Pacific Journal ofAllergyandImmunology Asian PacificJournal 32 European Journal ofEndocrinology European Journal ). New England Journal ofMedicine New EnglandJournal et al. 30 et al. ). Theretrospectivedesignalongwith 2020 Clinicalcharacteristicsofcoronavirusdisease The use of anti-inflammatory drugsinthe Theuseofanti-inflammatory 214 Downloaded fromBioscientifica.com at09/29/202103:24:04AM 108393. 2020 (https://doi.org/10.1016/j. 183 2003 53 2020 368–370. :4 148 Journal of Journal 382 383–388. 2020 1708–1720. (https://doi. 38 386 1–9. via freeaccess European Journal of Endocrinology

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Accepted 6July2020 Revised versionreceived15June2020 Received 8April2020

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